Proving of a Mathematical Model of Cell Calculation Based on Apparent Diffusion Coefficient

OBJECTIVES: Recently, Atuegwu et al. proposed a mathematical model based on ADC_mean and ADC_min to calculation of cellularity. Our purpose was to compare the calculated cellularity according to the formula with the estimated cell count by histopathology in different tumors. METHODS: For this study, we re-analyzed our previous data regarding associations between ADC parameters and histopathological findings. Overall, 134 patients with different tumors were acquired for the analysis. For all tumors, the number of tumor cells was calculated according to Atuegwu et al. 2013. We performed a correlation analysis between the calculated and estimated cellularity. Thereby, Pearson's correlation coefficient was used and P < .05 was taken to indicate statistical significance in all instances. RESULTS: The estimated and calculated cellularity correlated well together in HNSCC (r = 0.701, P = .016) and lymphomas (r = 0.661, P = .001), and moderately in rectal cancer (r = 0.510, P = .036). There were no statistically significant correlations between the estimated and calculated cellularity in uterine cervical cancer, meningiomas, and in thyroid cancer. CONCLUSION: The proposed formula for cellularity calculation does not apply for all tumors. It may be used for HNSCC, cerebral lymphomas and rectal cancer, but not for uterine cervical cancer, meningioma, and thyroid cancer. Furthermore, its usefulness should be proved for other tumors.     

Can Imaging Parameters Provide Information Regarding Histopathology in Head and Neck Squamous Cell Carcinoma? A Meta-Analysis

OBJECT: Our purpose was to provide data regarding relationships between different imaging and histopathological parameters in HNSCC. METHODS: MEDLINE library was screened for associations between different imaging parameters and histopathological features in HNSCC up to December 2017. Only papers containing correlation coefficients between different imaging parameters and histopathological findings were acquired for the analysis. RESULTS: Associations between ¹⁸F-FDG positron emission tomography (PET) and KI 67 were reported in 8 studies (236 patients). The pooled correlation coefficient was 0.20 (95% CI = [?0.04; 0.44]). Furthermore, in 4 studies (64 patients), associations between ¹⁸F-fluorothymidine PET and KI 67 were analyzed. The pooled correlation coefficient between SUV_max and KI 67 was 0.28 (95% CI = [?0.06; 0.94]). In 2 studies (23 patients), relationships between KI 67 and dynamic contrast-enhanced magnetic resonance imaging were reported. The pooled correlation coefficient between K_trans and KI 67 was ?0.68 (95% CI = [?0.91; ?0.44]). Two studies (31 patients) investigated correlation between apparent diffusion coefficient (ADC) and KI 67. The pooled correlation coefficient was ?0.61 (95% CI = [?0.84; ?0.38]). In 2 studies (117 patients), relationships between ¹⁸F-FDG PET and p53 were analyzed. The pooled correlation coefficient was 0.0 (95% CI = [?0.87; 0.88]). There were 3 studies (48 patients) that investigated associations between ADC and tumor cell count in HNSCC. The pooled correlation coefficient was ?0.53 (95% CI = [?0.74; ?0.32]). Associations between ¹⁸F-FDG PET and HIF-1α were investigated in 3 studies (72 patients). The pooled correlation coefficient was 0.44 (95% CI = [?0.20; 1.08]). CONCLUSIONS: ADC may predict cell count and proliferation activity, and SUV_max may predict expression of HIF-1α in HNSCC. SUV_max cannot be used as surrogate marker for expression of KI 67 and p53.     

Comparison of Two Mathematical Models of Cellularity Calculation

OBJECT: Nowadays, there is increasing evidence that functional magnetic resonance imaging (MRI) modalities, namely, diffusion-weighted imaging (DWI) and dynamic-contrast enhanced MRI (DCE MRI), can characterize tumor architecture like cellularity and vascularity. Previously, two formulas based on a logistic tumor growth model were proposed to predict tumor cellularity with DWI and DCE. The purpose of this study was to proof these formulas. METHODS: 16 patients with head and neck squamous cell carcinomas were included into the study. There were 2 women and 14 men with a mean age of 57.0 ± 7.5 years. In every case, tumor cellularity was calculated using the proposed formulas by Atuegwu et al. In every case, also tumor cell count was estimated on histopathological specimens as an average cell count per 2 to 5 high-power fields. RESULTS: There was no significant correlation between the calculated cellularity and histopathologically estimated cell count by using the formula based on apparent diffusion coefficient (ADC) values. A moderate positive correlation (r=0.515, P=.041) could be identified by using the formula including ADC and V_e values. CONCLUSIONS: The formula including ADC and V_e values is more sensitive to predict tumor cellularity than the formula including ADC values only.     

