Rethinking extent of resection of contrast-enhancing and non-enhancing tumor: different survival impacts on adult-type diffuse gliomas in 2021 World Health Organization classification.

OBJECTIVES: Extent of resection (EOR) of contrast-enhancing (CE) and non-enhancing (NE) tumors may have different impacts on survival according to types of adult-type diffuse gliomas in the molecular era. This study aimed to evaluate the impact of EOR of CE and NE tumors in glioma according to the 2021 World Health Organization classification. METHODS: This retrospective study included 1193 adult-type diffuse glioma patients diagnosed between 2001 and 2021 (183 oligodendroglioma, 211 isocitrate dehydrogenase [IDH]-mutant astrocytoma, and 799 IDH-wildtype glioblastoma patients) from a single institution. Patients had complete information on IDH mutation, 1p/19q codeletion, and O6-methylguanine-methyltransferase (MGMT) status. Cox survival analyses were performed within each glioma type to assess predictors of overall survival, including clinical, imaging data, histological grade, MGMT status, adjuvant treatment, and EOR of CE and NE tumors. Subgroup analyses were performed in patients with CE tumor. RESULTS: Among 1193 patients, 935 (78.4%) patients had CE tumors. In entire oligodendrogliomas, gross total resection (GTR) of NE tumor was not associated with survival (HR = 0.56, p = 0.223). In 86 (47.0%) oligodendroglioma patients with CE tumor, GTR of CE tumor was the only independent predictor of survival (HR = 0.16, p = 0.004) in multivariable analysis. GTR of CE and NE tumors was independently associated with better survival in IDH-mutant astrocytoma and IDH-wildtype glioblastoma (all ps < 0.05). CONCLUSIONS: GTR of both CE and NE tumors may significantly improve survival within IDH-mutant astrocytomas and IDH-wildtype glioblastomas. In oligodendrogliomas, the EOR of CE tumor may be crucial in survival; aggressive GTR of NE tumor may be unnecessary, whereas GTR of the CE tumor is recommended. CLINICAL RELEVANCE STATEMENT: Surgical strategies on contrast-enhancing (CE) and non-enhancing (NE) tumors should be reassessed considering the different survival outcomes after gross total resection depending on CE and NE tumors in the 2021 World Health Organization classification of adult-type diffuse gliomas. KEY POINTS: The survival impact of extent of resection of contrast-enhancing (CE) and non-enhancing (NE) tumors was evaluated in adult-type diffuse gliomas. Gross total resection of both CE and NE tumors may improve survival in isocitrate dehydrogenase (IDH)-mutant astrocytomas and IDH-wildtype glioblastomas, while only gross total resection of the CE tumor improves survival in oligodendrogliomas. Surgical strategies should be reconsidered according to types in adult-type diffuse gliomas.

Radiomics and PD-L1 expression predict immunotherapy benefits in patients with head and neck squamous cell carcinoma.

Aim: To evaluate the performance of MRI-derived radiomic risk score (RRS) and PD-L1 expression to predict overall survival (OS) and progression-free survival (PFS) of patients with recurrent head and neck squamous cell carcinoma receiving nivolumab therapy. Materials & methods: Three hundred forty radiomic features from pretreatment MRI were used to construct the RRS. The integrated area under the receiver operating characteristic curve (iAUC) was calculated to evaluate the performance of the RRS and PD-L1. Results: The RRS showed iAUCs of 0.69 and 0.57 for OS and PFS, respectively. PD-L1 expression showed iAUCs of 0.61 and 0.62 for OS and PFS, respectively. Conclusion: RRS and PD-L1 potentially predict the OS and PFS of patients with recurrent head and neck squamous cell carcinoma receiving nivolumab therapy.

[Box: see text].

Identification of schizophrenia by applying interpretable radiomics modeling with structural magnetic resonance imaging of the cerebellum.

