Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) comprises a group of aggressive and heterogeneous breast carcinoma. Chemotherapy is the mainstay for the treatment of triple-negative tumors. Nevertheless, the success of chemotherapeutic treatments is limited by their toxicity and development of acquired resistance leading to therapeutic failure and tumor relapse. Hence, there is an urgent need to explore novel targeted therapies for TNBC. Receptor tyrosine kinases (RTKs) are a family of transmembrane receptors that are key regulators of intracellular signaling pathways controlling cell proliferation, differentiation, survival, and motility. Aberrant activity and/or expression of several types of RTKs have been strongly connected to tumorigenesis. RTKs are frequently overexpressed and/or deregulated in triple-negative breast tumors and are further associated with tumor progression and reduced survival in patients. Therefore, targeting RTKs could be an appealing therapeutic strategy for the treatment of TNBC. This review summarizes the current evidence regarding the antitumor activity of RTK inhibitors in preclinical models of TNBC. The review also provides insights into the clinical trials evaluating the use of RTK inhibitors for the treatment of patients with TNBC.

HPLC with Fluorescence and Photodiode Array Detection for Quantifying Capmatinib in Biological Samples: Application to In Vivo and In Vitro Studies.

Capmatinib, a recently approved tyrosine kinase inhibitor, is used for the treatment of non-small cell lung cancer. We describe two new HPLC methods for capmatinib quantification in vivo and in vitro. HPLC with a fluorescence detection method was used to quantify capmatinib in plasma for the first time. The method was successfully applied in a pharmacokinetic study following a 10 mg/kg oral dose of capmatinib given to rats. The chromatographic separation was performed using a Eurospher II 100-3 C18H (50 × 4 mm, 3 µm) column and a mobile phase containing 10 mM of ammonium acetate buffer (pH 5.5): acetonitrile (70:30, v/v), at a flow rate of 2.0 mL min-1. The study also describes the use of HPLC-PDA for the first time for the determination of capmatinib in human liver microsomes and describes its application to study its metabolic stability in vitro. Our results were in agreement with those reported using LC-MS/MS, demonstrating the reliability of the method. The study utilized a Gemini-NX C18 column and a mobile phase containing methanol: 20 mM ammonium formate buffer pH 3.5 (53:47, v/v), delivered at a flow rate of 1.1 mL min-1. These methods are suitable for supporting pharmacokinetic studies, particularly in bioanalytical labs lacking LC-MS/MS capabilities.

A Survey of Knowledge and Barriers of Healthcare Professionals toward Opioid Analgesics in Cancer Pain Management.

Purpose: Pain is among the most frequent and troubling symptoms in cancer patients. Despite the availability of updated treatment guidelines and effective pharmacological therapies, undertreatment of cancer pain remains a global problem. Opioids are the mainstay analgesics to treat moderate-to-severe cancer pain. The goal of this study was to assess the knowledge and barriers towards opioid analgesics for cancer pain management among healthcare professionals in Oncology Units in Jordan. Methods: A structured questionnaire was administered to healthcare professionals (consultant doctors, resident doctors, pharmacists, and nurses) at three Oncology Units in a cross-sectional study design. Results: A total of 201 healthcare professionals completed the questionnaire. The average age was 34.8 ± 8.1 years (range 23-58) and 49.3% of respondents were nurses. The mean score for the knowledge of opioids was 12.5 ± 3.2 out of 24 points (range 2-20). An acceptable level of knowledge was observed in 50.7% of participants, while 49.3% had poor knowledge. Knowledge items mostly answered incorrectly were related to opioid administration, pharmacology, dosing, adverse events, rotation, and toxicity. Knowledge scores were significantly higher for consultant doctors compared to pharmacists and nurses (p=0.016 and p < 0.001, respectively). Healthcare professionals who handled opioid analgesics had significantly higher mean knowledge scores than those who did not (p=0.012). Linear regression analysis revealed that being a consultant physician has an independent, statistically significant association with higher knowledge scores. Among perceived barriers to using opioids, fear of addiction by patients was the most frequently reported barrier by respondents (79.6%). Other highly recognized barriers were fear of adverse effects by patients (67.2%) and lack of training programs on opioid dosing and monitoring (63.7%). Conclusions: This study revealed major gaps in the knowledge of opioids and pain management among healthcare professionals. There is an urgent need for developing innovative interventions to improve the knowledge of opioid analgesics and the understanding of pain management guidelines among healthcare professionals in Jordan.

