The O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and clinical outcomes of Ewing sarcoma patients treated with irinotecan and temozolomide.

Background: There remains an unmet need to identify molecular biomarkers in Ewing sarcoma (ES). We sought to assess the influence of the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation on response and progression-free survival (PFS) following initiation of irinotecan and temozolomide (IT), PFS following initiation of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC-IE), and overall survival (OS). Materials and methods: Data of advanced ES patients, treated with IT were retrospectively collected. Patients were required to have progression after prior VDC-IE. MGMT promoter methylation was assessed on non-decalcified Formalin-fixed paraffin embedded (FFPE) tissue using methylation sensitive restriction enzyme-quantitative PCR (MSRE-qPCR). Survival was estimated by the Kaplan-Meier method. Results: A total of 20 ES patients underwent MGMT promoter methylation testing, and were eligible for analysis. Five patients (25%) had methylated MGMT, whereas the remaining (15; 75%) had unmethylated promoter. Five (25%) had objective response to IT, with no observed difference by promoter methylation (p = 0.76). Median PFS from initiation of IT for methylated vs. unmethylated MGMT patients was 4.9 and 1.2 months, respectively, p = 0.69. Median PFS from date of initiation of VDC-IE was significantly superior in the methylated group; 27.8 vs. 8.6 months, p = 0.034. Median OS was superior but not statistically significant in the methylated group. Conclusion: MGMT-promoter methylation did not correlate with clinical activity or outcomes following the IT regimen for advanced ES. However, methylated MGMT predicted significantly superior PFS following initiation of the standard VDC-IE protocol.

Effect of level of hormone-receptor expression on treatment outcomes of "triple-positive" early-stage breast cancer.

PURPOSE: Breast cancer that overexpresses the human epidermal growth factor receptor-2 (HER2) and both estrogen (ER) and progesterone (PR) receptors is recently recognized as a subtype (triple-positive) with distinctive behavior and response to treatment. In this study, we investigate the treatment outcomes and the beneficial effect of anti-HER2 treatment in relation to level of hormone-receptor (HR) expression. METHODS: Consecutive breast cancer patients with triple-positive disease, diagnosed, treated and followed at our institution between 2006 and 2016 were enrolled. Disease-free survival (DFS) was studied in relation to the level of HR-positivity. RESULTS: During the study period, a total of 312 were enrolled; median age (range) was 47 (20-83) years. Fifty (16.0%) of the enrolled patients received adjuvant chemotherapy without trastuzumab (cohort A). All remaining patients were treated with both chemotherapy and trastuzumab and were divided into two groups: Cohort B with both ER and PR scores ≥ 50% (n = 130, 41.7%) and Cohort C with ER and/or PR < 50% (n = 132, 42.3%). After a median follow-up of 47 months, 14 (28.0%), 30 (23.1%) and 20 (15.2%) patients in cohorts A, B, and C had an event in a form of local/system relapse or death while disease-free. The estimated 5-year DFS was 56.2%, 75.4%, and 80.8%, respectively, and at 7 year was 56.2%, 67.1%, and 78.0%, respectively (p < 0.001). CONCLUSIONS: HER2-positive tumors are not homogeneous; stronger ER/PR co-expression may weaken the beneficial effect of anti-HER2 therapy. Such findings may have potential implication on modifying anti-HER2 treatment based on the strength of HR expression.

Multi-Gene Panel Testing for Hereditary Cancer Predisposition Among Patients Sixty-Five Years and Above Diagnosed With Breast Cancer.

Background: The availability and affordability of germline genetic testing (GGT) has resulted in a broader utilization in daily clinical practice. However, adherence to testing guidelines is low, especially among older patients, where testing is often not offered. Methods: In this study, consecutive, newly diagnosed patients with breast cancer (BC) aged ≥ 65 years and eligible for GGT, as per the National Comprehensive Cancer Network (NCCN) guidelines (version 1, 2021), were invited to participate, from March 2021 to December 2022. Patients were offered a restricted (two- or 20-gene panel), or an expanded 84-gene panel. Results: During the study period, 204 patients were enrolled. The mean (standard deviation (SD)) age at BC diagnosis was 70.5 (5.13) years, ranging 65 - 81 years. All patients were Arab and the majority were Jordanian. The majority (n = 188, 92.2%) had early-stage (stages I and II) disease. One hundred three (50.5%) patients were tested with a restricted two-gene (n = 13) or 20-gene (n = 90) panel, while the remaining 101 (49.5%) patients had an expanded 84-gene panel. Family history of close blood relative(s) with BC was the most common indication for testing (n = 110, 53.9%). Among the entire study cohort, 22 (10.8%) had pathogenic/likely pathogenic germline variants (PGVs) and another 97 (47.5%) had ≥ 1 variants of uncertain significance (VUS). PGV rates were significantly higher with the expanded panel (14.9%) compared to restricted testing (6.8%) (P = 0.032). Similarly, VUS rates were significantly higher with the expanded panel (64.4%) compared to the restricted panel (31.1%) (P < 0.001). The most prevalent genes with PGVs were BRCA1/2 (31.3% of all PGV-positive patients), CHEK2 (23.1%) and ATM (19.2%). Conclusion: GGT should not be overlooked in older BC patients, as this study demonstrates that > 10% of patients have PGVs, largely in potentially actionable genes.