AIMS: The cerebellum is involved in higher-order mental processing as well as sensorimotor functions. Although structural abnormalities in the cerebellum have been demonstrated in schizophrenia, neuroimaging techniques are not yet applicable to identify them given the lack of biomarkers. We aimed to develop a robust diagnostic model for schizophrenia using radiomic features from T1-weighted magnetic resonance imaging (T1-MRI) of the cerebellum. METHODS: A total of 336 participants (174 schizophrenia; 162 healthy controls [HCs]) were allocated to training (122 schizophrenia; 115 HCs) and test (52 schizophrenia; 47 HCs) cohorts. We obtained 2568 radiomic features from T1-MRI of the cerebellar subregions. After feature selection, a light gradient boosting machine classifier was trained. The discrimination and calibration of the model were evaluated. SHapley Additive exPlanations (SHAP) was applied to determine model interpretability. RESULTS: We identified 17 radiomic features to differentiate participants with schizophrenia from HCs. In the test cohort, the radiomics model had an area under the curve, accuracy, sensitivity, and specificity of 0.89 (95% confidence interval: 0.82-0.95), 78.8%, 88.5%, and 75.4%, respectively. The model explanation by SHAP suggested that the second-order size zone non-uniformity feature from the right lobule IX and first-order energy feature from the right lobules V and VI were highly associated with the risk of schizophrenia. CONCLUSION: The radiomics model focused on the cerebellum demonstrates robustness in diagnosing schizophrenia. Our results suggest that microcircuit disruption in the posterior cerebellum is a disease-defining feature of schizophrenia, and radiomics modeling has potential for supporting biomarker-based decision-making in clinical practice.

Brain volume in Tanzanian children with sickle cell anaemia: A neuroimaging study.

Brain injury is a common complication of sickle cell anaemia (SCA). White matter (WM) and cortical and subcortical grey matter (GM), structures may have reduced volume in patients with SCA. This study focuses on whether silent cerebral infarction (SCI), vasculopathy or anaemia affects WM and regional GM volumes in children living in Africa. Children with SCA (n = 144; aged 5-20 years; 74 male) and sibling controls (n = 53; aged 5-17 years; 29 male) underwent magnetic resonance imaging. Effects of SCI (n = 37), vasculopathy (n = 15), and haemoglobin were assessed. Compared with controls, after adjusting for age, sex and intracranial volume, patients with SCA had smaller volumes for WM and cortical, subcortical and total GM, as well as bilateral cerebellar cortex, globus pallidus, amygdala and right thalamus. Left globus pallidus volume was further reduced in patients with vasculopathy. Putamen and hippocampus volumes were larger in patients with SCA without SCI or vasculopathy than in controls. Significant positive effects of haemoglobin on regional GM volumes were confined to the controls. Patients with SCA generally have reduced GM volumes compared with controls, although some subcortical regions may be spared. SCI and vasculopathy may affect the trajectory of change in subcortical GM and WM volume. Brain volume in non-SCA children may be vulnerable to contemporaneous anaemia.

Revisiting prognostic factors in glioma with leptomeningeal metastases: a comprehensive analysis of clinical and molecular factors and treatment modalities.

PURPOSE: To comprehensively investigate prognostic factors, including clinical and molecular factors and treatment modalities, in adult glioma patients with leptomeningeal metastases (LM). METHODS: Total 226 patients with LM (from 2001 to 2021 among 1495 grade 2 to 4 glioma patients, 88.5% of LM patients being IDH-wildtype) with complete information on IDH mutation, 1p/19q codeletion, and MGMT promoter methylation status were enrolled. Predictors of overall survival (OS) of entire patients were determined by time-dependent Cox analysis, including clinical, molecular, and treatment data. Subgroup analyses were performed for patients with LM at initial diagnosis and LM diagnosed at recurrence (herein, initial and recurrent LM). Identical analyses were performed in IDH-wildtype glioblastoma patients. RESULTS: Median OS was 17.0 (IQR 9.7-67.1) months, with shorter median OS in initial LM than recurrent LM patients (12.2 vs 20.6 months, P < 0.001). In entire patients, chemotherapy and antiangiogenic therapy were predictors of longer OS, while male sex and initial LM were predictors of shorter OS. In initial LM, higher KPS, chemotherapy, and antiangiogenic therapy were predictors of longer OS, while male sex was a predictor of shorter OS. In recurrent LM, chemotherapy and longer interval between initial glioma and LM diagnoses were predictors of longer OS, while male sex was a predictor of shorter OS. A similar trend was observed in IDH-wildtype glioblastoma. CONCLUSION: Active chemotherapy and antiangiogenic therapy demonstrated survival benefit in glioma patients with LM. There is consistent female survival advantage, whereas longer interval between initial glioma diagnosis and LM development suggests longer OS in recurrent LM.

Multiparametric MRI-based radiomics model for predicting human papillomavirus status in oropharyngeal squamous cell carcinoma: optimization using oversampling and machine learning techniques.