Community pharmacists' routine provision of drug-related problem-reduction services.

OBJECTIVES: The present study aimed to assess the degree of the provision of services for drug-related problems (DRPs) and the factors affecting provision within the community pharmacy setting in Irbid, a large city in Northern Jordan. METHODS: A cross-sectional survey was developed and administered to community pharmacists in Irbid, Jordan during the period from January to May 2017. The survey is composed of background and practice characteristics, services provided routinely by the community pharmacists to address DRPs, and barriers and facilitators for DRP-reduction services. A summated score quantifying the degree of DRP-reduction service provision was calculated, which included overall scores and scores for the different scales and domains. Statistical analysis included descriptive statistics and a multivariate linear regression model for factors associated with the high provision of DRP-reduction service. RESULTS: Two hundred community pharmacists out of 210 pharmacists approached completed the surveys yielding a response rate of 95.2%. The most frequent DRPs encountered within the routine practice in the community pharmacy were economic aspects (76.0%). The mean total score relating to different DRP-reduction services was 32.9 (58.8%) out of 56 as the maximum possible score. It was estimated that 28.2% of the responding pharmacists provided the service overall (scored more than 50% of the scale). For the assessment, intervention, and referral dimensions, similar percentages of providers of the services were achieved: 59.7%, 61.9%, and 49.0%, respectively. Lower rates of providers were achieved on the documentation scale (12.9%). The lack of recognition of the pharmacist role by physicians was the most commonly reported barrier to effective DRP-reduction services among community pharmacists (78.9%). The ability to receive external guidance was indicated by the majority of surveyed pharmacists (94.5%) as a potential facilitator to DRP-reduction services in this study. Predictors associated with high total scores were the presence of medical records for the patients in the pharmacy, patients contact the pharmacy using email, a high satisfaction in professional relationships with physicians, and pharmacists' age. CONCLUSION: Even though community pharmacists in this study have been shown to deliver certain activities to address DRPs to a high degree, the overall rate of DRPs services was suboptimal. Community pharmacists reported several barriers that should be taken into consideration to facilitate the role of community pharmacists in providing adequate DRP reduction services to patients.

Estrogen-Related Receptors Gene Expression and Copy Number Alteration Association With the Clinicopathologic Characteristics of Breast Cancer.

Purpose: It has been suggested that dysregulation of transcription factors expression or activity plays significant roles in breast cancer (BC) severity and poor prognosis. Therefore, our study aims to thoroughly evaluate the estrogen-related receptor isoforms (ESRRs) expression and copy number alteration (CNA) status and their association with clinicopathologic characteristics in BC. Methods: A METABRIC dataset consist of 2509 BC patients' samples was obtained from the cBioPortal public domain. The gene expression, putative CNA, and relevant tumor information of ESRRs were retrieved. ESRRs messenger RNA (mRNA) expression in BC cell lines was obtained from the Cancer Cell Line Encyclopedia (CCLE). Association and correlation analysis of ESRRs expression with BC clinicopathologic characteristics and molecular subtype were performed. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of ESRRs expression on patient survival. Results: ESRRα expression correlated negatively with patients' age and overall survival, whereas positively correlated with tumor size, the number of positive lymph nodes, and Nottingham prognostic index (NPI). Conversely, ESRRγ expression was positively correlated with patients' age and negatively correlated with NPI. ESRRα and ESRRγ expression were significantly associated with tumor grade, expression of hormone receptors, human epidermal growth factor receptor 2 (HER2), and molecular subtype, whereas ESRRß was only associated with tumor stage. A significant and distinct association of each of ESRRs CNA with various clinicopathologic and prognostic factors was also observed. Kaplan-Meier survival analysis demonstrated no significant difference for survival curves among BC patients with high or low expression of ESRRα, ß, or γ. On stratification, high ESRRα expression significantly reduced survival among premenopausal patients, patients with grade I/II, and early-stage disease. In BC cell lines, only ESRRα expression was significantly higher in HER2-positive cells. No significant association was observed between ESRRß expression and any of the clinicopathologic characteristics examined. Conclusions: In this clinical dataset, ESRRα and ESRRγ mRNA expression and CNA show a significant correlation and association with distinct clinicopathologic and prognostic parameters known to influence treatment outcomes; however, ESRRß failed to show a robust role in BC pathogenesis. ESRRα and ESRRγ can be employed as therapeutic targets in BC-targeted therapy. However, the role of ESRRß in BC pathogenesis remains unclear.