Wet gravity separation and froth floatation techniques for rare earth elements beneficiation from monazite ore in Jordan.

The demand for extracting Rare Earth Elements (REEs) from their deposits is growing significantly around the world since they are essential in many mature and growing industries. This study investigated the elemental and mineralogical composition of a Bulk sample and its potential for rare earth elements (REEs) beneficiation through Wet Gravity Separation (WGS) and Froth Floatation (FF) processes. Results obtained from WDXRF analysis showed that Si, Hf, Ti, Fe and Zr were the major elements present in the Bulk sample, with SiO2 accounting for 64.79 wt%. The TREOs concentration was around 0.90 wt%, dominated by Ce, La, and Nd, with other REEs present in smaller concentrations. XRD analysis indicated that Quartz was the major mineral present in the Bulk sample. WGS and FF were then used to beneficiate the oxides CeO2, La2O3, Nd2O3, Pr6O11, Y2O3, Gd2O3, and Sm2O3. Results showed significant concentration increases of these elements in the WGS concentrate, with high grade and good recoveries achieved for Ce, La, and Nd. Overall, the study provides insights into the potential of WGS and FF as a beneficiation technique for REEs in monazite ore.

The Impact of Graft CD3+ T-Cell Dose on the Outcome of T-Cell Replete Human Leukocyte Antigen-Mismatched Allogeneic Hematopoietic Peripheral Blood Stem Cells Transplantation.

Background: Data on whether the graft CD3-positive (CD3+) T-cell dose in T-cell-replete human leukocyte antigen (HLA)-mismatched allogeneic hematopoietic peripheral blood stem cells transplantation (PBSCT) influences post-transplant outcomes are controversial. Methods: Using King Hussein Cancer Center (KHCC) Blood and Marrow Transplantation (BMT) Registry database, 52 adult subjects, receiving the first T-cell-replete HLA-mismatched allogeneic hematopoietic PBSCT for acute leukemias or myelodysplastic syndrome, were identified, from January 2017 to December 2020. The cutoff value of graft CD3+ T-cell dose was identified using the receiver operating characteristic (ROC) formula and Youden's analysis. Subjects were divided into two cohorts: cohort 1 with low CD3+ T-cell dose (n = 34) and cohort 2 with high CD3+ T-cell dose (n = 18). Correlative analyses were performed between CD3+ T-cell dose and the risk of graft-versus-host disease (GvHD), relapse, relapse-free survival (RFS), and overall survival (OS). P-values were two-sided and considered significant when P < 0.05. Results: Subject covariates were displayed. Subject's characteristics were comparable, except for higher nucleated cells and more female donors in the high CD3+ T-cell cohort. The 100-day cumulative incidence of acute GvHD (aGvHD) was 45±7% and 3-year cumulative incidence of chronic GvHD (cGvHD) was 28±6.7%. There was no statistically significant difference between the two cohorts in aGvHD (50% vs. 39%, P = 0.4) or cGvHD (29% vs. 22%, P = 0.7). The 2-year cumulative incidence of relapse (CIR) was 67.5±16.3% for low compared with 14.3±6.8% for high CD3+ T-cell cohort (P = 0.018). Fifteen subjects relapsed and 24 have died, 13 due to disease relapse. There was an improvement in 2-year RFS (94% vs. 83%; P = 0.0022) and 2-year OS (91% vs. 89%; P = 0.025) in low CD3+ T-cell cohort compared with high CD3+ T-cell cohort. Graft CD3+ T-cell dose is the only significant risk factor for relapse (P = 002), and OS (P = 0.030) in univariate analysis which was maintained in multivariate for relapse (P = 0.003), but not for OS (P = 0.050). Conclusions: Our data suggest that high graft CD3+ T-cell dose is associated with lower risk of relapse, and might improve long-term survival, but has no influence on the risk of developing aGvHD or cGvHD.

