Publications by authors named "Sara Nasser"

36 Publications

Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.

Cancer Res 2021 12 5;81(23):5818-5832. Epub 2021 Oct 5.

Translational Genomics Research Institute (TGen), Phoenix, Arizona.

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1033DOI Listing
December 2021

Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.

PLoS One 2021 7;16(4):e0248097. Epub 2021 Apr 7.

Translational Genomics Research Institute, Phoenix, AZ, United States of America.

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248097PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026051PMC
September 2021

Prognostic Value and Therapeutic Implications of Pleural Carcinosis and Malignant Pleural Effusion in Advanced Epithelial Ovarian Cancer.

Anticancer Res 2021 Apr;41(4):2033-2038

Department of Gynecological Oncology and Tumor Surgery, European Competence Center for Ovarian Cancer, Charité Campus Virchow Clinic, Berlin, Germany;

Aim: To demonstrate the prognostic value of pleural carcinosis/effusion in a cohort of patients with advanced epithelial ovarian cancer (EOC) and the associated therapeutic implications.

Patients And Methods: Overall, data for 388 patients with EOC with confirmed malignant pleural effusion (MPE) or pleural carcinosis were retrospectively analyzed. Exclusion criteria were non-epithelial ovarian malignancies and presence of other comorbidities associated with pleural effusions.

Results: The prognosis after the occurrence of MPE during the EOC in relapsed cases was poor with an overall survival of 9.9 months. In the multivariate analysis, the time point of the manifestation of the pleural effusion (p<0.001), platinum sensitivity (p=0.003), performance status (p=0.045) and presence of ascites (p=0.004) were significant prognostic factors for overall survival.

Conclusion: Even in this less favorable collective, well-established EOC prognostic factors were associated with a significantly better overall survival. This suggests that the overall behavioral pattern of the disease has strong similarities in patients with and without pleural effusion or carcinosis and merits an equally high therapeutic effort.
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http://dx.doi.org/10.21873/anticanres.14971DOI Listing
April 2021

A systematic review of Antimicrobial Stewardship Program implementation in Middle Eastern countries.

Int J Infect Dis 2021 Apr 15;105:746-752. Epub 2021 Mar 15.

Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.

Background: Antimicrobial resistance is a serious threat to global health. Antimicrobial Stewardship Programs (ASPs) are adopted by healthcare systems worldwide. This review aimed to evaluate the published practices of ASPs in Middle Eastern countries.

Methods: Searches were carried out in PubMed/MEDLINE, Embase, EBSCO, Cochrane Library, Google, and Google Scholar electronic databases for studies published from January 2005 to December 2020 that assessed ASP practices in Middle Eastern countries, following PRISMA guidelines.

Results: Of the 422 titles identified, 20 studies met the inclusion criteria. Eight studies were conducted in the Kingdom of Saudi Arabia, five in Qatar, two each in Lebanon and Jordan, and one each in Palestine and UAE; there was also one multinational study. Different ASP practices, including prospective auditing and feedback, pre-authorization, tracking, antibiotic restriction, education, de-escalation, and intravenous-to-oral switch, were reported. ASP practices correlated with improved susceptibility rates and decreases in antimicrobial use.

Conclusion: The outcomes of this review reveal the scarcity of data on ASP practices. The introduction of ASPs in hospitals in Middle Eastern countries has led to favorable clinical effects. Policymakers and stakeholders should promote and invest in implementing these programs as an essential component of their healthcare systems.
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http://dx.doi.org/10.1016/j.ijid.2021.03.035DOI Listing
April 2021

Subspecialty training in Europe: a report by the European Network of Young Gynaecological Oncologists.

Int J Gynecol Cancer 2021 04 24;31(4):575-584. Epub 2020 Dec 24.

Gynaecological Department, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: ESGO (European Society of Gynaecological Oncology) and partners are continually improving the developmental opportunities for gynaecological oncology fellows. The objectives of this survey were to evaluate the progress in the infrastructure of the training systems in Europe over the past decade. We also evaluated training and assessment techniques, the perceived relevance of ENYGO (European Network of Young Gynaecological Oncologists) initiatives, and unmet needs of trainees.

Methodology: National representatives of ENYGO from 39 countries were contacted with an electronic survey. A graduation in well/moderately/loosely-structured training systems was performed. Descriptive statistical analysis and frequency tables, as well as two-sided Fisher's exact test, were used.

