Histogram analysis of quantitative parameters from synthetic MRI: correlations with prognostic factors in nasopharyngeal carcinoma.

OBJECTIVES: To evaluate the correlation between histogram parameters derived from synthetic magnetic resonance imaging (SyMRI) and prognostically relevant factors in nasopharyngeal carcinoma (NPC). METHODS: Fifty-nine consecutive NPC patients were prospectively enrolled. Quantitative parameters (T1, T2, and proton density (PD)) were obtained by outlining the three-dimensional volume of interest (VOI) of all lesions. Then, histogram analysis of these quantitative parameters was performed and the correlations with prognostically relevant factors were assessed. By choosing appropriate cutoff, we divided the sample into two groups. Independent-samples t test/Mann-Whitney U test was used and ROC curve analysis was further processed. RESULTS: Histogram parameters of the T1, T2, and PD maps were positively correlated with the Ki-67 expression levels, and PD_mean was the most representative parameter (AUC: 0.861). The PD map exhibited good performance in differentiating epidermal growth factor receptor (EGFR) expression levels (AUC: 0.706~0.732) and histological type (AUC: 0.650~0.660). T2_minimum was highest correlated with Epstein-Barr virus (EBV) DNA levels (r = - 0.419), and PD_75th percentile exhibited the highest performance in distinguishing positive and negative EBV DNA groups (AUC: 0.721). T1_minimum was statistically correlated with EA-IgA expression (r = - 0.313). Additionally, several histogram parameters were negatively correlated with tumor stage (T stage: r = - 0.259 ~ - 0.301; N stage: r = - 0.348 ~ - 0.456; clinical stage: r = - 0.419). CONCLUSIONS: Histogram parameters of SyMRI could reflect tissue intrinsic characteristics and showed potential value in assessing the Ki-67 and EGFR expression levels, histological type, EBV DNA level, EA-IgA, and tumor stage. KEY POINTS: • SyMRI combined with histogram analysis may help clinicians to assess different prognostic factor statuses in nasopharyngeal carcinoma. • The PD map exhibited good discriminating performance in the Ki-67 and EGFR expression levels. • Histogram parameters of SyMRI were negatively correlated with EBV-related blood biomarkers and TNM stage.

DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer.

BACKGROUND: MicroRNAs act as tumor suppressors or oncogenes. The pathological roles of miRNAs in gastric tumorigenesis are largely unknown. Although miR-10b was identified as an miRNA deregulator expressed in gastric cancer (GC), there also exists some debate on whether miR-10b is acting as tumor suppressor or oncogene in GC. METHODS: Quantitative RT-PCR was employed to investigate the level of miR-10b in GC tissues and matched adjacent normal tissues (n = 100). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate the biological effects of miR-10b. Because silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorigenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-10b were subsequently examined by quantitative RT-PCR. Furthermore, the methylation status of the CpG island upstream of miR-10b was analyzed by methylation-specific PCR in GC tissues (n = 29). RESULTS: We showed here that miR-10b was significantly downregulated in GC cell lines and tissues as demonstrated by quantitative real-time PCR. Overexpression of miR-10b in MGC-803 and HGC-27 dramatically suppressed cell proliferation, migration, invasion, and induced apoptosis. Moreover, we demonstrated that T-cell lymphoma invasion and metastasis (Tiam1) was a target of miR-10b. Furthermore, 5-aza-2'-deoxycytidine and trichostain A increased miR-10b expression, and the methylation level was high in the CpG islands upstream of miR-10b gene. CONCLUSIONS: Taken together, these findings suggest that miR-10b may function as a novel tumor suppressor and is partially silenced by DNA hypermethylation in GC.

Development and validation of nomograms for predicting axillary non-SLN metastases in breast cancer patients: A retrospective analysis.