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches.

Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.

Organophosphate pesticide exposure prenatally influence on pregnancy outcomes.

BACKGROUND: Organophosphorus (OP) pesticides are widely used worldwide. The effect of OP exposure during pregnancy on the offspring is inconsistent in the current literature. Moreover, similar studies in the Middle East are lacking. PURPOSE: To examine the effects of OP exposure in utero on the outcome of pregnancies in an agricultural region in Jordan. METHOD: A prospective study, employing a questionnaire to collect women demographic data. Hospital records were collected for newborns' birth data. In addition, urine samples during the third trimester were collected from pregnant women and then analyzed for six OP metabolites to measure exposure. RESULTS: One of the metabolites, DEDTP, was negatively correlated with gestational age and Apgar scores 1 and 5. There were no other significant associations. CONCLUSIONS: Exposure to OP during pregnancy is not highly associated with any negative anthropometric characteristics of the newborns; it is probably offset by other factors.

Programmed Death-Ligand 1 Expression in Breast Cancer Patients: Clinicopathological Associations from a Single-Institution Study.

PURPOSE: Tumor expression of programmed death-ligand 1 (PD-L1) is associated with evasion of immune response in several types of malignancies and such expression may render patients eligible for PD-L1 inhibitors. The use of immune checkpoint blockade therapy has been recently approved for the treatment of breast cancer. However, PD-L1 expression data are lacking among Jordanian breast cancer patients. In this study, the tumor PD-L1 expression was characterized in breast cancer patients to assess their eligibility for immune checkpoint blockade therapy. The study also aimed to explore the association between tumoral PD-L1 expression and the clinicopathologic characteristics and the prognostic factors in patients with breast cancer. PATIENTS AND METHODS: Tissue samples were available from 153 female patients with primary invasive breast cancer. Immunohistochemistry was performed on paraffin-embedded tumor sections that were stained with a PD-L1 antibody. Expression of tumor PD-L1 was correlated with demographics, clinicopathologic characteristics, and prognosis. RESULTS: The mean age at diagnosis was 54.2±12.8 years (median 52, interquartile range 45-65). The percentage of PD-L1-positive tumors was 26.1%. PD-L1 expression on tumor cells significantly and positively correlated with tumor size (rho=0.174, p=0.032). PD-L1 positivity was significantly associated with the grade of carcinoma (p=0.001), HER2-positivity (p=0.015), and lymphovascular invasion (p=0.036). PD-L1 intensity was significantly associated with tumor stage (p=0.046). No significant associations were observed for the PD-L1 expression status or intensity with patient menopausal status, hormone receptor expression, and molecular subtypes. PD-L1 expression significantly correlated with a worse prognosis of breast cancer patients at the time of diagnosis (rho=0.230, p=0.005). CONCLUSION: Tumor PD-L1 expression was associated with advanced clinicopathologic features and worse prognosis in this cohort of Jordanian breast cancer patients. Future studies are needed to better understand the impact of PD-L1 blockade therapy on treatment outcomes in eligible breast cancer patients in Jordan.