Results: National representatives from 33 countries answered our survey questionnaire, yielding a response rate of 85%. A national fellowship is offered in 22 countries (66.7%). A logbook to document progress during training is mandatory in 24 (72.7%) countries. A logbook of experience is only utilized in a minority of nations (18%) for assessment purposes. In 42.4% of countries, objective assessments are recognized. Trainees in most countries (22 (66.7%)) requested additional training in advanced laparoscopic surgery. 13 (39.4%) countries have a loosely-structured training system, 11 (33.3%) a moderately-structured training system, and 9 (27.3%) a well-structured training system.

Conclusion: Since the last publication in 2011, ENYGO was able to implement new activities, workshops, and online education to support training of gynaecological oncology fellows, which were all rated by the respondents as highly useful. This survey also reveals the limitations in establishing more accredited centers, centralized cancer care, and the lack of laparoscopic training.
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http://dx.doi.org/10.1136/ijgc-2020-002176DOI Listing
April 2021

Role of predictive markers for severe postoperative complications in gynecological cancer surgery: a prospective study (RISC-Gyn Trial).

Int J Gynecol Cancer 2020 12 27;30(12):1975-1982. Epub 2020 Nov 27.

Department of Gynecology with Center for Oncological Surgery, European Competence Center for Ovarian Cancer, Charite Universitatsmedizin Berlin, Berlin, Germany.

Background: Surgery for gynecological cancer involves highly invasive and complex procedures potentially associated with various complications, which can cause extended hospital stays and delay of subsequent therapy, with a detrimental effect on the prognosis. The aim of this study was to explore and define the predictors of severe postoperative complications in patients undergoing surgery for gynecologic cancer.

Methods: Patients undergoing surgery for gynecologic cancers were analyzed prospectively from October 2015 through January 2017. Using validated assessment tools preoperatively, we assessed comorbidities, performance status, quality of life, nutritional and body composition by bioelectrical impedance analysis, and the surgical data of each patient. Surgical complications were graded using the Clavien-Dindo criteria. Using stepwise logistic regression models, we identified predictive markers for postoperative complications.

Results: Of the 226 enrolled patients, 40 (17.7%) experienced a grade ≥IIIb complication according to the Clavien-Dindo criteria. In the regression analysis, overweight/obesity (body mass index >25) (OR 6.41, 95% CI 2.38 to 17.24; p<0.001) and impaired physical functioning defined by a quality of life questionnaire (OR 4.19, 95% CI 1.84 to 9.50; p=0.001) emerged as significant predictors of postoperative complications. Moreover, postoperative complications were predicted by phase angle of bioelectrical impedance analysis <4.75° (OR 3.11, 95% CI 1.35 to 7.16; p=0.008) and Eastern Cooperative Oncology Group (ECOG) performance status >1 (OR 2.51, 95% CI 1.06 to 5.92; p=0.04). Intraoperative factors associated with higher risk of postoperative complications were increased use of norepinephrine (>11 µg/kg/min) (OR 5.59, 95% CI 2.16 to 14.44; p<0.001) and performance of large bowel resection (OR 4.28, 95% CI 1.67 to 10.97; p=0.002).

Conclusion: In patients undergoing surgery for gynecological cancer, preoperative evaluation of performance status according to ECOG, domains of quality of life and nutritional status, as well as intraoperative monitoring of risk factors, might help to identify patients at high risk for severe postoperative complications, and thus reduce surgical morbidity and mortality.
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http://dx.doi.org/10.1136/ijgc-2020-001879DOI Listing
December 2020

Unmet family planning needs among female refugees and asylum seekers in Germany - is free access to family planning services enough? Results of a cross-sectional study.

Reprod Health 2020 Jul 29;17(1):115. Epub 2020 Jul 29.

Department of Gynecology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: After the 1968 United Nations International Conference on Human Rights, access to family planning services became a human right. Such a service is of central importance to women's empowerment and is empirically needed to provide adequate healthcare. For registered refugees and asylum seekers in Germany complementary family planning services, including all forms of contraception, are free of charge. Yet, the success of these services remains unclear. The aim of this study is to describe the current reproductive health status of female refugees and to provide an initial overview of their existing unmet family planning and contraception needs.

Methods: Over the course of 2 years, from December 2015 to December 2017, a set of 50 female-only discussion groups were conducted in community shelters for registered refugees in Berlin. A total of 410 women between the ages of 14 and 74 participated. A convenience sampling strategy was then applied and a total of 307 semi-structured questionnaires covering 41 items related to demographic data and women's health were distributed to volunteering female participants over the age of 17. The statistical analysis of the questionnaires was performed using SPSS (IBM, PASW, Version 24). P-values less than or equal to 0.05 were considered statistically significant.

