Currently, there are no molecular biomarkers for the early detection of breast cancer. This study focused on identifying surface proteins found on circulating extracellular vesicles (EVs) for ...detecting early-stage breast cancer.
Circulating EVs, isolated from the plasma of 10 patients with breast cancer (stages I and II) and 5 healthy controls, were analyzed using LC-MS/MS. Developmental endothelial locus-1 protein (Del-1) was selected as a candidate biomarker. Two different ELISAs were used to measure Del-1 in plasma samples from healthy controls (n= 81), patients with breast cancer (n= 269), breast cancer patients after surgical resection (n= 50), patients with benign breast tumors (n= 64), and patients with noncancerous diseases (n= 98) in two cohorts.
Plasma Del-1 levels were significantly higher (P< 0.0001) in patients with breast cancer than in all controls and returned to almost normal after tumor removal. The diagnostic accuracy of Del-1 was AUC, 0.961 95% confidence interval (CI), 0.924-0.983, sensitivity of 94.70%, and specificity of 86.36% in test cohort and 0.968 (0.933-0.988), 92.31%, and 86.62% in validation cohort for early-stage breast cancer by one type of ELISA. Furthermore, Del-1 maintained diagnostic accuracy for patients with early-stage breast cancer using the other type of ELISA 0.946 (0.905-0.972), 90.90%, and 77.14% in the test cohort; 0.943 (0.900-0.971), 89.23%, and 80.99% in the validation cohort.
Del-1 on circulating EVs is a promising marker to improve identification of patients with early-stage breast cancer and distinguish breast cancer from benign breast tumors and noncancerous diseases.
Abstract
Peritumoral edema (PE) of breast cancer at T2-weighted MR images is considered a poor prognostic sign and may represent the microenvironment surrounding the tumor; however, its ...histopathological mechanism remains unclear. The purpose of the study was to identify and describe detailed histopathological characteristics associated with PE at preoperative breast MRI in breast cancer patients. This retrospective study included breast cancer patients who had undergone preoperative MRI and surgery between January 2011 and December 2012. Two radiologists determined the presence of PE in consensus based on the signal intensity surrounding the tumor at T2-weighted images. The following detailed histopathological characteristics were reviewed by two breast pathologists using four-tiered grades; lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor budding. Tumor necrosis and tumor infiltrating lymphocytes were assessed using a percent scale. Baseline clinicopathological characteristics, including age and histologic grade, were collected. The associations between detailed histopathologic characteristics and PE were examined using multivariable logistic regression with odds ratio (OR) calculation. A total of 136 women (median age, 49 ± 9 years) were assessed; among them 34 (25.0%) had PE. After adjustment of baseline clinicopathological characteristics that were significantly associated with PE (age, T stage, N stage, histologic grade, and subtype, all
P
s < 0.05), lymphovascular invasion (
P
= 0.009), vessel ectasia (
P
= 0.021), stromal fibrosis (
P
= 0.024), growth pattern (
P
= 0.036), and tumor necrosis (
P
< 0.001) were also associated with PE. In comparison with patients without PE, patients with PE were more likely to have a higher degree of lymphovascular invasion (OR, 2.9), vessel ectasia (OR, 3.3), stromal fibrosis (OR, 2.5), lesser degree of infiltrative growth pattern (OR, 0.4), and higher portion of tumor necrosis (OR, 1.4). PE of breast cancer at MRI is associated with detailed histopathological characteristics of lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor necrosis, suggesting a relevance for tumor microenvironment.
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Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell ...transplantation (ASCT). The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population.
Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m(2) intravenous (IV) infusion on day 1 and bendamustine 120 mg/m(2) by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety.
Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients ≥ 65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%).
BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation.
The pathogenic variant (PV) or likely pathogenic variant (LPV) BRCA1/2 gene is strongly associated with hereditary breast or ovarian cancer. Therefore, it is important to screen blood relatives to ...establish preventive modalities and surveillance. This study evaluated the feasibility of targeted cascade genetic testing for family members of BRCA1/2 gene PV or LPV carriers. We screened 18 families for BRCA1/2 gene status via the conventional cascade genetic test (n = 9) and targeted cascade genetic test (n = 9), which targeted the exon region wherein the index patient showed PV or LPV. The pedigree and clinicopathologic characteristics were reviewed and analyzed. All index patients were diagnosed with breast cancer, while the third family members were all healthy. In the conventional cascade test group, 3 index patients and 3 family members had the BRCA1/2 gene PV or LPV. In the targeted cascade test group, 5 family members had same type of BRCA1/2 gene PV or LPV as their index patients. Two families had an identical string of BRCA1/2 gene PV or LPV. Although the targeted cascade genetic test cannot completely characterize the BRCA1/2 gene, it is sufficient for determining its PV or LPV status. This limited genetic test can be used for family members of PV or LPV carriers.