MRI Texture Analysis Reflects Histopathology Parameters in Thyroid Cancer – A First Preliminary Study

OBJECT: Thyroid cancer represents the most frequent malignancy of the endocrine system with an increasing incidence worldwide. Novel imaging techniques are able to further characterize tumors and even predict histopathology features. Texture analysis is an emergent imaging technique to extract extensive data from an radiology images. The present study was therefore conducted to identify possible associations between texture analysis and histopathology parameters in thyroid cancer. METHODS: The radiological database was retrospectively reviewed for thyroid carcinoma. Overall, 13 patients (3 females, 23.1%) with a mean age of 61.6 years were identified. The MaZda program was used for texture analysis. The T1-precontrast and T2-weighted images were analyzed and overall 279 texture feature for each sequence was investigated. For every patient cell count, Ki67-index and p53 count were investigated. RESULTS: Several significant correlations between texture features and histopathology were identified. Regarding T1-weighted images, S(0;1)Sum Averg correlated the most with cell count (r = 0.82). An inverse correlations with S(5;0)AngScMom, S(5;0)DifVarnc S(5;0), DiffEntrp and GrNonZeros (r = ?0.69, ?0.66, ?0.69 and ?0.63, respectively) was also identified. For T2-weighted images, Variance with r = 0.63 was the highest coefficient, WavEnLL_S3 correlated inversely with cell count (r = ?0.57). WavEnLL_S2 derived from T1-weighted images was the highest coefficient r = ?0.80, S(0;5)SumVarnc was positively with r = 0.74. Regarding T2-weighted images WavEnHL_s-1 was inverse correlated with Ki67 index (r = ?0.77). S(1;0)Correlat was with r = 0.75 the best correlation with Ki67 index. For T1-weighed images S(5;0)SumofSqs was the best with r = 0.65 with p53 count. For T2-weighted images S(1;?1)SumEntrp was the inverse correlation with r = ?0.72, whereas S(0;4)AngScMom correlated positively with r = 0.63. CONCLUSIONS: MRI texture analysis derived from conventional sequences reflects histopathology features in thyroid cancer. This technique might be a novel noninvasive modality to further characterize thyroid cancer in clinical oncology.     

Whole Tumor Histogram-profiling of Diffusion-Weighted Magnetic Resonance Images Reflects Tumorbiological Features of Primary Central Nervous System Lymphoma

PURPOSE: Diffusion weighted imaging (DWI) quantifies motion of hydrogen nuclei in biological tissues and hereby has been used to assess the underlying tissue microarchitecture. Histogram-profiling of DWI provides more detailed information on diffusion characteristics of a lesion than the standardly calculated values of the apparent diffusion coefficient (ADC)—minimum, mean and maximum. Hence, the aim of our study was to investigate, which parameters of histogram-profiling of DWI in primary central nervous system lymphoma can be used to specifically predict features like cellular density, chromatin content and proliferative activity. PROCEDURES: Pre-treatment ADC maps of 21 PCNSL patients (8 female, 13 male, 28–89 years) from a 1.5T system were used for Matlab-based histogram profiling. Results of histopathology (H&E staining) and immunohistochemistry (Ki-67 expression) were quantified. Correlations between histogram-profiling parameters and neuropathologic examination were calculated using SPSS 23.0. RESULTS: The lower percentiles (p10 and p25) showed significant correlations with structural parameters of the neuropathologic examination (cellular density, chromatin content). The highest percentile, p90, correlated significantly with Ki-67 expression, resembling proliferative activity. Kurtosis of the ADC histogram correlated significantly with cellular density. CONCLUSIONS: Histogram-profiling of DWI in PCNSL provides a comprehensible set of parameters, which reflect distinct tumor-architectural and tumor-biological features, and hence, are promising biomarkers for treatment response and prognosis.     