OBJECTIVES: To develop and validate a multiparametric MRI-based radiomics model with optimal oversampling and machine learning techniques for predicting human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma (OPSCC). METHODS: This retrospective, multicenter study included consecutive patients with newly diagnosed and pathologically confirmed OPSCC between January 2017 and December 2020 (110 patients in the training set, 44 patients in the external validation set). A total of 293 radiomics features were extracted from three sequences (T2-weighted images [T2WI], contrast-enhanced T1-weighted images [CE-T1WI], and ADC). Combinations of three feature selection, five oversampling, and 12 machine learning techniques were evaluated to optimize its diagnostic performance. The area under the receiver operating characteristic curve (AUC) of the top five models was validated in the external validation set. RESULTS: A total of 154 patients (59.2 ± 9.1 years; 132 men [85.7%]) were included, and oversampling was employed to account for data imbalance between HPV-positive and HPV-negative OPSCC (86.4% [133/154] vs. 13.6% [21/154]). For the ADC radiomics model, the combination of random oversampling and ridge showed the highest diagnostic performance in the external validation set (AUC, 0.791; 95% CI, 0.775-0.808). The ADC radiomics model showed a higher trend in diagnostic performance compared to the radiomics model using CE-T1WI (AUC, 0.604; 95% CI, 0.590-0.618), T2WI (AUC, 0.695; 95% CI, 0.673-0.717), and a combination of both (AUC, 0.642; 95% CI, 0.626-0.657). CONCLUSIONS: The ADC radiomics model using random oversampling and ridge showed the highest diagnostic performance in predicting the HPV status of OPSCC in the external validation set. CLINICAL RELEVANCE STATEMENT: Among multiple sequences, the ADC radiomics model has a potential for generalizability and applicability in clinical practice. Exploring multiple oversampling and machine learning techniques was a valuable strategy for optimizing radiomics model performance. KEY POINTS: • Previous radiomics studies using multiparametric MRI were conducted at single centers without external validation and had unresolved data imbalances. • Among the ADC, CE-T1WI, and T2WI radiomics models and the ADC histogram models, the ADC radiomics model was the best-performing model for predicting human papillomavirus status in oropharyngeal squamous cell carcinoma. • The ADC radiomics model with the combination of random oversampling and ridge showed the highest diagnostic performance.

MRI radiomics may predict early tumor recurrence in patients with sinonasal squamous cell carcinoma.

OBJECTIVES: Sinonasal squamous cell carcinoma (SCC) follows a poor prognosis with high tendency for local recurrence. We aimed to evaluate whether MRI radiomics can predict early local failure in sinonasal SCC. METHODS: Sixty-eight consecutive patients with node-negative sinonasal SCC (January 2005-December 2020) were enrolled, allocated to the training (n = 47) and test sets (n = 21). Early local failure, which occurred within 12 months of completion of initial treatment, was the primary endpoint. For clinical features (age, location, treatment modality, and clinical T stage), binary logistic regression analysis was performed. For 186 extracted radiomic features, different feature selections and classifiers were combined to create two prediction models: (1) a pure radiomics model; and (2) a combined model with clinical features and radiomics. The areas under the receiver operating characteristic curves (AUCs) were calculated and compared using DeLong's method. RESULTS: Early local failure occurred in 38.3% (18/47) and 23.8% (5/21) in the training and test sets, respectively. We identified several radiomic features which were strongly associated with early local failure. In the test set, both the best-performing radiomics model and the combined model (clinical + radiomic features) yielded higher AUCs compared to the clinical model (AUC, 0.838 vs. 0.438, p = 0.020; 0.850 vs. 0.438, p = 0.016, respectively). The performances of the best-performing radiomics model and the combined model did not differ significantly (AUC, 0.838 vs. 0.850, p = 0.904). CONCLUSION: MRI radiomics integrated with a machine learning classifier may predict early local failure in patients with sinonasal SCC. CLINICAL RELEVANCE STATEMENT: MRI radiomics intergrated with machine learning classifiers may predict early local failure in sinonasal squamous cell carcinomas more accurately than the clinical model. KEY POINTS: • A subset of radiomic features which showed significant association with early local failure in patients with sinonasal squamous cell carcinomas was identified. • MRI radiomics integrated with machine learning classifiers can predict early local failure with high accuracy, which was validated in the test set (area under the curve = 0.838). • The combined clinical and radiomics model yielded superior performance for early local failure prediction compared to that of the radiomics (area under the curve 0.850 vs. 0.838 in the test set), without a statistically significant difference.