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We report on our experience of ultrasound (US)-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy (NAC) with clip and activated charcoal to guide axillary surgery ...in breast cancer patients.
Between November 2017 and May 2018, a dual-localization procedure was performed under US guidance for the most suspicious axillary nodes noted at initial staging (before NAC, with clip) and restaging (after NAC, with activated charcoal) in 28 cytologically proven node-positive breast cancer patients. Patients underwent axillary sampling or dissection, which involved removing not only the sentinel nodes (SNs), but also clipped nodes (CNs) and tattooed nodes (TNs). Success (or failure) rates of biopsies of SNs, CNs, and TNs and inter-nodal concordance rates were determined. Sensitivities for the individual and combined biopsies were calculated.
SN biopsy failed in four patients (14%), whereas the CN biopsy failed in one patient (4%). All TNs were identified in the surgical field. Concordance rates were 79% for CNs-TNs, 63% for CNs-SNs, and 58% for TNs-SNs. Sensitivity for SN, CN, and TN biopsy was 73%, 67%, and 67%, respectively. Sensitivity was 80% for any combination of biopsies (SN plus CN, SN plus TN, SN plus CN plus TN).
US-guided dual-localization of axillary nodes before and after NAC with clip and activated charcoal was a feasible approach that might facilitate more reliable nodal staging with less-invasive strategies in node-positive breast cancer patients.
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The surgical range of breast cancer that shows pathologic complete response (pCR) without change in microcalcifications after neoadjuvant chemotherapy (NAC) is controversial. This study examined ...whole breast specimens to evaluate the necessity of mastectomy in those cases. The viability of cancer cells around the residual microcalcification was assessed using prospectively collected breast samples to confirm the presence or absence of cancer cells. A total of 144 patients with breast cancer and diffuse microcalcifications were classified into the reduced mass with no change in residual microcalcification (RESMIN, n = 49) and non-RESMIN (n = 95) groups. Five specimens were prospectively evaluated to assess the presence of viable cancer cells around the microcalcification. Tumor responses to NAC were significantly better with high pCR rates in the RESMIN group (p = 0.005 and p = 0.002). The incidence of human epidermal growth factor receptor 2-positive and triple-negative breast cancers was significantly high in the RESMIN group (p = 0.007). Although five (10.2%) patients had locoregional recurrence in the RESMIN group, no local recurrence in the breast was reported. Although pCR was highly estimated, residual cancers, including ductal carcinoma in situ, remained in 80% cases. Therefore, given the weak scientific evidence available currently, complete removal of residual microcalcifications should be considered for oncologic safety.
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Purpose The incidence of depression and anxiety is higher in patients with breast cancer than in the general population. We evaluated the degree of depression and anxiety and investigated the changes ...in patients with breast cancer during the treatment period and short-term follow-up period. Methods Overall, 137 patients with breast cancer were evaluated using the Patient Health Questionnaire 9-item depression scale (PHQ-9) and Generalized Anxiety Disorder scale (GAD-7). The scales were developed as a web-based electronic patient-reported outcome measure, and serial results were assessed before the operation, after the operation, in the post-treatment period, and in the 6-month follow-up period after surgery. Results The degree of depression and anxiety increased during treatment and decreased at 6-month follow-up, even if there were no statistical differences among the four periods (PHQ-9: p = 0.128; GAD-7: p = 0.786). However, daily fatigue (PHQ-9 Q4) and insomnia (PHQ-9 Q3) were the most serious problems encountered during treatment and at 6-month follow-up, respectively. In the GAD-7, worrying too much (Q3) consistently showed the highest scores during the treatment and follow-up periods. Of the patients, 7 (5.11%) and 11 (8.03%) patients had a worsened state of depression and anxiety, respectively, after treatment compared with before treatment. Conclusion Most factors associated with depression and anxiety improved after treatment. However, factors such as insomnia and worrying too much still disturbed patients with breast cancer, even at 6-month follow-up. Therefore, serial assessment of depression and anxiety is necessary for such patients. Keywords: Breast cancer, Depression, Anxiety, Serial assessment
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Purpose: Vascular endothelial growth factor (VEGF) or its family may be considered to play an important role in lymphangiogenesis
and lymphatic tumor spread, thereby affecting prognosis of colorectal ...cancer. Accordingly, the present study analyzed VEGF gene polymorphisms and their effect on the prognosis for patients with colorectal cancer.
