The effectiveness of Wilms tumor screening in Beckwith–Wiedemann spectrum

Abstract

Purpose

It is well documented that patients with Beckwith–Wiedemann spectrum (BWS) have a significantly higher risk of developing Wilms tumor (WT) than the general population. There has been little research on the timing of WT diagnosis in BWS in regard to optimizing suggested screening protocols.

Methods

A literature search was performed to identify all reports of patients with BWS and WT. These data were combined with unpublished data from patients in the authors’ cohorts. Age at WT diagnosis was compared against data collected through the NIH Surveillance, Epidemiology, and End Results Program (SEER) registry.

Results

Patients with BWS had a significantly higher incidence of WT diagnoses between age 12 and 84 months compared to patients in the SEER registry. Patients with BWS and WT diagnosed through screening had significantly lower stages at diagnosis compared to patients with BWS that were not screened.

Conclusions

Screening until age 7 years is effective in detecting close to 95% of all WT in patients with BWS.

Variability of predictive markers (hormone receptors, Her2, Ki67) and intrinsic subtypes of breast cancer in four consecutive years 2015–2018

Abstract

Purpose

Accurate monitoring of predictive markers is of utmost importance as oncological treatment decisions almost entirely depend on these factors. In this study, we conducted a quality control assessment on hormone receptors, Her2 status, Ki67 Labelling Index (LI) and histological grading in breast cancer over 4 years (2015–2018).

Methods

Altogether 2214 consecutive breast cancer cases were included. Data on estrogen (ER) and progesterone receptors (PR), Her2 and Ki67, were available in all cases and were tested mostly on preoperative biopsies, in selected cases on postoperative surgical specimens. ER, PR, and Ki67 were assessed with immunohistochemistry (IHC), Her2 status with IHC and fluorescence in situ hybridization.

Results

ER/PR were positive in 74–79% cases, ER/PR/Her2 negative in 6.16–10.70% and Her2 positive in 11.49–13.88%/year. Ki67 had median values as 15–17.5% in ER/PR-positive cases, 55–60% in triple-negative cases and 30–32.50% in Her2-positive cases. Histological grading distribution for well (G1), moderately (G2) and poorly (G3) differentiated carcinomas was 15.8–19.1% for G1, 54.2–54.8% for G2 and 21.7–23.7% for G3 cases. Variation in yearly distributions was not significant in any of these markers.

Conclusions

Predictive markers displayed a yearly similar distribution in breast cancer cases independently of grading or of intrinsic subtypes. These results point to a qualitative high performance of predictive marker assessment in breast cancer, corresponding to expected on average positivity rate per marker and per year. It is recommended to monitor positivity rate of ER, PR, Ki67 and Her2 yearly or periodically to comply with quality assurance requirements.

Circular RNAs: pivotal molecular regulators and novel diagnostic and prognostic biomarkers in non-small cell lung cancer

Abstract

Purpose

Circular RNAs (circRNAs), a large class of non-coding RNAs with covalently closed-loop structures, are abundant, stable, conserved, and have tissue and developmental-stage specificities. The biological functions of circRNAs are varied. Moreover, circRNAs participate in various pathological processes, especially in multiple cancers. Lung cancer is the most frequent malignant tumor worldwide. Many studies have suggested that circRNAs are pivotal in non-small cell lung cancer. This article aims to provide a retrospective review of the latest research on the functions of circRNAs in non-small cell lung cancer. In particular, we focus our discussion on the role of circRNAs in cell-cycle regulation and the epithelial–mesenchymal transition, and also discuss the known regulatory molecular mechanisms of circRNAs in non-small cell lung cancer.

Methods

We reviewed the literature on circRNAs and non-small cell lung cancer from PubMed databases. Specifically, we focused on the roles and mechanisms of circRNAs in regulating the cell cycle and the epithelial–mesenchymal transition.