Natural language processing to predict isocitrate dehydrogenase genotype in diffuse glioma using MR radiology reports.

OBJECTIVES: To evaluate the performance of natural language processing (NLP) models to predict isocitrate dehydrogenase (IDH) mutation status in diffuse glioma using routine MR radiology reports. MATERIALS AND METHODS: This retrospective, multi-center study included consecutive patients with diffuse glioma with known IDH mutation status from May 2009 to November 2021 whose initial MR radiology report was available prior to pathologic diagnosis. Five NLP models (long short-term memory [LSTM], bidirectional LSTM, bidirectional encoder representations from transformers [BERT], BERT graph convolutional network [GCN], BioBERT) were trained, and area under the receiver operating characteristic curve (AUC) was assessed to validate prediction of IDH mutation status in the internal and external validation sets. The performance of the best performing NLP model was compared with that of the human readers. RESULTS: A total of 1427 patients (mean age ± standard deviation, 54 ± 15; 779 men, 54.6%) with 720 patients in the training set, 180 patients in the internal validation set, and 527 patients in the external validation set were included. In the external validation set, BERT GCN showed the highest performance (AUC 0.85, 95% CI 0.81-0.89) in predicting IDH mutation status, which was higher than LSTM (AUC 0.77, 95% CI 0.72-0.81; p = .003) and BioBERT (AUC 0.81, 95% CI 0.76-0.85; p = .03). This was higher than that of a neuroradiologist (AUC 0.80, 95% CI 0.76-0.84; p = .005) and a neurosurgeon (AUC 0.79, 95% CI 0.76-0.84; p = .04). CONCLUSION: BERT GCN was externally validated to predict IDH mutation status in patients with diffuse glioma using routine MR radiology reports with superior or at least comparable performance to human reader. CLINICAL RELEVANCE STATEMENT: Natural language processing may be used to extract relevant information from routine radiology reports to predict cancer genotype and provide prognostic information that may aid in guiding treatment strategy and enabling personalized medicine. KEY POINTS: • A transformer-based natural language processing (NLP) model predicted isocitrate dehydrogenase mutation status in diffuse glioma with an AUC of 0.85 in the external validation set. • The best NLP models were superior or at least comparable to human readers in both internal and external validation sets. • Transformer-based models showed higher performance than conventional NLP model such as long short-term memory.

Sex as a prognostic factor in adult-type diffuse gliomas: an integrated clinical and molecular analysis according to the 2021 WHO classification.

PURPOSE: To investigate whether type-specific sex differences in survival exist independently of clinical and molecular factors in adult-type diffuse gliomas according to the 2021 World Health Organization (WHO) classification. METHODS: A retrospective chart and imaging review of 1325 patients (mean age, 54 ± 15 years; 569 females) with adult-type diffuse gliomas (oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, n = 183; astrocytoma, IDH-mutant, n = 211; glioblastoma, IDH-wildtype, n = 800; IDH-wildtype diffuse glioma, NOS, n = 131) was performed. The demographic information, extent of resection, imaging data, and molecular data including O6-methylguanine-methyltransferase promoter methylation (MGMT) promotor methylation were collected. Sex differences in survival were analyzed using Cox analysis. RESULTS: In patients with glioblastoma, IDH-wildtype, female sex remained as an independent predictor of better overall survival (hazard ratio = 0.91, P = 0.031), along with age, histological grade 4, MGMT promoter methylation status, and gross total resection. Female sex showed a higher prevalence of MGMT promoter methylation (40.2% vs 32.0%, P = 0.017) but there was no interaction effect between female sex and MGMT promoter methylation status (P-interaction = 0.194), indicating independent role of female sex. The median OS for females were 19.2 months (12.3-35.0) and 16.2 months (10.5-30.6) for males. No sex difference in survival was seen in other types of adult-type diffuse gliomas. CONCLUSION: There was a female survival advantage in glioblastoma, IDH-wildtype, independently of clinical data or MGMT promoter methylation status. There was no sex difference in survival in other types of adult-type diffuse gliomas, suggesting type-specific sex effects solely in glioblastoma, IDH-wildtype.

