Publications by authors named "Anteneh Tesfaye"

22 Publications

  • Page 1 of 1

Clinical and Functional Characterization of Atypical / Mutations in Metastatic Colorectal Cancer.

Clin Cancer Res 2021 Jun 11. Epub 2021 Jun 11.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Mutations in () predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all mutations have similar impact, and atypical mutations beyond those in standard guidelines exist.

Experimental Design: We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical variants. Using an cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and xenograft models of transduced isogenic clones, we assessed signaling changes across mutations.

Results: exon 2, extended , and atypical mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no codon 117/146 and only one codon 59 mutation was noted. Atypical mutations had worse overall survival than wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; = 0.014). We functionally characterized 114 variants with the FACT assay. All exon 2 and extended mutations appeared activating. Of 57 atypical variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts.

Conclusions: We provide best available evidence to guide treatment when atypical variants are identified. L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included variants and functionally relevant.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0180DOI Listing
June 2021

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer.

Clin Cancer Res 2021 May 10;27(9):2470-2480. Epub 2021 Feb 10.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.

Patients And Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink.

Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8 and CD8/PD-1/Ki-67 T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood.

Conclusions: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102320PMC
May 2021

Corrigendum to "In Vitro Evaluation of Probiotic Properties of Lactic Acid Bacteria Isolated from Some Traditionally Fermented Ethiopian Food Products".

Int J Microbiol 2020 24;2020:6401356. Epub 2020 Jul 24.

Institute of Biotechnology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa 1176, Ethiopia.

[This corrects the article DOI: 10.1155/2019/7179514.].
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http://dx.doi.org/10.1155/2020/6401356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414344PMC
July 2020

Protective Effect of Potential Probiotic Strains from Fermented Ethiopian Food against Typhimurium DT104 in Mice.

Int J Microbiol 2020 13;2020:7523629. Epub 2020 Apr 13.

Institute of Biotechnology, Addis Ababa University, Addis Ababa 1176, Ethiopia.

is one of the most harmful pathogens responsible for foodborne outbreaks, illnesses and deaths. The aim of this study was to evaluate the effect of potentially probiotic strains against Typhimurium DT104 in mice. The compatibility test among the selected potential probiotic strains ( K132 K114 and E124) using the cross-streaking method showed the absence of antagonism. The anti- activities of coculture of the isolated potential probiotics in the form of mixed or single culture showed a remarkable anti- activity with 96.50 to 100% growth inhibition. The combination of strains, which showed the highest growth inhibition rates against Typhimurium DT104, was used to test their effect on the colonization of mice by Typhimurium DT104. White albino male mice were pretreated with the mixed potential probiotics for 7 days and infected with Typhimurium DT104 for 1 day. A total of 3 treatments were applied, during which the negative control group was treated with phosphate-buffered saline (PBS); a positive control group (typ) was challenged with Typhimurium DT104 alone. The treated group (pro-typ) was pretreated with mixed potential probiotic culture and then infected with Typhimurium DT104. The survival rate of mice and counts of in feces were recorded. The survival rate of mice on day 21 after the oral challenge with Typhimurium DT104 was significantly ( < 0.05) higher in the experimental pro-typ group (100% survival) compared with the positive control group (20% survival). The counts (colony-forming unit per ml) of in feces were significantly lower ( < 0.05) for the pro-typ group compared to the typ group. The combination of potential probiotic strains was able to protect mice against Typhimurium DT104 infection that demonstrates their potential to be used as probiotic cultures for the production of functional fermented products.
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http://dx.doi.org/10.1155/2020/7523629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178517PMC
April 2020

Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth.

Cancers (Basel) 2020 Mar 22;12(3). Epub 2020 Mar 22.

Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation.
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http://dx.doi.org/10.3390/cancers12030750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140111PMC
March 2020

Preclinical Assessment with Clinical Validation of Selinexor with Gemcitabine and Nab-Paclitaxel for the Treatment of Pancreatic Ductal Adenocarcinoma.

Clin Cancer Res 2020 03 12;26(6):1338-1348. Epub 2019 Dec 12.

Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC and in orthotopic models.

Experimental Design: We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial.