Results

Dysregulation of circRNAs is closely correlated with proliferation, migration, and invasion of non-small cell lung cancer, especially in terms of modulating cell-cycle regulation and the epithelial–mesenchymal transition.

Conclusion

Taken together, circRNAs have potential as biomarkers for the diagnosis, prognosis, and treatment of non-small cell lung cancer.

Differential expression of p52 and RelB proteins in the metastatic and non-metastatic groups of uveal melanoma with patient outcome

Abstract

Purpose

Non-canonical NFκB (NC-NFκB) pathway plays an influential role in metastasis, which promotes cancer proliferation and progression. The aim of the study was to examine the expression of NC-NFκB proteins and their correlation with clinicopathological factors associated with metastatic cases of uveal melanoma (UM) and with the patient outcome.

Method

Expression of NC-NFκB proteins (p52, RelB, and co-expression of p52/RelB) was evaluated in 75 formalin-fixed cases of uveal melanoma by immunohistochemistry. Validation of nuclear immunoreactivity was done by western blotting. Transcriptional status of NC-NFκB genes was assessed in 60 fresh tumor tissues by quantitative real-time PCR. Co-immunoprecipitation was performed to determine the presence of native p52/RelB heterodimer in UM. Prognostic relevance was determined using Cox proportional hazard and Kaplan–Meier methods.

Results

Immunohistochemical expression of p52, RelB, and their co-expression was observed in 81%, 68.7%, 56.2% of metastatic cases, respectively, while their expression was seen only in 38%, 33% and 30% of non-metastatic cases. Loss of BAP-1 was correlated with expression of p52 and RelB proteins. Co-immunoprecipitation assay confirmed the putative interaction of p52 with RelB protein in metastatic cases of uveal melanoma. Co-expression of p52/RelB and expression of p52 protein was significantly correlated with decreased metastasis-free survival (MFS) (p = 0.004; p = 0.002) and overall survival (OS) (p = 0.004; p = 0.032), while the RelB expression only correlated with reduced MFS (p = 0.003).

Conclusion

Our data showed that non-canonical NFκB proteins were significantly higher in metastatic cases and associated with poor outcome of the patients. Furthermore, the p52 protein could be used as a potential therapeutic biomarker for metastatic cases in uveal melanoma.

Vimentin expression in circulating tumor cells (CTCs) associated with liver metastases predicts poor progression-free survival in patients with advanced lung cancer

Abstract

Objective

To investigate the presence of vimentin expression in CTCs and its clinical relevance in patients with advanced lung cancer.

Methods

Peripheral blood was obtained from 61 treatment-naive patients with advanced lung cancer. Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform was applied to identify, enumerate and characterize CTCs based on cell size, aneuploidy of chromosome 8 (Chr8) and vimentin expression. Quantification and analysis of CTCs were performed on patients before chemotherapy administration and after two cycles of therapy.

Results

Before treatment, CTCs were detected in 60 (98.4%) patients, small cell CTCs (≤ 5 µm of WBCs) accounted for 52.8% of the absolute CTCs number, while 12 (19.7%) of the included patients had detectable vimentin-positive CTCs (vim⁺ CTCs). Liver metastases were reported in 7 (11.5%) patients and were significantly correlated to the presence of Vim⁺ CTCs (p = 0.002), with a high positivity rate of 71.4% (5/7). Vim⁺ CTCs were mostly in small cell size and Chr8 aneuploidy (77.0% and 82.05%, respectively). Baseline small cell CTCs ≥ 2/6 ml, triploid CTCs ≥ 2/6 ml, Vim⁺ CTCs ≥ 1/6 ml were found to significantly correlate with poor progression-free survival (PFS) (p = 0.017, p = 0.009 and p = 0.001, respectively). After adjusting for clinically significant factors, baseline Vim⁺ CTCs ≥ 1/6 ml was the only independent predictor of poor PFS [hazard ratio (HR):2.756, 95% confidence interval (CI): 1.239–6.131; p = 0.013].