Salvage multiple burr hole surgery in patients with Moyamoya disease: efficacy evaluation using probabilistic independent component analysis of dynamic susceptibility contrast perfusion MRI.

PURPOSE: Multiple burr hole surgery is considered to be an option for achieving indirect revascularization in patients with ischemic Moyamoya disease (MMD). We aimed to investigate the efficacy of stand-alone multiple burr hole surgery for salvage revascularization in patients with MMD by assessing the hemodynamic changes via normalized time-to-peak (nTTP) analysis and independent component analysis (ICA) of preoperative and postoperative dynamic susceptibility contrast (DSC) perfusion MRI data. METHODS: The DSC perfusion MRI data of 25 hemispheres from 21 patients with MMD, who underwent multiple burr hole surgery for salvage revascularization due to persistent or recurrent symptoms after primary revascularization with modified encephaloduroarteriosynangiosis (mEDAS), were analyzed. The nTTP, which was measured using the region of interests covering the entire surgical hemisphere, was compared between the preoperative and postoperative images. ICA was used to compare the relative arterial and venous components of the surgical hemispheres between the respective preoperative and postoperative images. RESULTS: The median postoperative nTTP (1.80 s) was significantly shorter than the median preoperative nTTP (4.10 s) (P < 0.001). The postoperative relative arterial component of the surgical hemisphere (median: 0.04) was significantly higher than the preoperative relative arterial component (median: - 0.02, P < 0.001). In contrast, the postoperative relative venous component of the surgical hemisphere (median: - 0.05) was significantly lower than the preoperative value (median: 0.05, P < 0.001). CONCLUSION: The improvement in cerebral perfusion parameters observed on postoperative DSC perfusion MRI demonstrated that stand-alone multiple burr hole surgery could be a favorable salvage revascularization technique after mEDAS failure in patients with ischemic MMD.

Clinical factors and conventional MRI may independently predict progression-free survival and overall survival in adult pilocytic astrocytomas.

PURPOSE: Pilocytic astrocytoma (PA) is rare in adults, and only limited knowledge on the clinical course and prognosis has been available. The combination of clinical information and comprehensive imaging parameters could be used for accurate prognostic stratification in adult PA patients. This study was conducted to predict the prognostic factors from clinical information and conventional magnetic resonance imaging (MRI) features in adult PAs. METHODS: A total of 56 adult PA patients were enrolled in the institutional cohort. Clinical characteristics including age, sex, anaplastic PA, presence of neurofibromatosis type 1, Karnofsky performance status, extent of resection, and postoperative treatment were collected. MRI characteristics including major axis length, tumor location, presence of the typical 'cystic mass with enhancing mural nodule appearance', proportion of enhancing tumor, the proportion of edema, conspicuity of the nonenhancing margin, and presence of a cyst were evaluated. Univariable and multivariable Cox proportional hazard modeling were performed. RESULTS: The 5-year progression-free survival (PFS) and overall survival (OS) rates were 83.9% and 91.l%, respectively. On univariable analysis, older age, larger proportion of edema, and poor definition of nonenhancing margin were predictors of shorter PFS and OS, respectively (all Ps < .05). On multivariable analysis, older age (hazard ratio [HR] = 1.04, P = .014; HR = 1.14, P = .030) and poor definition of nonenhancing margin (HR = 3.66, P = .027; HR = 24.30, P = .024) were independent variables for shorter PFS and OS, respectively. CONCLUSION: Age and the margin of the nonenhancing part of the tumor may be useful biomarkers for predicting the outcome in adult PAs.

The feasibility of performing multiple burr hole surgery in pediatric moyamoya patients as a response to failed mEDAS.