Results: SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin-bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient-derived (PDX) subcutaneous xenografts. Selinexor-GEM-nab-paclitaxel blocked PDX and orthotopic tumor growth. In a phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1,000 mg/m i.v.) and nab-paclitaxel (125 mg/m i.v.) on days 1, 8, and 15 of 28-day cycle. Two patients showed partial response, and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression-free survival of 16 months and overall survival of 22 months.

Conclusions: Our preclinical and ongoing clinical study lends support to the use of selinexor-GEM-nab-paclitaxel as an effective therapy for metastatic PDAC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073299PMC
March 2020

Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer.

Int J Mol Sci 2019 Sep 28;20(19). Epub 2019 Sep 28.

Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.
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http://dx.doi.org/10.3390/ijms20194826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801932PMC
September 2019

Evaluation of Probiotic Properties of Lactic Acid Bacteria Isolated from Some Traditionally Fermented Ethiopian Food Products.

Int J Microbiol 2019 25;2019:7179514. Epub 2019 Aug 25.

Institute of Biotechnology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa 1176, Ethiopia.

Probiotics are live microorganisms which when consumed in large number together with a food promote the health of the consumer. The aim of this study was to evaluate probiotic properties of lactic acid bacteria (LAB) isolated from traditional Ethiopian fermented dough, , and products. A total of 90 LAB were isolated, of which 4 (4.44%) isolates showed 45.35-97.11% and 38.40-90.49% survival rates at pH values (2, 2.5, and 3) for 3 and 6 h, in that order. The four acid-tolerant isolates were found tolerant to 0.3% bile salt for 24 h with 91.37 to 97.22% rate of survival. The acid-and-bile salt-tolerant LAB isolates were found inhibiting some food-borne test pathogenic bacteria to varying degrees. All acid-and-bile-tolerant isolates displayed varying sensitivity to different antibiotics. The adherence to stainless steel plates of the 4 screened probiotic LAB isolates were ranged from 32.75 to 36.30% adhesion rate. The four efficient probiotic LAB isolates that belonged to species were identified to the strain level using 16S rDNA gene sequence comparisons and, namely, were strain CIP 103151, subsp. strain NBRC 15906, strain NBRC 15889, and strain JCM 1149. The four strains were found to be potentially useful to produce probiotic products.
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http://dx.doi.org/10.1155/2019/7179514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732631PMC
August 2019

Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design.

Future Oncol 2019 Jun 16;15(18):2073-2082. Epub 2019 May 16.

University of California Los Angeles Medical Center (UCLA), Los Angeles, CA, USA.

Bemarituzumab is an afucosylated monoclonal antibody against FGFR2b (a FGF receptor) with demonstrated monotherapy clinical activity in patients with late-line gastric cancer whose tumors overexpress FGFR2b (NCT02318329). We describe the rationale and design of the FIGHT trial (NCT03343301), a global, randomized, double-blind, placebo-controlled Phase III study evaluating the role of bemarituzumab in patients with previously untreated, FGFR2b-overexpressing advanced gastroesophageal cancer. Patients are randomized in a blinded fashion to the combination of mFOLFOX6 and bemarituzumab or mFOLFOX6 and placebo. Eligible patients are selected based on the presence of either FGFR2b protein overexpression determined by immunohistochemistry or gene amplification determined by circulating tumor DNA. The primary end point is overall survival, and secondary end points include progression-free survival, objective response rate and safety.
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http://dx.doi.org/10.2217/fon-2019-0141DOI Listing
June 2019

A Pilot Trial of Molecularly Tailored Therapy for Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

J Pancreat Cancer 2019 2;5(1):12-21. Epub 2019 May 2.

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.

Despite the wide adoption of tumor molecular profiling, there is a dearth of evidence linking molecular biomarkers for treatment selection to prediction of treatment outcomes in patients with metastatic pancreatic cancer. We initiated a pilot study to test the feasibility of designing a larger phase II trial of molecularly tailored treatment for metastatic pancreatic cancer. Our study aimed to assess the feasibility of following a treatment algorithm based on the expression of three published predictive markers of response to chemotherapy: ribonucleotide reductase catalytic subunit M1 (for gemcitabine); excision repair cross-complementation group 1 (for platinum agents); and thymidylate synthase (for 5-fluorouracil) in patients with untreated, metastatic pancreatic cancer. Results of the tumor biopsy analysis were used to assign patients to one of seven doublet regimens. Key secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Between December 2012 and March 2015, 30 patients were enrolled into the study. Ten patients failed screening primarily due to inadequate tumor tissue availability. Of the remaining 20 patients, 19 were assigned into 6 different chemotherapy doublets, and achieved an RR of 28%, with a DCR rate of 78%. The median PFS and OS were 5.78 and 8.21 months, respectively. The incorporation of biomarkers into a treatment algorithm is feasible and resulted in a PFS and OS similar to other doublet therapies for patients with metastatic pancreatic cancer. Based on the results from this pilot study, a larger phase II randomized trial of molecularly targeted therapy versus physicians' choice of standard of care has been initiated in the second-line setting (NCT02967770).
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http://dx.doi.org/10.1089/pancan.2019.0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503449PMC
May 2019