Purpose: The aim of this study was to develop a nomogram for predicting positive non-sentinel lymph nodes (non-SLNs) in positive SLN breast cancer patients and validate the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram for non-SLN metastasis in Chinese patients. Methods: The pathological features of 2,561 breast cancer patients were retrospectively reviewed, and the patients were divided into training and validation cohorts. Positive non-SLN predictors were identified using univariate and multivariate analyses and used to construct the nomogram. In patients with positive SLNs, the MSKCC nomogram was used to calculate the probability of non-SLN metastasis. The area under the receiver operating characteristic curve (AUC) was calculated to assess the accuracy of this model and the MSKCC nomogram. Results: According to multivariate logistic regression analysis, the number of positive and negative SLNs, tumor stage, lymphovascular invasion, perineural invasion, and extracapsular extension were independent predictive factors for non-SLN metastasis and were selected to establish the nomogram for predicting positive non-SLNs. This nomogram performed favorably in predicting positive non-SLNs, with AUCs of 0.765 and 0.741 for the training and validation cohorts, respectively. The MSKCC nomogram predicted non-SLN metastasis with an AUC of 0.755. Conclusion: A nomogram was developed and validated to assist clinicians in evaluating the likelihood of positive non-SLN. For Chinese patients with a known ER status before surgery, the MSKCC nomogram can be used to predict non-SLN metastases.

Histogram analysis of synthetic magnetic resonance imaging: Correlations with histopathological factors in head and neck squamous cell carcinoma.

PURPOSE: To analyse the association between histogram parameters derived from synthetic MRI (SyMRI) and different histopathological factors in head and neck squamous cell carcinoma (HNSCC). METHOD: Sixty-one patients with histologically proven primary HNSCC were prospectively enrolled. The correlations between histogram parameters of SyMRI (T1, T2 and proton density (PD) maps) and histopathological factors were analysed using Spearman analysis. The Mann-Whitney U test or Student's t test was utilized to differentiate histological grades and human papillomavirus (HPV) status. The ROC curves and leave-one-out cross-validation (LOOCV) were used to evaluate the differentiation performance. Bootstrapping was applied to avoid overfitting. RESULTS: Several histogram parameters were associated with histological grade: T1 map (r = 0.291) and PD map (r = 0.294 - 0.382/-0.343), and PD_75th Percentile showed the highest differentiation performance (AUC: 0.721 (ROC) and 0.719 (LOOCV)). Moderately negative correlations were found between p16 status and the histogram parameters: T1 map (r = -0.587 - -0.390), T2 map (r = -0.649 - -0.357) and PD map (r = -0.537 - -0.338). In differentiating HPV infection, Entropy was the most discriminative parameter in each map and T2_Entropy showed the highest diagnostic performance (AUC: 0.851 [ROC] and 0.851 [LOOCV]). Additionally, several histogram parameters were correlated with Ki-67 (r = -0.379/-0.397), epidermal growth factor receptor (EGFR) (r = 0.318/0.322) status and p53 (r = 0.452 - 0.665/-0.607) status. CONCLUSIONS: Histogram parameters derived from SyMRI may serve as a potential biomarker for discriminating relevant histopathological features, including histological differentiation grade, HPV infection, Ki-67, EGFR and p53 statuses.

Assessment of the expression pattern of HER2 and its correlation with HER2-targeting antibody-drug conjugate therapy in urothelial cancer.

Background: Human epidermal growth factor receptor 2 (HER2) overexpression is related to anti-HER2 therapy in many tumors. RC48- antibody-drug conjugate (ADC) has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (UC). The characteristic expression and scoring systems of HER2 are nonexistent in UC. We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC. Methods: A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2, respectively, from March 2009 to December 2018. The patients in cohort 2 were enrolled in a phase II study of RC48-ADC. UC samples were tested for HER2 status using immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC. Results: The HER2-positive (IHC 2+ or 3+) rate was 24.1% (33/137). In HER2 IHC 2+ or 3+ patients, the HER2 gene amplification rate was 31% (13/42). The objective response rates (ORRs) in RC48-ADC-treated patients with IHC 3+, IHC 2+ and FISH+, IHC 2+ and FISH- were 58.8%, 66.7% and 40%, respectively. The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification (61.5% vs. 44.8%, P = 0.059). The heterogeneity of HER2 expression in the primary tumor was 55.5% (15/27), and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity. Conclusions: IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy. There was a trend toward a better benefit for patients with HER2 amplification, and tumor heterogeneity did not influence the drug efficacy.