Pathogenic germline variants in patients with breast cancer: conversations across generations, practices and patients' attitude.

Background: Breast cancer susceptibility genes such as BRCA1, BRCA2, PALB2, CHEK2 and many others are increasingly recognized among our patient population. In addition to their impact on treatment decisions of tested patients themselves, identifying at-risk family members offer opportunities for cancer preventive measures. Methods: This is an observational cross-sectional study of adult breast cancer patients with positive breast-cancer-susceptibility germline variants who received treatment at our institution. Patients with variants of uncertain significance (VUS), or who refused to give consent, were excluded. The data was collected from an eligible sample of breast cancer patients using a structured questionnaire developed by the study team and tested for validity and reliability, as well as a clinical chart review form. Patients were invited to participate in the study during their scheduled oncology clinics visit. Results: 169 patients were enrolled, including 42 (24.9%) with pathogenic/likely pathogenic (P/LP) BRCA1 variants, 84 (49.7%) with BRCA2 and 43 (25.4%) with non-BRCA variants. All patients were female and the mean age was 45 ± 9.9 years. Among 140 eligible patients, 104 (74.3%) underwent prophylactic mastectomy, while 79 (59.0%) of 134 eligible patients had prophylactic bilateral salpingo-oophorectomy (BSO). Results were communicated with family members by majority (n = 160, 94.7%), including 642 first degree female relatives, and 286 (44.5%) of them have taken no action. Fear of positive test results, cost of testing, unwillingness to undergo preventive measures, and social stigma were cited as barriers to genetic testing in 54%, 50%, 34% and 15%, respectively. Conclusion: Risk-reducing interventions including mastectomy and BSO were carried by majority of patients with P/LP variants. However, though the rate of communication of genetic testing results with family members was high, proper preventive measures were relatively low. Cost and fear of cancer diagnosis, were the leading causes that prevented cascade testing in our cohort.

Late presentation and suboptimal treatment of breast cancer among Syrian refugees: a retrospective study.

OBJECTIVES: The crisis in Syria has had a profound impact on the entire region. In this study, we report the patterns of presentation and management of Syrian patients with breast cancer treated at our institution. METHODS: We retrospectively collected data on Syrian refugees treated for breast cancer over the past 10 years at our center. Management was compared against our approved clinical practice guidelines. RESULTS: A total of 113 patients were eligible and included. The median age (range) at diagnosis was 47 (21-84) years and most women presented with locally advanced or metastatic disease (n = 74, 65.5%). Breast-conserving surgery and breast reconstruction were performed in 27 (33.8%) and 11 (35.4%) patients, respectively. Only a few patients received targeted (35.5%) or advanced endocrine therapy (30.0%). In total, 37 (32.7%) patients had considerable deviations from our institutional treatment guidelines and had worse outcomes. CONCLUSIONS: Syrian refugees with breast cancer present late, have more advanced-stage disease, and are more likely to receive delayed and suboptimal therapy. An international systematic approach for cancer care among such vulnerable populations is urgently needed.

Patterns and predictors of thromboembolic events among patients with gastric cancer.

Patients with gastric cancer are at higher risk for venous thromboembolic events (VTE). Majority of such patients are treated in ambulatory settings where thromboprophylaxis is not routinely offered. In this study, we report on VTE rates and search for predictors that may help identify patients at higher risk to justify VTE-prophylaxis in ambulatory settings. Patients with pathologically-confirmed gastric adenocarcinoma were retrospectively reviewed for VTE detected by imaging studies. Clinical and pathological features known to increase the risk of VTE were studied. Khorana risk assessment model was applied on patients receiving chemotherapy. A total of 671 patients; median age 55 years, were recruited. VTE were diagnosed in 150 (22.4%) patients, including 42 (28.0%) pulmonary embolism and 18 (12.0%) upper extremity deep vein thrombosis (DVT). Majority (> 80%) developed VTE while in ambulatory settings and none had been on thromboprophylaxis. Rate was higher (27.1%) among 365 patients with metastatic compared to 16.7% among 306 patients with nonmetastatic disease, p = 0.001. Patients with metastatic disease who received multiple lines of chemotherapy (n = 85) had significantly higher rate of VTE compared to those who received a single line; 48.2% versus 19.4%, p < 0.001. Among the whole group, Khorana risk score, age, gender, smoking and obesity had no impact on VTE rates. Patients with metastatic gastric cancer, especially when treated with multiple lines of chemotherapy, are at a significantly higher risk of VTE. Khorana risk score had no impact on VTE rates. Thromboprophylaxis in ambulatory patients with metastatic gastric cancer worth studying.