Adjuvant treatment of surgically resectable pancreatic ductal adenocarcinoma.

Clin Adv Hematol Oncol 2019 Jan;17(1):54-63

Wayne State University, Detroit, Michigan.

Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related mortality in the United States. Surgical resection of early and localized disease provides the only chance for a cure; however, the majority of patients who have PDAC present with advanced disease that cannot be removed surgically. In the minority of patients who undergo surgical resection, there is a high rate of disease recurrence that eventually leads to death. The use of systemic therapy improves the outcome of patients who undergo surgery by targeting early micrometastatic disease. This review focuses on the medical management (both chemotherapy and radiation therapy) of surgically resectable pancreatic cancer, including the findings of recent practice-changing clinical trials that favor combination chemotherapy for adjuvant treatment and neoadjuvant chemoradiation therapy. The review also highlights important ongoing trials that aim to improve outcomes in patients with resectable pancreatic cancer.
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January 2019

Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma With the Introduction of New Chemotherapeutic Drugs: 10-Year Experience of a Single NCI-designated Comprehensive Cancer Center.

Am J Clin Oncol 2019 03;42(3):243-246

Department of Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, Detroit, MI.

Objectives: Adenocarcinoma of the pancreas represents the third leading cause of cancer-related death in the United States. Drug combinations, FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel, showed a clinically meaningful benefit when compared with single-agent gemcitabine in phase III trials. The goal of this study was to investigate whether there was an increase in overall survival (OS) for patients treated for metastatic pancreatic cancer after the introduction of the above regimens.

Materials And Methods: Patients were grouped into 2 treatment eras that were before and after the introduction of these newer chemotherapeutic regimens; 2006-2010 and 2011-2015, respectively. Baseline demographics and disease-related variables were collected from metastatic pancreatic cancer treated at the Barbara Ann Karmanos Cancer Institute in Detroit, MI.

Results: When stratified by treatment era, the later era had an improvement in survival (hazard ratio for death of 0.61; P=0.005). Median OS was 8.97 and 9.95 months for the earlier (n=59) versus latter era (n=99), respectively. There was an increase from 28.3% to 38.9% at 12 months between the earlier and later era, an improvement of 37.4%. African Americans had a worse outcome with a hazard ratio of 1.63 (P=0.02) for death. When comparing the eras, Caucasians had a longer median OS in each era in addition to having a greater improvement in median OS between eras.

Conclusions: There was a modest improvement in median OS between 2006-2010 and 2011-2015 with the introduction of newer chemotherapeutic regimens. However, there has been no significant improvement in outcomes for African Americans or in short-term survival.
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http://dx.doi.org/10.1097/COC.0000000000000507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800038PMC
March 2019

miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma.

Am J Pathol 2019 01;189(1):58-70

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease that is mostly diagnosed late in the course of the illness. Unlike other cancers in which measurable successes have been achieved with traditional chemotherapy, targeted therapy, and, recently, immunotherapy, PDAC has proved to be poorly responsive to these treatments, with only marginal to modest incremental benefits using conventional cytotoxic therapy. There is, therefore, a great unmet need to develop better therapies based on improved understanding of biology and identification of predictive and prognostic biomarkers that would guide therapy. miRNAs are small noncoding RNAs that regulate the expression of some key genes by targeting their 3'-untranslated mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been identified as potential tools for early diagnosis, prediction of treatment response, and prognosis of patients with PDAC. In this review, we present a summary of the miRNAs that have been studied in PDAC in the context of disease biology.
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http://dx.doi.org/10.1016/j.ajpath.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854437PMC
January 2019

Isolation and Molecular Identification of Lactic Acid Bacteria Using 16s rRNA Genes from Fermented ( (Zucc.)) Dough.