OBJECTIVE: To investigate the feasibility and clinical effectiveness of performing multiple burr hole surgery in pediatric moyamoya patients as a response to failed modified encephaloduroarteriosynangiosis (mEDAS). METHODS: From January 2014 to May 2018, multiple burr hole surgery (MBS) was conducted on 16 hemispheres in 12 patients as a secondary treatment following mEDAS. The male-to-female ratio was 1:2 and the average age at the time of mEDAS was 6 years old. The average patient age was 9 ± 3 years olds (range 7-17) at the time of MBS which occurred an average of 46 months after mEDAS. An average of 10 ± 1 holes (range 8-13) were made. Time-to-peak (TTP) magnetic resonance images (MRI) were taken along 20 axial cuts. Of these cuts, two consecutive cuts on the lateral ventricle were selected to calculate the average value of the region of interest (ROI). The value of the cerebellum was subtracted from the average value of two consecutive cuts. The ROI value was analyzed using a paired t test by SPSS 20 (SPSS Inc., Chicago, IL, USA). RESULTS: All 16 cases presented improvement of clinical symptoms as determined by ROI analysis of the TTP MRI images. The average ROI value was 5.03 ± 6.36 before MBS and - 15.54 ± 9.42 after MBS. The average change in the ROI value was - 20.58 ± 12.59. The ROI value decreased in all cases after MBS. Magnetic resonance angiography (MRA) also showed a positive effect on vascularization. CONCLUSION: In pediatric moyamoya patients, MBS is recommended as secondary option as a response to failed mEDAS. Its clinical effectiveness was shown by analyzing TTP images and assisted by MRA and digital subtraction angiography.

Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck.

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Current treatments have low response rates (RRs). METHODS: Fifty-three patients with R/M SCCHN received continuous oral buparlisib. In parallel, patient-derived xenografts (PDXs) were established in mice to evaluate resistance mechanisms and efficacy of buparlisib/cetuximab combination. Baseline and on-treatment tumour genomes and transcriptomes were sequenced. Based on the integrated clinical and PDX data, 11 patients with progression under buparlisib monotherapy were treated with a combination of buparlisib and cetuximab. RESULTS: For buparlisib monotherapy, disease control rate (DCR) was 49%, RR was 3% and median progression-free survival (PFS) and overall survival (OS) were 63 and 143 days, respectively. For combination therapy, DCR was 91%, RR was 18% and median PFS and OS were 111 and 206 days, respectively. Four PDX models were originated from patients enrolled in the current clinical trial. While buparlisib alone did not inhibit tumour growth, combination therapy achieved tumour inhibition in three of seven PDXs. Genes associated with apoptosis and cell-cycle arrest were expressed at higher levels with combination treatment than with buparlisib or cetuximab alone. CONCLUSIONS: The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN. CLINICAL TRIAL REGISTRATION: NCT01527877.

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer.

BACKGROUND: We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. METHODS: Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. RESULTS: From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P < 0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P < 0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P = 0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor. CONCLUSIONS: Genetically and clinically annotated HNSCC PDXs could be useful preclinical tools for evaluating biomarkers, therapeutic targets, and new drug discovery.

Prognostic Value of Cervical Nodal Necrosis Observed in Preoperative CT and MRI of Patients With Tongue Squamous Cell Carcinoma and Cervical Node Metastases: A Retrospective Study.

OBJECTIVE. The prognosis of tongue squamous cell carcinoma (SCC) with cervical lymph node metastases is poor, and a subset of patients with aggressive disease experiences treatment failure. The current study evaluated the prognostic value of cervical nodal necrosis (CNN) observed on preoperative imaging studies of patients with tongue SCC and cervical node metastases. MATERIALS AND METHODS. We identified patients with tongue SCC who had undergone preoperative neck CT or MRI (or both) and retrospectively reviewed their demographic and clinical data. Patients with metastatic cervical lymph nodes were divided into two groups according to the presence (CNN group) or absence (non-CNN group) of necrosis, and radiologic extranodal extension (ENE) was assessed for all patients. Follow-up biopsy, imaging, and clinical examinations were used to determine survival and treatment failure. Cox proportional hazard regression analyses were performed to determine clinical, demographic, and pathologic factors for survival. RESULTS. Seventy-two patients with a mean follow-up period of 28.4 months were included. The incidence of CNN was 55.6% (40/72). In univariate analysis, patient age, evidence of CNN on preoperative imaging, radiologic ENE, clinical N classification, and overall stage were significantly associated with survival. The multivariate Cox proportional hazard model showed that patient age and CNN on preoperative imaging were independent negative prognostic factors. CONCLUSION. CNN observed on preoperative imaging studies is an independent predictor of a poor prognosis for patients with tongue SCC, and it may serve as a useful imaging biomarker for tailoring individual treatment regimens.

Gadolinium deposition in the brain: association with various GBCAs using a generalized additive model.