Conclusions

This study demonstrates an important morphologic, karyotypic and phenotypic CTCs heterogeneity in advanced lung cancer patients. The majority of Vim⁺ CTCs are in small size and Chr8 aneuploidy. Baseline presence of Vim⁺ CTCs is correlated with liver metastases and may help predict poor PFS.

Are shape morphologies associated with survival? A potential shape-based biomarker predicting survival in lung cancer

Abstract

Purpose

Imaging biomarkers (IBMs) are increasingly investigated as prognostic indicators. IBMs might be capable of assisting treatment selection by providing useful insights into tumor-specific factors in a non-invasive manner.

Methods

We investigated six three-dimensional shape-based IBMs: eccentricities between (I) intermediate–major axis (E_imaj), (II) intermediate–minor axis (E_imin), (III) major–minor axis (E_mj-mn) and volumetric index of (I) sphericity (VioS), (II) flattening (VioF), (III) elongating (VioE). Additionally, we investigated previously established two-dimensional shape IBMs: eccentricity (E), index of sphericity (IoS), and minor-to-major axis length (Mn_Mj). IBMs were compared in terms of their predictive performance for 5-year overall survival in two independent cohorts of patients with lung cancer. Cohort 1 received surgical excision, while cohort 2 received radiation therapy alone or chemo-radiation therapy. Univariate and multivariate survival analyses were performed. Correlations with clinical parameters were evaluated using analysis of variance. IBM reproducibility was assessed using concordance correlation coefficients (CCCs).

Results

E was associated with reduced survival in cohort 1 (hazard ratio [HR]: 0.664). E_imin and VioF were associated with reduced survival in cohort 2 (HR 1.477 and 1.701). VioS was associated with reduced survival in cohorts 1 and 2 (HR 1.758 and 1.472). Spherical tumors correlated with shorter survival durations than did irregular tumors (median survival difference: 1.21 and 0.35 years in cohorts 1 and 2, respectively). VioS was a significant predictor of survival in multivariate analyses of both cohorts. All IBMs showed good reproducibility (CCC ranged between 0.86–0.98).

Conclusions

In both investigated cohorts, VioS successfully linked shape morphology to patient survival.

The efficacy and toxicity of the CHG priming regimen (low-dose cytarabine, homoharringtonine, and G-CSF) in higher risk MDS patients relapsed or refractory to decitabine

Abstract

Purpose

Myelodysplastic syndromes (MDSs) refractory or relapsed after hypomethylating agents (HMAs) remain a therapeutic challenge. The CHG regimen has been demonstrated to be effective in initially treating higher risk MDS. The current study evaluated the efficacy and toxicity of the CHG regimen in patients who were resistant to decitabine.

Methods

Patients with higher risk MDS relapsed or refractory to decitabine were enrolled in this study. Each patient received the CHG regimen (cytarabine (25 mg/day, days 1–14) and homoharringtonine (1 mg/day, days 1–14) intravenously with G-CSF (300 μg/day) subcutaneously from day 0 until neutrophil count recovery to 2.0 × 10⁹ cells/L). Next gene sequencing with a 31-gene panel was carried out in patients.

Results

Thirty-three patients were enrolled, including 12 relapsed and 21 refractory cases. The overall response rate (ORR) was 39.4% (13 of 33), with 9 (27.3%) achieving complete remission (CR), 2 having marrow CR (mCR), and 2 achieving partial remission (PR). The CR rate was higher in patients harboring fewer gene mutations (0–1) (55.6%) than in those with more gene mutations (> 1) (12.5%) (p = 0.021). The median overall survival (OS) of the 33 patients was 7.0 months. Patients who achieved a response had significantly longer survival times than were found in those without a response (21.0 M vs. 4.0 M, p < 0.0001). The regimen was endurable for most of the patients.

Conclusions

The CHG priming regimen provided a safe and effective salvage regimen for higher risk MDS patients who were resistant to decitabine. Further studies involving larger samples will be needed. Clinical trial No. ChiCTR-ONC-11001501.