Knowledge and Practice of Breast Cancer Screening Methods among Female Community Pharmacists in Jordan: A Cross-Sectional Study.

OBJECTIVES: Our study is aimed at exploring the knowledge and personal practice of breast cancer screening among female community pharmacists in Jordan. METHODS: A cross-sectional survey was carried out using a nonrandom sample selection method for pharmacists in community pharmacies. RESULTS: A total of 551 female pharmacists completed the questionnaire. The mean age of pharmacists was 29.1 ± 7.3 years (range 21-67), and most have bachelor degrees in pharmacy (89.1%). The mean score of knowledge of breast cancer signs and symptoms was 4.2 ± 1.5 out of 6 points (range 0-6). The mean score of knowledge of risk factors was 7.6 ± 1.9 out of 12 points (ranging from 2-12). The mean score for knowledge of screening guidelines was 2.8 ± 0.9 out of 4 points (range 0-4). Overall, 452 pharmacists (85.8%) had acceptable knowledge while 75 pharmacists (14.2%) had poor knowledge of breast cancer. Pharmacists surveyed were aware of the different screening methods of breast cancer. The percentage of pharmacists who has performed breast self-examination (BSE), clinical breast examination (CBE), and mammography was 46.6%, 16.5%, and 5.4%, respectively. The most common reason for the lack of BSE and CBE performance was the absence of breast symptoms. Not being at the age recommended for mammography was the most common reason for not undergoing this screening method. Knowledge and practice of screening methods were influenced by age, years of experience, geographic region, personal history of breast cancer, and educational level among community pharmacists. CONCLUSIONS: This study revealed some gaps in the knowledge of breast cancer among female community pharmacists. The practice of the different screening methods was suboptimal, and variable reasons were indicated for the low uptake of these screening methods. Community pharmacists need to practice preventive behaviors to a satisfactory level to encourage women in the community to adopt similar behavior.

Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies.

Targeted therapy is a hallmark of cancer treatment that has changed the landscape of cancer management and enabled a personalized treatment approach. Nevertheless, the development of cancer resistance is a major challenge that is currently threatening the effective utilization of targeted therapies. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and tumorigenic potential. MET is a well-known driver of cancer resistance. A growing body of evidence revealed a major role of MET in mediating acquired resistance to several classes of targeted therapies. Deregulations of MET commonly associated with the development of cancer resistance include gene amplification, overexpression, autocrine activation, and crosstalk with other signaling pathways. Small-molecule tyrosine kinase inhibitors of MET are currently approved for the treatment of different solid cancers. This review summarizes the current evidence regarding MET-mediated cancer resistance toward targeted therapies. The molecular mechanisms associated with resistance are described along with findings from preclinical and clinical studies on using MET inhibitors to restore the anticancer activity of targeted therapies for the treatment of solid tumors.

A baseline survey of community pharmacies' workforce, premises, services and satisfaction with medical practitioners in Jordan.

PURPOSE: The aim of the present study was to describe the local situation in community pharmacies in Jordan by assessing the baseline resources available in terms of workforce, premises and services provided. METHODS: A survey was developed and administered to community pharmacists from Amman, the capital of Jordan, and Irbid, a large city in North Jordan. RESULTS: Three hundred sixty-seven community pharmacists, 167 from Amman and 200 from Irbid, completed the surveys. The community pharmacists were mostly females (66.6%) and predominantly (about three quarters) younger than 30 years old. The community pharmacists were in independent (69.2%) and chain (30.8%) pharmacies. Respondent pharmacists reported delivering medication review services (93.1% of the respondents delivered the service), smoking-cessation services (86.7%), nutrition services (71.5%), blood pressure testing (86.7%), diabetes screening (86.9%) and home delivery (18.8%). Patient counselling is carried out by 94.5% of respondents. Community pharmacists spend most of their time dispensing prescriptions and counselling patients on prescription and non-prescription medicines and chronic diseases. The study also shed the light on a related aspect of practice which was the relationship with local doctors. Only 9.9% of the respondents indicated high satisfaction with their professional relationship with local medical practitioners, 81.6% had a mid-level of satisfaction and 8.5% had the lowest level of satisfaction. CONCLUSION: The present study identified baseline characteristics of the local situation in community pharmacies. The majority of pharmacists dispensed medications, provided counselling, reviewed medications and provided smoking cessation service.