Int J Food Sci 2018 5;2018:8510620. Epub 2018 Aug 5.

Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, RI 02912, USA.

Injera is soft fermented baked product, which is commonly prepared from teff ( (Zucc.)) flour and believed to be consumed on daily basis by two-thirds of Ethiopians. As it is a product of naturally fermented dough, the course of fermentation is done by consortia of microorganisms. The study was aimed at isolating and identifying some dominant bacteria from fermenting dough. A total of 97 dough samples were collected from households, microenterprises, and hotels with different fermentation stage from Addis Ababa. The bacterial isolates obtained from the fermenting dough samples were selected on the basis of their acid production potentials. A total of 24 purified bacterial isolates were found to be Gram-positive (they are coccus and rod under microscope) and were good acid producers. Genomic DNA of bacterial isolates were extracted using Invisorb® Spin DNA Extraction kit. 16S rRNA of bacterial isolates were amplified using the bacteria universal primers (rD1 and fD1). The amplified product was sequenced at Genewiz, USA. Sequence analysis and comparison with the resources at the database were conducted to identify the isolated microbes into species and strain levels. The bacterial isolates were identified as and . All identified lactic acid bacteria were able to produce acid at 12 h time of incubation. This study has confirmed the presence of different bacterial species in the fermenting dough and also supports the involvement of various groups of bacterial species in the course of the fermentation.
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http://dx.doi.org/10.1155/2018/8510620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098851PMC
August 2018

Clinical Impact of PI3K/BRAF Mutations in RAS Wild Metastatic Colorectal Cancer: Meta-analysis Results.

J Gastrointest Cancer 2019 Jun;50(2):269-275

Department of Hematology and Medical Oncology, Winship Cancer Center, Emory University, Atlanta, GA, USA.

Background: Understanding the molecular mechanisms of colorectal cancer has evolved during the last decade ushering the era of personalized medicine. Alteration of BRAF and PI3K is common in colorectal cancer, and can affect several signaling pathways including EGFR (epidermal growth factor receptor). The aim of this meta-analysis is to evaluate the clinical role of PI3K and BRAF mutations in patients with KRAS wild-type metastatic colorectal cancer (MCRC) receiving an EGFR monoclonal antibody (anti-EGFR) inhibitor as first-line therapy.

Methods: A literature search was performed to identify studies exploring the association between PI3K/BRAF mutations and clinical outcomes of KRAS wild-type mCRC patients treated with anti-EGFR as a first-line therapy. The primary clinical outcome was overall response rate (ORR). The secondary outcomes included progression-free survival (PFS) and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effect model or random effect model according to heterogeneity between studies.

Results: Ten studies with 1470 mCRC patients (357 for PI3K studies and 1113 from BRAF studies) met selection criteria. We observed a trend towards lower ORR in patients with PI3K mutations (3 studies, 357 patients; ORR = 14.3% in mutant-type PI3K vs. 52.4% in wild-type PIK3CA [95% CI - 0.12-0.02]; P = 0.13). Patients with mutant-type PI3K have significant shorter PFS (3 studies, 357 patients, 3.8 vs. 4.15 months, HR = 1.36; [95% CI 1.04-1.77]; P = 0.02]), and OS (3 studies, 357 patients, 14.17 vs. 16.3 months, HR = 1.50; [95% CI 1.14-1.97]; P = 0.004) compared to those with wild PI3K. For BRAF, patients with mutant type have significantly lower ORR (7 studies, 1113 patients; ORR = 33% vs. 39%; [95% CI - 0.16-0.01]; P = 0.03), shorter PFS (5 studies, 814 patients, 3.9 vs. 5.7 months, HR = 1.72; [95% CI 1.47-2.01]; P = 0.00001), and shorter OS (4 studies, 766 pts., 9.1 vs. 18.9 months, HR = 1.22; [95% CI 1.04-1.44]; P = 0.01) compared to those with wild-type.

Conclusion: This analysis suggests that patients with mCRC and either PI3K or BRAF mutation may have a lower response and worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, routine testing for BRAF and PI3K mutational status should be considered. Novel therapeutic approaches are needed for patients with mutations in BRAF or PI3K.
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http://dx.doi.org/10.1007/s12029-018-0062-yDOI Listing
June 2019

The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities.