Tumor-infiltrating lymphocytes and CD8 + T cells predict survival of triple-negative breast cancer

Abstract

Purpose

Tumor inflammatory response was evaluated as a prognostic feature in triple-negative breast cancer (TNBC) and compared with the clinical prognosticators of breast cancer and selected biomarkers of cancer cell proliferation.

Methods

TNBC patients (n = 179) with complete clinical data and up to 18-year follow-up were obtained from Auria biobank, Turku University Hospital, Turku, Finland. Tumor-infiltrating lymphocytes (TILs) and several subtypes of inflammatory cells detected with immunohistochemistry were evaluated in different tumor compartments in full tissue sections and tissue microarrays.

Results

Deficiency of stromal TILs and low number of CD8⁺ T cells independently predicted mortality in TNBC (HR 2.4, p 0.02 and HR 2.1, p 0.02, respectively). Each 10% decrease in stromal TILs resulted in 20% increased risk of mortality. An average of 13.2-year survival difference was observed between the majority (> 75%) of patients with low (< 14% of TILs) vs high (≥ 14% of TILs) frequency of CD8⁺ T cells. The prognostic value of TILs and CD8⁺ T cells varied when evaluated in different tumor compartments. TILs and CD8⁺ T cells were significantly associated with Securin and Separase, essential regulators of metaphase–anaphase transition of the cell cycle.

Discussion

TILs and CD8⁺ T cells provide additional prognostic value to the established clinical prognostic markers in TNBC. However, possible clinical applications would still benefit from systematic guidelines for evaluating tumor inflammatory response. Increasing understanding on the interactions between the regulation of cancer cell proliferation and inflammatory response may in future advance treatment of TNBC.

Radiomics for diagnosis of dual-phenotype hepatocellular carcinoma using Gd-EOB-DTPA-enhanced MRI and patient prognosis

Abstract

Purpose

To describe the clinical characteristics and outcomes of patients with dual-phenotype hepatocellular carcinoma (DPHCC) and investigate the use of radiomics to establish an image-based signature for preoperative differential diagnosis.

Methods

This study included 50 patients with a postoperative pathological diagnosis of DPHCC (observation group) and 50 patients with CK7- and CK19-negative HCC (control group) who attended our hospital between January 2015 and December 2018. All patients underwent Gd-EOB-DTPA-enhanced MRI within 1 month before surgery. Arterial phase (AP), portal venous phase (PVP), delayed phase (DP) and hepatobiliary phase (HBP) images were transferred into a radiomics platform. Volumes of interest covered the whole tumor. The dimensionality of the radiomics features were reduced using LASSO. Four classifiers, including multi-layer perceptron (MLP), support vector machines (SVM), logistic regression (LR) and K-nearest neighbor (KNN) were used to distinguish DPHCC from CK7- and CK19-negative HCC. Kaplan–Meier survival analysis was used to assess 1-year disease-free survival (DFS) and overall survival (OS) in the observation and control groups.

Results

The best preoperative diagnostic power for DPHCC will likely be derived from a combination of different phases and classifiers. The sensitivity, specificity and accuracy of LR in PVP (0.740, 0.780, 0.766), DP (0.893, 0.700, 0.798), HBP (0.800, 0.720, 0.756) and MLP in PVP (0.880, 0.720, 0.798) were better performance. The 1-year DFS and OS of the patients in the observation group were 69% and 78%, respectively. The 1-year DFS and OS of the patients in the control group were 83% and 85%, respectively. Kaplan–Meier survival analysis showed no statistical difference in DFS and OS between groups (P = 0.231 and 0.326), but DFS and OS were numerically lower in patients with DPHCC.

Conclusion

The radiomics features extracted from Gd-EOB-DTPA-enhanced MR images can be used to diagnose preoperative DPHCC. DPHCC is more likely to recur and cause death than HCC, suggesting that active postoperative management of patients with DPHCC is required.