Combined crizotinib and endocrine drugs inhibit proliferation, migration, and colony formation of breast cancer cells via downregulation of MET and estrogen receptor.

Hormone-dependent breast cancer is the most abundant molecular subtype of the disease. Despite the availability of endocrine treatments, the use of these drugs is limited by their serious adverse reactions and development of acquired resistance often mediated by growth factor receptors. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and mediating resistance to targeted therapies. Crizotinib is a small-molecule tyrosine kinase inhibitor of MET. In this study, the anticancer effects of combined crizotinib and endocrine drugs were investigated in breast cancer cells in vitro along with the molecular mechanisms associated with these effects. Results showed that crizotinib inhibited growth of MCF7 and T-47D breast cancer cells in a dose-dependent manner with IC50 values of 2.88 µM and 0.93 µM, respectively. Combined treatment of crizotinib and 4-hydroxytamoxifen resulted in synergistic growth inhibition of MCF7 and T-47D cells with combination index values of 0.39 and 0.8, respectively. The combined treatment significantly suppressed migration and colony formation of MCF7 and T-47D cells. Immunofluorescence showed a significant reduction of the expression of the nuclear protein Ki-67 with the combination of crizotinib and 4-hydroxytamoxifen in both cell lines. Western blotting indicated that the combination treatment reduced the levels of active and total MET, estrogen receptor α (ERα), total and active levels of AKT, ERK, c-SRC, NFĸB p65, GSK-3ß, and the anti-apoptotic BCL-2 protein. Findings from this study suggest a potential role of MET inhibitors in breast cancer treatment as monotherapy or combination with endocrine drugs.

ING4 Expression Landscape and Association With Clinicopathologic Characteristics in Breast Cancer.

BACKGROUND: Breast cancer (BC) development and progression is complex and still not fully understood. The expression or dysregulation of a variety of transcription factors has been suggested as contributing to disease severity and a poor prognosis. Therefore, the present study was designed to systematically outline ING4 expression and characteristics in clinical samples and cell lines of BC. MATERIALS AND METHODS: A METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) dataset was obtained from a cBioPortal public domain. ING4 gene expression, putative copy number alterations, and pertinent tumor information were retrieved. ING4 gene expression was identified for 1904 BC patients. ING4 mRNA expression data in BC cell lines were obtained from the Cancer Cell Line Encyclopedia. Analyses were conducted for associations between ING4 expression and age at diagnosis, tumor clinicopathologic characteristics, and molecular subtypes. The prognostic value of ING4 in BC patients was evaluated using Kaplan-Meier survival analysis. RESULTS: The ING4 mRNA expression log intensity mean was 6.95, and 1005 (52.8%) of patients were determined to have high ING4 mRNA expression (mRNA log intensity > 6.95). Although ING4 gene expression correlated significantly and negatively with the Nottingham Prognostic Index and the number of positive lymph nodes (P < .05) and positively with overall survival time (P < .001). However, these correlations were weak in magnitude (r ∼ 0.1). The expression of ING4 was significantly associated with tumor grade, hormone receptor expression, human epidermal growth factor receptor 2, and molecular subtype. ING4 copy number alteration was also significantly associated with several clinicopathologic and prognostic factors. Kaplan-Meier survival analysis demonstrated greater overall survival for BC patients with high ING4 expression (P = .0046). Stratification of the data by menopausal status and tumor characteristics revealed a significant effect of ING4 expression on survival among premenopausal patients and women with a nonluminal subtype. Furthermore, the expression of ING4 in BC cell lines was significantly greater in luminal A and basal-like cells compared with human epidermal growth factor receptor 2-positive cells, which was also observed in the clinical samples. CONCLUSIONS: The present study showed that ING4 gene expression is modulated in BC. High ING4 gene expression was associated with favorable prognostic parameters and positive clinical outcomes in our series of BC patients. ING4 could be used as a potential therapeutic target in BC-targeted therapy.