Expert Rev Anticancer Ther 2018 02 19;18(2):131-148. Epub 2017 Dec 19.

a Department of Oncology, School of Medicine , Wayne State University , Detroit , MI , USA.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer related mortality in the United States in 2030, with a 5-year overall survival of less than 10% despite decades of extensive research. Pancreatic cancer is marked by the accumulation of complex molecular changes, complex tumor-stroma interaction, and an immunosuppressive tumor microenvironment. PDAC has proven to be resistant to many cytotoxic, targeted and immunologic treatment approaches. Areas covered: In this paper, we review the major areas of research in PDAC, with highlights on the challenges and areas of opportunity for personalized treatment approaches. Expert commentary: The focus of research in pancreatic cancer has moved away from developing conventional cytotoxic combinations. The marked advances in understanding the molecular biology of this disease especially in the areas of the microenvironment, metabolism, and DNA repair have opened new opportunities for developing novel treatment strategies. Improved understanding of molecular abnormalities allows the development of personalized treatment approaches.
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http://dx.doi.org/10.1080/14737140.2018.1417844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121777PMC
February 2018

Approach to the medical management of surgically resectable gastric cancer.

Clin Adv Hematol Oncol 2016 Feb;14(2):129-35

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.

The optimal adjuvant management of patients with resectable gastric cancer remains a therapeutic challenge. Although the benefit of adjuvant therapy for these patients is clearly established, recurrence and mortality rates remain high despite such treatment. Moreover, surgical comorbidities and treatment toxicities result in high rates of failure to complete treatment after surgery. Two divergent approaches to adjuvant treatment have emerged as standard: postoperative chemoradiotherapy and perioperative chemotherapy. Because these approaches have never been compared directly, recommendations for adjuvant treatment require multidisciplinary discussion. During this discussion, the characteristics of the symptoms, the histology, location, and stage of the tumor, and the feasibility of the patient's completing all recommended therapy may be considered. In our own practice, we favor perioperative chemotherapy for patients with asymptomatic, proximal, higher-stage disease and adjuvant chemoradiotherapy for patients with symptomatic, distal, lower-stage disease. Herein, we summarize the available data for approaches to the adjuvant treatment of gastric cancer, with special consideration of the characteristics of the patients enrolled in the various studies. We also describe how we developed our paradigm for recommending a particular approach to adjuvant treatment for each patient.
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February 2016

Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC.

Cancer Immunol Res 2016 May 11;4(5):419-30. Epub 2016 Mar 11.

Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Washington, District of Columbia.

Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3(+) and CD8(+) cells and clinical outcome. High densities of both CD3(+) and CD8(+) T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3(+) and CD8(+) cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6-21.8] for CD3(+) and 3.9 (95% CI, 1.1-14.1) for CD8(+) Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD-L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419-30. ©2016 AACR.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303359PMC
May 2016

Comprehensive multiplatform biomarker analysis of 199 anal squamous cell carcinomas.

Oncotarget 2015 Dec;6(41):43594-604

Department of Medicine, GI Center, Roswell Park Cancer Institute, Buffalo, NY, USA.

Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy typically diagnosed in early stages and definitively treated with chemoradiation. In situations where patients exhibit metastatic or recurrent disease, treatment options are severely limited. In this study, molecular alterations were identified that could be used to aid in therapeutic decisions for patients with metastatic or recurrent anal squamous cell carcinoma. Specimens from patients with this cancer were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing, protein expression by immunohistochemistry, and gene amplification with in situ hybridization. Utilizing these techniques, novel treatment strategies that could be explored were identified, including potential benefit with anti-EGFR therapies, immune checkpoint inhibitors, topoisomerase inhibitors, and taxanes. The frequency of overexpression of proteins that mark resistance to chemotherapeutic drugs, such as MRP1 (chemotherapy efflux pump), ERCC1 (resistance to platinum-based chemotherapy), and thymidylate synthase (resistance to fluoropyrimidines) were also identified, suggesting a lack of benefit. This multiplatform strategy could be explored for its potential to generate a personalized treatment selection for patients with advanced ASCC, provide a guide for future therapeutic development for this cancer, and be extended to other rare cancer types as well.
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http://dx.doi.org/10.18632/oncotarget.6202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791253PMC
December 2015

Phase II study of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma.