Prognostic Value of Tumor-Infiltrating Lymphocytes for Patients With Head and Neck Squamous Cell Carcinoma

BACKGROUND: The prognostic value of tumor-infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) remains controversial. Additionally, there is no standardized approach or cutoff value for evaluating TIL levels. The aim of this study was to establish a feasible method and criterion to assess TIL levels for future clinical practice and research use and to explore the relationship between TIL levels and prognosis. PATIENTS AND METHODS: This retrospective cohort study reviewed the records and pathological sections of 202 patients with HNSCC who were surgically treated at Beijing Stomatological Hospital, Capital Medical University, from January 1998 to January 2011. The predictor variable was the TIL level. The main outcome assessment parameters were disease-free survival (DFS) and disease-specific survival (DSS). RESULT: The T stage (P = .008), smoking history (P = .042), alcohol history (P = .048), need for radiotherapy (P = .012) and microscopic extracapsular spread (ECS) (P = .012) were associated with the TIL level. A cutoff value equal to 70% could be taken as a threshold for TIL assessment, with a TIL level higher than 70% associated with a better prognosis (DFS rate: 51.9%, P = .018; DSS rate: 59.3%, P = .049). The Cox regression model showed that the TIL level was an independent prognostic factor for DFS (hazard ratio (HR): 0.786, 95% CI: 0.618-0.999, P = .049). CONCLUSION: The TIL level is closely related to the prognosis of patients with HNSCC. A threshold value of 70% is appropriate for TIL assessment, as patients with a TIL level higher than 70% show a better prognosis. Thus, the TIL level might serve as an independent predictor for HNSCC recurrence.     

Preoperative T Staging of Potentially Resectable Esophageal Cancer: A Comparison between Free-Breathing Radial VIBE and Breath-Hold Cartesian VIBE,with Histopathological Correlation

Purpose: To compare the T staging of potentially resectable esophageal cancer using free-breathing radial VIBE (r-VIBE) and breath-hold Cartesian VIBE (C-VIBE), with pathologic confirmation of the T stage. Materials and Methods: Fifty patients with endoscopically proven esophageal cancer and indeterminate T1/T2/T3 stage by CT scan were examined on a 3-T scanner. The MRI protocol included C-VIBE at 150 seconds post–IV contrast, immediately followed by a work-in-progress r-VIBE with identical spatial resolution (1.1 mm × 1.1 mm × 3.0 mm). Two independent readers assigned a T stage on MRI according to the 7th edition of UICC-AJCC TNM Classification, and postoperative pathologic confirmation was considered the gold standard. Interreader agreement was also calculated. Results: The T staging agreement between both VIBE techniques and postoperative pathologic T staging was 52% (26/50) for C-VIBE, 80% (40/50) for r-VIBE for reader 1, and 50% (25/50), 82% (41/50) for reader 2, respectively. For the esophageal cancer with invading lamina propria, muscularis mucosae, or submucosa (T1 stage), r-VIBE achieved 86% (12/14) agreement for both readers 1 and 2. For invasion of muscularis propria (T2 stage), r-VIBE achieved 83% (25/30) for both readers 1 and 2, whereas for the invasion of adventitia (T3 stage), r-VIBE could only achieve agreement in 50% (3/6) and 67% (4/6) for readers 1 and 2, respectively. Conclusion: Contrast-enhanced free-breathing r-VIBE is superior to breath-hold CVIBE in T staging of potentially resectable esophageal cancer, especially for T1 and T2.     

Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies

The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)–based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.     

Hydrogen Sulfide Demonstrates Promising Antitumor Efficacy in Gastric Carcinoma by Targeting MGAT5