ProBDNF is a Novel Mediator of the Interaction Between MDA-MB- 231 Breast Cancer Cells and Brain Microvascular Endothelial Cells.

AIM: The current work aims to assess the role of proBDNF/BDNF in the interaction between brain microvascular endothelial cells and the MDA-MB-231 breast cancer cell line that has been consistently reported to cause brain metastasis. BACKGROUND: Breast cancer brain metastasis (BM) is a significant health problem with limited therapeutic options. The development of BM is a multistep process that requires constant interaction with brain vasculature and the development of tumor blood supply. The benefits of anti-angiogenic modalities, based on antagonizing vascular endothelial growth factor in breast cancer metastasis, did not prove to be effective. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with a reported angiogenic effect. There is a lack of data regarding the involvement of BDNF in metastatic breast cancer interaction with brain microvascular endothelial cells (HBEC-5i). METHODS: Using an adaptive transfer design, the cross-talk between HBEC-5i and MDAMB- 231 cell was investigated. HBEC-5i were treated with MDA-MB-231-conditioned media, and the involvement of BDNF/proBDNF in the interaction was assessed using both release and inhibitor-based assays in migration and in vitro tube formation assay. RESULTS: MDA-MB-231 and HBEC-5i released total BDNF (250 vs. 80 pg/ml, respectively). MDA-MB-231 conditioned media inhibited the migration of HBEC-5i by more than 80% (p<0.05) and tube formation by 75% (p<0.05). Neutralizing mature BDNF did not alter the MDA-MB-231 induced anti-angiogenic effect, which was completely blunted by antagonizing proBDNF. MDA-MB-231 released proBDNF (131.5 pg/ml), and more than 60% of total BDNF released was in the pro-form. CONCLUSION: proBDNF is a novel mediator of breast cancer-induced anti-angiogenic effect in brain endothelial cells.

Crizotinib induced antitumor activity and synergized with chemotherapy and hormonal drugs in breast cancer cells via downregulating MET and estrogen receptor levels.

MET is a receptor tyrosine kinase known to drive neoplastic transformation and aggressive tumor phenotypes. Crizotinib is an oral multi-targeted tyrosine kinase inhibitor of MET, ALK, RON, and ROS1 kinases. In this study, the anticancer effects of crizotinib on breast cancer cells were investigated in vitro along with the molecular mechanisms associated with these effects. Besides, the antiproliferative effects of crizotinib in combination with chemotherapy, hormonal drugs, and targeted agents were examined. Results showed that crizotinib produced dose-dependent antiproliferative effects in BT-474 and SK-BR-3 breast cancer cells with IC50 values of 1.7 µM and 5.2 µM, respectively. Crizotinib inhibited colony formation of BT-474 cells at low micromolar concentrations (1-5 µM). Immunofluorescence and Western blotting indicated that crizotinib reduced total levels of MET and estrogen receptor (ERα) in BT-474 cells. Also, crizotinib reduced the levels of phosphorylated (active) MET and HER2 in BT-474 cells. The combined treatment of crizotinib with doxorubicin and paclitaxel resulted in synergistic growth inhibition of BT-474 cells with combination index values of 0.46 and 0.35, respectively. Synergy was also observed with the combination of crizotinib with the hormonal drugs 4-hydroxytamoxifen and fulvestrant in BT-474 cells. Alternatively, the combination of crizotinib with lapatinib produced antagonistic antiproliferative effects in both BT-474 and SK-BR-3 cells. Collectively, these findings demonstrate the anticancer effects of crizotinib in breast cancer cells and reveal ERα as a potential therapeutic target of the drug apart from its classical kinase inhibitory activity. Crizotinib could be an appealing option in combination with chemotherapy or hormonal drugs for the management of breast cancer.

Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine.