Metastatic adenocarcinoma to the breast from the lung simulates primary breast carcinoma-a clinicopathologic study.

BACKGROUND: Rare extra-mammary metastases of adenocarcinoma to the breast closely mimic primary invasive breast carcinoma (PBC), and specifically without an aware of clinical history, pose a difficult diagnostic issue. METHODS: With the aim to improve differential diagnosis of lung adenocarcinoma metastasis and primary breast carcinoma in the breast, we retrieved 41 breast metastases from lung adenocarcinoma, seven of which were from the archived pathologic files of Cancer Hospital, Chinese Academy of Medical Science (CHCAMS) between 2001 and 2019, and the other 34 cases were collected from the published literatures. Clinicopathological features were collected and analyzed for differential diagnosis of primary lung malignancy, triple negative breast pathology and breast lesions without ipsilateral axillary lymphadenopathy or with contralateral axillary lymphadenopathy. Supplementary breast (GCDFP-15, or GATA-3) and lung-lineage (TTF-1) immunostaining plus genetic alternation analysis were also recorded and analyzed. RESULTS: Among the 41 cases, there were 37 females and four males, with a median age of 63 (range, 40-81) years at diagnosis of the breast lesion. Twenty-four cases (58.5%, 24/41) were detected metachronously to the counterpart of the lung. Strikingly, 13 cases (31.7%, 13/41) were initially misdiagnosed as primary breast cancer, and differential diagnostic factors were compared and analyzed between the correct and misdiagnosed cases, among which a documentation of lung cancer history showed significant difference. Pathologist initially misinterpreted six cases (46.2%, 6/13) as PBC on needle biopsy of breast mass with an unknown lung cancer history. The clinical diagnosis was considered two cases (15.4%, 2/13) to be either a primary breast tumor with lung and pleural metastasis or two synchronous primary tumors. Three cases (23.1%, 3/13) were initially misinterpreted as PBC by breast ultrasonography. TTF-1 immunostaining was found to be critical for a correct diagnosis of metastatic lesion (84.6%, 11/13) from the initially misdiagnosed cases as PBC. CONCLUSIONS: Metastatic lung adenocarcinoma to the breast, although rare, should be considered in the differential diagnosis of primary breast carcinoma, especially when the breast lesion exhibits as a "triple-negative invasive carcinoma". A documented lung cancer history combined with the clinicoradiological assessment and pathological evaluation are essential to make a correct differential diagnosis. TTF-1 immunostaining is crucial in approaching the diagnosis.

EGFR mutation is positively correlated with C-Met protein expression: a study of 446 resected lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation and mesenchymal-epithelial transition factor (C-Met) amplification are known factors for primary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in advanced primary lung adenocarcinoma. However, little is known about the relationship between high expression of C-Met protein and primary EGFR mutation. This research aims to investigate the correlation between EGFR mutation and C-Met protein expression in resected primary lung adenocarcinoma. METHODS: Four hundred and forty-six surgically resected lung adenocarcinoma between 2013-2015 were collected for EGFR mutation analysis by real-time PCR (RT-PCR) and C-Met protein expression by immunohistochemistry (IHC). The relationship between the two biomarkers and clinicopathological features were analyzed. RESULTS: The positive rate of EGFR mutation and C-Met protein expression were 66.4% (296/446) and 96.4% (430/446). EGFR mutation was significantly higher in female, mild to moderate differentiation, lepidic, acinar and papillary histological subtypes (P<0.05). C-Met expression was more prominent in female than male (201 vs. 123, 45.07% vs. 27.57%). EGFR mutation was found positively correlated with C-Met protein expression (P<0.05). CONCLUSIONS: EGFR mutation and C-Met protein expression are prone to have a female predominance, and are positively correlated with each other in surgically resected lung adenocarcinoma specimens. This finding may be beneficial in explaining some of the resistance mechanisms of EGFR-mutated cases, which is worth further study.