OBJECTIVES: To determine the relationship between the number of administrations of various gadolinium-based contrast agents (GBCAs) and increased T1 signal intensity in the globus pallidus (GP) and dentate nucleus (DN). METHODS: This retrospective study included 122 patients who underwent double-dose GBCA-enhanced magnetic resonance imaging. Two radiologists calculated GP-to-thalamus (TH) signal intensity ratio, DN-to-pons signal intensity ratio and relative change (Rchange) between the baseline and final examinations. Interobserver agreement was evaluated. The relationships between Rchange and several factors, including number of each GBCA administrations, were analysed using a generalized additive model. RESULTS: Six patients (4.9%) received linear GBCAs (mean 20.8 number of administration; range 15-30), 44 patients (36.1%) received macrocyclic GBCAs (mean 26.1; range 14-51) and 72 patients (59.0%) received both types of GBCAs (mean 31.5; range 12-65). Interobserver agreement was almost perfect (0.99; 95% CI: 0.99-0.99). Rchange (DN:pons) was associated with gadodiamide (p = 0.006) and gadopentetate dimeglumine (p < 0.001), but not with other GBCAs. Rchange (GP:TH) was not associated with GBCA administration. CONCLUSIONS: Previous administration of linear agents gadoiamide and gadopentetate dimeglumine is associated with increased T1 signal intensity in the DN, whereas macrocyclic GBCAs do not show an association. KEY POINTS: • Certain linear GBCAs are associated with T1 signal change in the dentate nucleus. • The signal change is related to the administration number of certain linear GBCAs. • Difference in signal change may reflect differences in stability of agents.

Increased sensitivity of African American triple negative breast cancer cells to nitric oxide-induced mitochondria-mediated apoptosis.

BACKGROUND: Breast cancer is a complex heterogeneous disease where many distinct subtypes are found. Younger African American (AA) women often present themselves with aggressive form of breast cancer with unique biology which is very difficult to treat. Better understanding the biology of AA breast tumors could lead to development of effective treatment strategies. Our previous studies indicate that AA but not Caucasian (CA) triple negative (TN) breast cancer cells were sensitive to nitrosative stress-induced cell death. In this study, we elucidate possible mechanisms that contribute to nitric oxide (NO)-induced apoptosis in AA TN breast cancer cells. METHODS: Breast cancer cells were treated with various concentrations of long-acting NO donor, DETA-NONOate and cell viability was determined by trypan blue exclusion assay. Apoptosis was determined by TUNEL and caspase 3 activity as well as changes in mitochondrial membrane potential. Caspase 3 and Bax cleavage, levels of Cu/Zn superoxide dismutase (SOD) and Mn SOD was assessed by immunoblot analysis. Inhibition of Bax cleavage by Calpain inhibitor, and levels of reactive oxygen species (ROS) as well as SOD activity was measured in NO-induced apoptosis. In vitro and in vivo effect of NO treatment on mammary cancer stem cells (MCSCs) was assessed. RESULTS AND DISCUSSION: NO induced mitocondria-mediated apoptosis in all AA but not in CA TN breast cancer cells. We found significant TUNEL-positive cells, cleavage of Bax and caspase-3 activation as well as depolarization mitochondrial membrane potential only in AA TN breast cancer cells exposed to NO. Inhibition of Bax cleavage and quenching of ROS partially inhibited NO-induced apoptosis in AA TN cells. Increase in ROS coincided with reduction in SOD activity in AA TN breast cancer cells. Furthermore, NO treatment of AA TN breast cancer cells dramatically reduced aldehyde dehydrogenase1 (ALDH1) expressing MCSCs and xenograft formation but not in breast cancer cells from CA origin. CONCLUSIONS: Ethnic differences in breast tumors dictate a need for tailoring treatment options more suited to the unique biology of the disease.

Human Papillomavirus and Epidermal Growth Factor Receptor in Oral Cavity and Oropharyngeal Squamous Cell Carcinoma: Correlation With Dynamic Contrast-Enhanced MRI Parameters.