Despite the great efforts for better treatment options for diffuse large B-cell lymphoma (DLBCL) (most common form of non-Hodgkin lymphoma, NHL) to treat and prevent relapse, it continues to be a challenge. Here, we present an overview of DLBCL and address the diagnostic assays and molecular techniques used in its diagnosis, role of biomarkers in detection, treatment of early and advanced stage DLBCL, and novel drug regimens. We discuss the significant biomarkers that have emerged as essential tools for stratifying patients according to risk factors and for providing insights into the use of more targeted and individualized therapeutics. We discuss techniques such as gene expression studies, including next-generation sequencing, which have enabled a more understanding of the complex pathogenesis of DLBCL and have helped determine molecular targets for novel therapeutic agents. We examine current treatment approaches, outline the findings of completed clinical trials, and provide updates for ongoing clinical trials. We highlight clinical trials relevant to the significant fraction of DLBCL patients who present with complex cases marked by high relapse rates. Supported by an increased understanding of targetable pathways in DLBCL, clinical trials involving specialized combination therapies are bringing us within reach the promise of an effective cure to DLBCL using precision medicine. Optimization of therapy remains a crucial objective, with the end goal being a balance between high survival rates through targeted and personalized treatment while reducing adverse effects in DLBCL patients of all subsets.

Pseurotin A as a novel suppressor of hormone dependent breast cancer progression and recurrence by inhibiting PCSK9 secretion and interaction with LDL receptor.

Hypercholesterolemia has been documented to drive hormone-dependent breast cancer (BC) progression and resistance to hormonal therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9) regulates cholesterol metabolism through binding to LDL receptor (LDLR) and targeting the receptor for lysosomal degradation. Inhibition of PCSK9 is an established strategy to treat hypercholesterolemia. Pseurotin A (PS) is a unique spiro-heterocyclic γ-lactam alkaloid isolated from the fungus Aspergillus fumigatus. Preliminary studies indicated that PS lowered PCSK9 secretion in cultured HepG2 hepatocellular carcinoma cells, with an IC50 value of 1.20 µM. Docking studies suggested the ability of PS to bind at the PCSK9 narrow interface pocket that accommodates LDLR. Surface plasmon resonance (SPR) showed PS ability to inhibit the PCSK9-LDLR interaction at a concentration range of 10-150 µM. PS showed in vitro dose-dependent reduction of PCSK9, along with increased LDLR levels in hormone-dependent BT-474 and T47D breast cancer (BC) cell lines. In vivo, daily oral 10 mg/kg PS suppressed the progression of the hormone-dependent BT-474 BC cells in orthotopic nude mouse xenograft model. Immunohistochemistry (IHC) investigation of BT-474 breast tumor tissue proved the PS ability to reduce PCSK9 expression. PS also effectively suppressed BT-474 BC cells locoregional recurrence after primary tumor surgical excision. Western blot analysis showed decreased PCSK9 expression in liver tissues of PS-treated mice compared to vehicle-treated control group. PS treatment significantly reduced PCSK9 expression and normalized LDLR levels in collected primary and recurrent breast tumors at the study end. PS-treated mice showed reduced plasma cholesterol and 17ß-estradiol levels. Inhibition of tumor recurrence was associated with significant reductions in plasma level of the human BC recurrence marker CA 15-3 in treated mice at the study end. Histopathological examination of various PS-treated mice organs indicated lack of metastatic tumor cells and any pathological changes. The results of this study provide the first evidence for the suppression of the hormone-dependent breast tumor progression and recurrence by targeting the PCSK9-LDLR axis. PS is a novel first-in-class PCSK9-targeting lead appropriate for the use to control hormone-dependent BC progression and recurrence.

The Role of Establishing a Multidisciplinary Team for Idiopathic Granulomatous Mastitis in Improving Patient Outcomes and Spreading Awareness about Recent Disease Trends.