Mannosyl (alpha-1,6-)-Glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase (MGAT5) is exclusively expressed in gastric carcinoma, and plays an essential role in cancer progression, but no targeted drug is available so far. The potential anti-cancer effect of Hydrogen Sulfide (H₂S), has not been widely recognized. It intrigued broad interest to explore the clinical benefits of cancer therapy, with the current understanding of molecular mechanisms of H₂S which remains very limited. In this study, we identify that H₂S is an effective inhibitor of MGAT5, leading to reduce the expression of exclusively abnormal glycoprotein processes in gastric carcinoma. H₂S specifically dissociation of karyopherin subunit alpha-2 (KPNA2) with Jun proto-oncogene (c-Jun) interaction, and blocking c-Jun nuclear translocation, and downregulation of MGAT5 expression at the level of gene and protein. Consequently, H₂S impairs growth and metastasis in gastric carcinoma by targeting inhibits MGAT5 activity. In an animal tumor model study, H₂S is well tolerated, inhibits gastric carcinoma growth and metastasis. Our preclinical work therefore supports that H₂S acts as a novel inhibitor of MGAT5 that block tumorigenesis in gastric carcinoma. SIGNIFICANCE: This study shows that H₂S can effective targeting inhibits MGAT5 activity, and demonstrates promising antitumor efficacy. These findings gain mechanistic insights into the anti-cancer capacity of H₂S and may provide useful information for the clinical explorations of H₂S in cancer treatment.     

Serum MicroRNAs Related with Chemoradiotherapy Resistance in Advanced-Stage Cervical Squamous Cell Carcinoma

OBJECTIVE: To investigate the serum microRNAs as biomarkers in predicting chemoradiotherapy resistance in advanced-stage cervical squamous cell carcinoma (ACSCC) patients. METHODS: Serum samples were collected from International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IIIB cervical squamous cell carcinoma patients treated with platinum based Concomitant Chemoradiotherapy (CCRT) in our hospital during September 2013 to November 2015. Twenty well-matched samples (10 resistant and 10 sensitive) were chosen to screen the miRNA expression profile using serum samples pooled with microarrays. miRNAs expressed significantly different between two groups were further verified in 131 patients (29 resistant and 102 sensitive) serum samples with TaqMan Real-time PCR. The AUC was used to evaluate the accuracy of the biomarkers for prediction. RESULTS: MiR-136-5, miR-152-3p and miR-206 were expressed significantly different between sensitive and resistant groups. Results of 131 patients verification showed that the levels of miR-206 in sensitive samples and resistant samples were 2.715 ± 0.2115 and 14.64 ± 1.184, respectively, which was significantly different (P < .0001), while miR-136-5p and miR-152-3p could not be tested without pre-amplification reactions. Univariate analysis revealed that miR-206 expression was significantly associated with patients' DFS. Multivariate analysis demonstrated that miR-206 expression, tumor differentiation and pelvic lymph nodes metastasis were the independent prognostic factors associated with DFS in this cohort (P = .008, 0.000, 0.000, respectively). The probability of the prognostic accuracy of miR-206 expression in predicting chemoradiotherapy sensitivity of ACSCC patients was 91.3% (79.3% sensitivity and 92.2% specificity). CONCLUSION: Serum miR-206 is a powerful tool in predicting chemoradiotherapy sensitivity in ACSCC patients.     

Relationship of In Vivo MR Parameters to Histopathological and Molecular Characteristics of Newly Diagnosed,Nonenhancing Lower-Grade Gliomas

The goal of this research was to elucidate the relationship between WHO 2016 molecular classifications of newly diagnosed, nonenhancing lower grade gliomas (LrGG), tissue sample histopathology, and magnetic resonance (MR) parameters derived from diffusion, perfusion, and ¹H spectroscopic imaging from the tissue sample locations and the entire tumor. A total of 135 patients were scanned prior to initial surgery, with tumor cellularity scores obtained from 88 image-guided tissue samples. MR parameters were obtained from corresponding sample locations, and histograms of normalized MR parameters within the T2 fluid-attenuated inversion recovery lesion were analyzed in order to evaluate differences between subgroups. For tissue samples, higher tumor scores were related to increased normalized apparent diffusion coefficient (nADC), lower fractional anisotropy (nFA), lower cerebral blood volume (nCBV), higher choline (nCho), and lower N-acetylaspartate (nNAA). Within the T2 lesion, higher tumor grade was associated with higher nADC, lower nFA, and higher Cho to NAA index. Pathological analysis confirmed that diffusion and metabolic parameters increased and perfusion decreased with tumor cellularity. This information can be used to select targets for tissue sampling and to aid in making decisions about treating residual disease.     