OBJECTIVE: The objective of this study was to investigate differences in dynamic contrast-enhanced MRI (DCE-MRI) parameters on the basis of the status of human papillomavirus (HPV) and epidermal growth factor receptor (EGFR) biomarkers in patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx by use of histogram analysis. MATERIALS AND METHODS: A total of 22 consecutive patients with oral cavity and oropharyngeal SCC underwent DCE-MRI before receiving treatment. DCE parameter maps of the volume transfer constant (K(trans)), the flux rate constant (kep), and the extravascular extracellular volume fraction (ve) were obtained. The histogram parameters were calculated using the entire enhancing tumor volume and were compared between the patient subgroups on the basis of HPV and EGFR biomarker statuses. RESULTS: The cumulative histogram parameters of K(trans) and kep showed lower values in the HPV-negative and EFGR-overexpression group than in the HPV-positive EGFR-negative group. These differences were statistically significant for the mean (p = 0.009), 25th, 50th, and 75th percentile values of K(trans) and for the 25th percentile value of kep when correlated with HPV status in addition to the mean K(trans) value (p = 0.047) and kep value (p = 0.004) when correlated with EGFR status. No statistically significant difference in ve was found on the basis of HPV and EGFR status. CONCLUSION: DCE-MRI is useful for the assessment of the tumor microenvironment associated with HPV and EGFR biomarkers before treatment of patients with oral cavity and oropharyngeal SCC.

Application of Dynamic Contrast-Enhanced MRI Parameters for Differentiating Squamous Cell Carcinoma and Malignant Lymphoma of the Oropharynx.

OBJECTIVE: The purpose of this study was to investigate the usefulness of histogram analysis of dynamic contrast-enhanced MRI (DCE-MRI) parameters for the differentiation of squamous cell carcinoma (SCC) and malignant lymphoma of the oropharynx. MATERIALS AND METHODS: Pretreatment DCE-MRI was performed in 21 patients with pathologically confirmed oropharyngeal SCC and six patients with malignant lymphoma. DCE-MRI parameter maps including the volume transfer constant (K(trans)), flux rate constant (kep), and extravascular extracellular volume fraction (ve) based on the Tofts model were obtained. Enhancing tumors were manually segmented on each slice of the parameter maps, and the data were collected to obtain a histogram for the entire tumor volume. The Wilcoxon rank sum test was used to compare the histogram parameters of each DCE-MRI-derived variable of oropharyngeal SCC and lymphoma. RESULTS: Histogram analysis of K(trans) and ve maps revealed that the median and mode of K(trans) were significantly higher in SCC than in lymphoma (p = 0.039 and 0.032, respectively), and the mode, skewness, and kurtosis of ve were significantly different in SCC than in lymphoma (p = 0.046, 0.039, and 0.032, respectively). On ROC analysis, the kurtosis of ve had the best discriminative value for distinguishing between oropharyngeal SCC and lymphoma (AUC, 0.865; cutoff value, 2.60; sensitivity, 83.3%; specificity, 90.5%). CONCLUSION: Our preliminary evidence using histogram analysis of DCE-MRI parameters based on the whole tumor volume suggests that it might be useful for differentiating SCC from malignant lymphoma of the oropharynx.

Is there an additive value of 18 F-FDG PET-CT to CT/MRI for detecting nodal metastasis in oropharyngeal squamous cell carcinoma patients with palpably negative neck?

Background Cervical node metastasis is one of the most significant prognostic factors in patients with oropharyngeal squamous cell carcinoma (SCC). There is little information regarding the comparison of histopathologic analysis following neck dissection with imaging results in oropharyngeal SCC. Purpose To investigate the clinical utility of PET-CT compared with computed tomography (CT) or magnetic resonance imaging (MRI) for detecting nodal metastasis in oropharyngeal SCC patients with palpably negative neck and to investigate whether pretreatment imaging modalities support the rationale for elective neck treatment. Material and Methods A total of 49 oropharyngeal SCC patients with palpably negative neck (42 men, 7 women; average age, 59.1 years) underwent primary tumor resection and neck dissection as a primary treatment. All patients were preoperatively evaluated with PET-CT and CT/MRI, and the diagnostic accuracy of each imaging modality was assessed by comparison with histopathologic results of the surgical specimen. Results Twenty-five (51.0%) of our 49 patients had neck metastases. On a level-by-level analysis, the sensitivity of PET-CT, CT/MRI, and a combination of PET-CT and CT/MRI was 54.6%, 54.6%, and 60.6%, respectively, at all neck levels. The area under the ROC showed that the diagnostic performance of the combined interpretation was not significantly different from that of CT/MRI alone (0.780 vs. 0.750, respectively; P = 0.158) and PET-CT alone (0.780 vs. 0.765, respectively; P = 0.501). Conclusion Addition of PET-CT to CT/MRI did not provide better diagnostic accuracy for detecting nodal metastasis in preoperative evaluation of oropharyngeal SCC patients with palpably negative neck, suggesting that current imaging studies might not replace elective neck dissection.