Safety and efficacy of endoscopic submucosal dissection for metachronous early cancer or precancerous lesions emerging at the anastomotic site after curative surgical resection of colorectal cancer.

BACKGROUND: The incidence of metachronous early cancer or precancerous lesions (MECPL) emerging at the anastomotic site (AS) after curative surgical resection of colorectal cancer (CRC) is so low that few study have been conducted to explore the clinical characteristics, diagnosis and treatment of these lesions. Endoscopic submucosal dissection (ESD) is technically difficult for these lesions because of the presence of severe fibrosis and AS. The aim of this study was to explore the safety and efficacy of ESD for MECPL emerging at the AS after curative surgical resection of CRC. METHODS: The data used in the analysis were retrospectively collected from CICAMS in Beijing China between January 2013 and May 2019 and from all the patients who underwent ESD for MECPL emerging at the AS after curative surgical resection of CRC. The rates of en bloc resection (ER), complete resection (CR), curative resection (CuR) and incidence of complications were analyzed by SPSS software. RESULTS: A total of 11 patients were included. The rates of ER, CR and CuR were 63.6%, 54.5% and 54.5%, respectively. No additional surgery was performed, and no recurrences were found. Bleeding occurred in only one case and there was no perforation after the operation. CONCLUSIONS: Overall, ESD is safe and effective in the treatment of MECPL emerging at the AS after curative surgical resection of CRC. Especially for patients with anastomotic recurrence close to anal margin, this method can avoid the risks of reoperation and improve the rate of anal preservation.

MicroRNA-219-2-3p functions as a tumor suppressor in gastric cancer and is regulated by DNA methylation.

BACKGROUND AIMS: Gastric cancer is the most frequent gastrointestinal tumor in adults and is the most lethal form of human cancer. Despite of the improvements in treatments, the underlying mechanism of gastric carcinogenesis is not well known. To define novel modulators that regulate susceptibility to tumorgenesis, we focused on miR-219-2-3p. METHODS: Quantitative RT-PCR was employed to investigate the level of miR-219-2-3p in gastric cancer (GC) tissues (n = 113) and their matched adjacent normal tissues (n = 113). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate biological effects of miR-219-2-3p. Since silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorgenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-219-2-3p were subsequently examined by quantitative RT-PCR. Finally, the methylation status of CpG island upstream of miR-219-2-3p was analyzed by methylation-specific PCR in GC tissues (n = 22). RESULTS: miR-219-2-3p was down-regulated in GC and cell lines. In addition, the experiments documented the lower expression of miR-219-2-3p in GC specimens with higher grade and later stage tumors. Meanwhile, miR-219-2-3p exerted antiproliferative, proapoptotic, and antimetastatic roles and reduced levels of p-ERK1/2 in GC cells. Furthermore, 5-aza-2'-deoxycytidine and trichostatin A increased the expression (~2 fold) of miR-219-2-3p in GC cells. By methylation-specific PCR, DNA methylation in the upstream region of miR-219-2-3p was detected in both adjacent normal tissues and cancer tissues. As expected, the methylation level was considerably higher in the miR-219-2-3p down-regulated group than up-regulated group. CONCLUSIONS: miR-219-2-3p is potentially involved in gastric cancer progression and metastasis by regulating ERK1/2-related signal pathways, which may provide a novel therapeutic strategy for treatment of gastric cancer. Methylation mechanism may be involved in modulating the expression level of miR-219-2-3p in gastric cancer.