Cancer Chemother Pharmacol 2015 Nov 8;76(5):1073-9. Epub 2015 Oct 8.

Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.

Purpose: To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC).

Methods: This single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1-7 and 150 mg/m(2) TMZ PO daily on days 1-5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03.

Results: We enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (n = 2), thrombocytopenia (n = 2), nausea (n = 1), and anemia (n = 1). The median PFS was 1.9 months, and median OS was 13.1 months.

Conclusion: The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit. CLINICALTRIALS.

Gov Identifier: NCT01205828.
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http://dx.doi.org/10.1007/s00280-015-2852-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612326PMC
November 2015

The effect of therapeutic anticoagulation on overall survival in men receiving first-line docetaxel chemotherapy for metastatic castration-resistant prostate cancer.

Clin Genitourin Cancer 2015 Feb 11;13(1):32-8. Epub 2014 Jun 11.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD. Electronic address:

Background: Anticoagulants have been postulated to possess antitumor activity, although clinical data supporting this claim are conflicting. No definitive data exist on the clinical impact of anticoagulation therapy in patients with prostate cancer. The aim of this study was to investigate the association between therapeutic anticoagulant use and survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel chemotherapy.

Patients And Methods: We retrospectively reviewed the records of 247 consecutive patients with mCRPC who received first-line docetaxel chemotherapy between 1998 and 2010 at a single institution. Among them, 29 patients (11.7 %) received therapeutic anticoagulation (low-molecular-weight heparin [LMWH] or warfarin) for the treatment of venous thromboembolism. Univariate and multivariable Cox proportional hazards regression models were used to investigate the effect of anticoagulant use on overall survival.

Results: In univariate analysis, anticoagulant use was associated with improved survival (hazard ratio [HR], 0.61; P = .024). Median survival was 20.9 months in the anticoagulation group versus 17.1 months in the control group (P = .024). In multivariable analysis, anticoagulant use remained a significant predictor of survival after adjusting for other baseline prognostic factors (HR, 0.49; P = .023). When each anticoagulant was considered separately in the multivariable model, LMWH remained significantly prognostic for survival (HR, 0.48; P = .035), whereas warfarin use did not.

Conclusions: Anticoagulant use (LMWH in particular) is an independent predictor of improved survival in men with mCRPC receiving docetaxel. These data provide the impetus to further explore the antitumor properties of anticoagulants in patients with prostate cancer and warrant validation in prospective studies.
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http://dx.doi.org/10.1016/j.clgc.2014.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332782PMC
February 2015

Prevalence and correlates of mental distress among regular undergraduate students of Hawassa University: a cross sectional survey.

Authors:
Anteneh Tesfaye

East Afr J Public Health 2009 Apr;6(1):85-94

Introduction: Mental health is gradually being recognized as an important public health concern. There is high level of mental distress in the community. Student integration in Universities is usually difficult and involves many factors which are potentially stressing.

Objective: To assess the prevalence of mental distress (Common mental disorders) among regular undergraduate students of Hawassa University, and to study its correlates

Method: This cross sectional study was conducted among regular undergraduate students of Hawassa University, during the period May 28-June 6, 2007, which was after the mid semester exam in the second semester of the academic year September, 2006- July, 2007. 'SRQ-20 items' was used to measure the prevalence of common mental disorders among the students. A total of 1198 students were included in the study.

Results: There was very high level of mental distress (49.1%). Highest levels of mental distress were observed among students of the Main Campus, in the Faculty of Business and economics, among freshman students and those students who never follow religious programs irrespective of their religion. Difficulty in making friends and dating; active sexual practice; conflicts in the dormitories with fellow students; income and stationary materials inadequacy; lack of adequate access to: academic reference materials; lack of adequate access to sanitary facility and recreational facility; overcrowding and worrying about personal safety were associated with higher levels of mental distress.

Conclusions And Recommendations: Detailed and focused study about the campus facilities that were proved to be deficient; correction of the deficiencies and the inclusion of a course in the freshman students' curricula that focuses on the mental well being of the young adult, means of coping with stress, possible challenges in the university life and other related issues (with their solutions) are discussed.
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http://dx.doi.org/10.4314/eajph.v6i1.45755DOI Listing
April 2009
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