BACKGROUND: Iidiopathic granulomatous mastitis (IGM) is stereotypically described as a mysterious entity that mimics breast carcinoma imposing management challenges. In 2002, we established a multidisciplinary team to treat patients with IGM. This study aimed to evaluate the role of this team in improving patient outcomes. Also, a review of literature is provided to highlight recent disease trends. Patients and Methods. Pertinent data for 44 patients treated for IGM from 2002 to 2018 were analyzed and compared to data prior to 2002. RESULTS: Mean age at diagnosis was 37.9 years ± 6.4. The diagnosis of IGM was confirmed by True-cut biopsy (TCB), Frozen section (FS), and surgical biopsy in 70.5%, 25%, and 4.5% of patients, respectively. FS was used to assess the resection margins in three patients. Suspicion for malignancy was raised in one out of 39 ultrasound reports, and one out of 20 mammography reports. Wide local excision was the main treatment modality (95.5%). 19 patients (43.2%) received corticosteroids. Prior to 2002, IGM was only recognized after surgical resection with a 71% initial false impression of carcinoma. After 2002, the initial false clinical impression of carcinoma dropped to 29.5%. Recurrence rate was 31.82%. Younger age at diagnosis was significantly associated with recurrence (χ 2 = 5.598; p = 0.018). Chi-square analysis showed no significant association between BMI and recurrence (χ 2 = 0.776; p = 0.678). CONCLUSION: The establishment of a multidisciplinary team for IGM was associated with a reduced erroneous impression of breast cancer, and a reduced false positive radiological diagnosis of breast carcinoma. FS was a useful confirmatory procedure. Our series included the first case of a diffuse papular rash as a systemic manifestation of IGM. Recent literature indicates that IGM is changing its face. IGM is being reported in all age groups, and even in males. The clinical manifestations have markedly expanded. Diagnosis by TCB has replaced blind surgical excision. More data regarding predictors of recurrence is accumulating.

Glycosylated Hemoglobin A1c Is Associated with Anthropometric Measurements and Tumor Characteristics in Breast Cancer Patients.

PURPOSE: To investigate the association between glycosylated hemoglobin A1c (HbA1c) with anthropometric measurements and clinicopathologic characteristics of breast cancer patients. Such data are lacking in Arabian countries. PATIENTS AND METHODS: A cross-sectional study was conducted at the Outpatient Oncology Unit at King Hussein Medical Center at the Royal Medical Services (RMS) and 223 breast cancer patients were included. Blood levels of HbA1c were measured and patients were classified into normal/non-diabetic (HbA1c <5.7%), prediabetic (HbA1c 5.7-6.4%), and diabetic (HbA1c ≥6.5%). RESULTS: The average age of patients was 49.9±10.3 years. Most patients had waist circumference equal to or more than 80 cm (91.9%) and more than half (55.2%) had waist-hip ratio equal to or more than 0.85. Mean body mass index (BMI) was 29.9±5.7 kg/m2. The mean level of HbA1c was 6.2±1.4% (range 4.7% to 12.6%). HbA1c levels revealed that most patients in this study classified as prediabetics (44.4%). There was a significant positive correlation between HbA1c levels and each of patient's age (r=0.267, p<0.001), waist circumference (r=0.180, p=0.008), and waist-hip ratio (r=0.278, p<0.001). Compared with premenopausal breast cancer patients, postmenopausal patients had significantly higher HbA1c blood levels (t=-3.542, p=0.003). HbA1c was significantly associated with stage (p=0.044) and grade (p=0.016) of carcinoma in premenopausal breast cancer patients. Among postmenopausal cases, HbA1c was significantly associated with molecular subtype of the disease (p=0.039). CONCLUSION: The majority of Jordanian breast cancer patients in this study are prediabetic, obese, and had visceral obesity. HbA1c levels are increased among older patients and those who have greater waist circumference and waist-hip ratio. HbA1c is associated with advanced stage and grade of breast carcinoma in premenopausal patients and with molecular subtype in postmenopausal cases. These findings urge the need to screen breast cancer patients for glycemic status upon disease presentation and to further consider treatments to control hyperglycemia in order to reduce the impact of metabolic derangements on disease prognosis and outcomes.