Contrast Enhancement on Cone-Beam Breast-CT for Discrimination of Breast Cancer Immunohistochemical Subtypes

PURPOSE: To evaluate whether contrast enhancement on cone-beam breast-CT (CBBCT) could aid in discrimination of breast cancer subtypes and receptor status. METHODS: This study included female patients age >40 years with malignant breast lesions identified on contrast-enhanced CBBCT. Contrast enhancement of malignant breast lesions was standardized to breast fat tissue contrast enhancement. All breast lesions were approved via image-guided biopsy or surgery. Immunohistochemical staining was conducted for expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor-2 (HER2) and Ki-67 index. Contrast enhancement of breast lesions was correlated with immunohistochemical breast cancer subtypes (Luminal A, Luminal B, HER2 positive, triple negative), receptor status and Ki-67 expression. RESULTS: Highest contrast enhancement was seen for Luminal A lesions (93.6 HU) compared to Luminal B lesions (47.6 HU, P = .002), HER2 positive lesions (83.5 HU, P = .359) and triple negative lesions (45.3 HU, P = .005). Contrast enhancement of HER2 positive lesions was higher than Luminal B lesions (P = .044) and triple negative lesions (P = .039). No significant difference was evident between Luminal B and triple negative lesions (P = .439). Lesions with high Ki-67 index showed lower contrast enhancement than those with low Ki-67 index (P = .0043). ER, PR and HER2 positive lesions demonstrated higher contrast enhancement than their receptor negative counterparts, although differences did not reach statistical significance (P = .1714; P = .3603; P = .2166). CONCLUSIONS: Contrast enhancement of malignant breast lesions on CBBCT correlates with immunohistochemical subtype and proliferative potential. Thereby, CBBCT might aid in selecting individualized treatment strategies for breast cancer patients based on pre-operative imaging.     

Expression and Functional Characterization of the BNIP3 Protein in Renal Cell Carcinomas

BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) is a BH3-only protein that regulates apoptosis and autophagy. BNIP3 plays also an important role in hypoxia-induced cell response and is regulated by HIF1. Here, we studied a possible association of BNIP3 expression and the prognosis of patients with renal cell carcinomas (RCCs) and examined the functional relevance of BNIP3 in the regulation of cell survival and apoptosis of renal carcinoma cells. BNIP3 expression was determined by immunohistochemistry in RCC tumor tissue samples of 569 patients using a tissue microarray. Functional characterization of BNIP3 in renal carcinoma cells indicates prosurvival effects. In human RCC tumor samples, high cytoplasmic BNIP3 expression was associated with high-grade RCCs and regional lymph node metastasis. BNIP3 expression correlated negatively with disease-specific survival. Multivariate Cox regression analysis retained BNIP3 expression as an independent prognostic factor in patients without distant metastasis. Together, our studies imply that BNIP3 regulates cell survival in RCCs and its expression is an independent prognostic marker in patients with localized RCCs.     

Early Lung Adenocarcinoma in Mice: Micro-Computed Tomography Manifestations and Correlation with Pathology

Lung cancer is the most common fatal malignancy for both men and women and adenocarcinoma is the most common histologic type. Early diagnosis of lung cancer can significantly improve the survival rate of patients. This study aimed to investigate the micro-computed tomography (micro-CT) manifestations of early lung adenocarcinoma (LAC) in mice and to provide a new perspective for early clinical diagnosis. Early LAC models in 10 mice were established by subcutaneously injecting 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) solution. Micro-CT scan and multiple planar reconstruction (MPR) were used for mouse lungs. Micro-CT features of early LAC, especially the relationships between tumor and bronchus, were analyzed and correlated with pathology. Micro-CT findings of early LAC were divided into three types: non-solid (n = 8, 6%), partly solid (n = 85, 64%) and totally solid (n = 39, 30%). Tumor-bronchus relationships, which could be observed in 110 of 132(83%) LAC, were classified into four patterns: type I (n = 16, 15%), bronchus was truncated at the margin of the tumor; type II (n = 33, 30%), bronchus penetrated into the tumor with tapered narrowing and interruption; type III (n = 38, 35%), bronchus penetrated into the tumor with a patent and intact lumen; type IV (n = 99, 90%), bronchus ran at the border of the tumor with an intact or compressed lumen. Micro-CT manifestations of early LAC correlated well with pathological findings. Micro-CT can clearly demonstrate the features of mouse early LAC and bronchus-tumor relationships, and can also provide a new tool and perspective for the study of early LAC.