Experimental Design: Four hundred and forty-five consecutive patients with surgically treated colorectal adenocarcinoma were enrolled in the present
study. The genomic DNA was extracted from fresh colorectal tissue and three VEGF (−2578C>A, −634G>C, and +936C>T) gene polymorphisms were determined using a PCR/denaturing high-performance liquid chromatography
assay.
Results: Multivariate survival analysis showed that the survival for the patients with the −634 G/C genotype overall survival (OS):
hazard ratio (HR), 0.158; P < 0.001 or C/C genotype (OS: HR, 0.188; P < 0.001) were better than for the patients with the −634G/G genotype, whereas the +936 C/T genotype (OS: HR, 12.809; P < 0.001) or T/T genotype (OS: HR, 37.260; P < 0.001) was associated with a worse survival compared with the +936 C/C genotype. In haplotype analysis, the −2578A/−634G/+936T
haplotype exhibited a significantly worse survival when compared with the wild −2578C/−634G/+936C haplotype (OS: HR, 3.866;
P < 0.001).
Conclusions: VEGF gene polymorphisms were found to be an independent prognostic marker for patients with colorectal cancer. Accordingly, the
analysis of VEGF gene polymorphisms can help identify patient subgroups at high risk of a poor disease outcome.
In an attempt to develop the tumor-targeted nanocarrier which can surmount major challenges for in vivo application, we prepared tumor microenvironment-specific nanoparticles which can be ...sequentially activated at the extracellular and intracellular levels of tumor tissue by stepwise transformation. This polymeric nanoparticle has been prepared using an amphiphilic polyethyleneimine derivative with the pH-responsive charge-convertible moiety and the reduction-responsive crosslink. Once reaching the tumor tissue in vivo after systemic administration, the surface charge of this nanoparticle can be converted from negative to positive by recognizing the mildly acidic extracellular matrix of tumor, allowing for the enhanced cellular uptake. After the cellular uptake, the nanoparticle can selectively release the drug at the intracellular level since it has the chemically crosslinked core by the disulfide bond which is cleaved in intracellular reductive environment. The tumor microenvironment-specific nanoparticle shows the high tumor targetability and dramatically improves the antitumor efficacy of the drug.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Genome-wide association studies (GWASs) have already identified at least 22 common susceptibility loci associated with an increased risk of colorectal cancer (CRC). This study examined the ...relationship between these single nucleotide polymorphisms (SNPs) and the clinical outcomes of patients with colorectal cancer. Seven hundred seventy-six patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Twenty-two of the GWAS-identified SNPs were genotyped using a Sequenom MassARRAY. Among the 22 SNPs, two (rs1321311G>T in CDKN1A and rs10411210C>T in RHPN2) were significantly associated with the survival outcomes of CRC in a multivariate survival analysis. In a recessive model, the rs1321311 TT genotype (vs. GG + GT) and rs10411210 TT genotype (vs. CC + CT) were associated with a worse prognosis for disease-free survival (adjusted HR = 1.90; 95% confidence interval = 1.00-3.60; P = 0.050, adjusted HR = 1.94; 95% confidence interval = 1.05-3.57; P = 0.034, respectively) and overall survival (adjusted HR = 2.05; 95% confidence interval = 1.00-4.20; P = 0.049, adjusted HR = 2.06; 95% confidence interval = 1.05-4.05; P = 0.036, respectively). None of the other SNPs was significantly associated with any clinicopathologic features or survival. The present results suggest that the genetic variants of the CDKN1A (rs1321311) and RHPN2 (rs10411210) genes can be used as prognostic biomarkers for patients with surgically resected colorectal cancer.
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