Results: Of the 307 participants, the majority were from Syria and Afghanistan (30% respectively). The mean age was 33 years (range: 18-63). On average, each woman had 2.5 births (range: 0-10). Twenty-four women (8%) were pregnant and fifty-four of the women (18%) were trying to become pregnant. The majority of women were classified as "requiring contraception" (n = 195; 63%) of which 183 gave further information on if and how they used family planning methods. The calculated unmet need for family planning in this group was 47%. Of the remaining 53% of the women who used contraception, many utilised "traditional" methods (34% withdrawal method; 8% calendar method) which have a pearl index of 4-18 and can therefore be classified as rather insufficient birth control methods. Intrauterine contraceptive devices were used by 30%.

Conclusion: Our study revealed that despite the provision of complementary family planning services, there remains unmet family planning and education needs in the female refugee community in Berlin. This study indicates that there is a major access gap to these services. Further research needs to be carried out to evaluate the access gap and clearly identify and implement action plans to address possible causes such as language barriers, lack of childcare and traumatic experiences.
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http://dx.doi.org/10.1186/s12978-020-00962-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389815PMC
July 2020

Scalable Generation of Mesenchymal Stem Cells and Adipocytes from Human Pluripotent Stem Cells.

Cells 2020 03 13;9(3). Epub 2020 Mar 13.

Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box, Doha 34110, Qatar.

Human pluripotent stem cells (hPSCs) can provide unlimited supply for mesenchymal stem cells (MSCs) and adipocytes that can be used for therapeutic applications. Here we developed a simple and highly efficient all--retinoic acid (RA)-based method for generating an off-the-shelf and scalable number of human pluripotent stem cell (hPSC)-derived MSCs with enhanced adipogenic potential. We showed that short exposure of multiple hPSC lines (hESCs/hiPSCs) to 10 μM RA dramatically enhances embryoid body (EB) formation through regulation of genes activating signaling pathways associated with cell proliferation, survival and adhesion, among others. Disruption of cell adhesion induced the subsequent differentiation of the highly expanded RA-derived EB-forming cells into a pure population of multipotent MSCs (up to 1542-fold increase in comparison to RA-untreated counterparts). Interestingly, the RA-derived MSCs displayed enhanced differentiation potential into adipocytes. Thus, these findings present a novel RA-based approach for providing an unlimited source of MSCs and adipocytes that can be used for regenerative medicine, drug screening and disease modeling applications.
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http://dx.doi.org/10.3390/cells9030710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140720PMC
March 2020

Effect of Hyaluronic Acid in Modifying Tensile Strength of Nonabsorbable Suture Materials: An Study.

J Int Soc Prev Community Dent 2020 Jan-Feb;10(1):16-20. Epub 2020 Feb 5.

Department of General Dentistry, Ajman University of science and Technology, Ajman, UAE.

Background And Aims: In periodontics and other surgical disciplines, sutures play a detrimental role in healing of wound. The use of chemical adjuncts to boost healing has been experimented in recent years. The aim of this study was to evaluate the role of hyaluronic acid rinse in influencing the tensile strengths of commonly used sutures.

Materials And Methods: Two commonly used nonabsorbable suture materials, silk and polyamide, were used for this study. Tensile strengths of the suture materials were determined by pre- and post-immersion in hyaluronic acid (test) and chlorhexidine (control). A Tinius Olsen Universal Testing Machine was used to assess the tensile strength of the samples. The variables were assessed for normality using the Kolmogorov-Smirnov test. The Wilcoxon signed rank test and Mann-Whitney test (for quantitative data within two groups) were used for quantitative data comparison of all the clinical indicators. The level of significance was set at ≤ 0.05.

Results: Polyamide showed better stability in terms of tensile strength when compared to silk. Hyaluronic acid as a chemical adjunct did not alter the tensile strengths of both suture materials pre- and post-immersion.

Conclusion: This study has shown a promising property of hyaluronic acid with relation to stabilization of tensile strength of suture materials, which needs to be evaluated in clinical settings.
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http://dx.doi.org/10.4103/jispcd.JISPCD_343_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055341PMC
February 2020

Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.

PLoS One 2019 27;14(12):e0219724. Epub 2019 Dec 27.

GE Research Center, Niskayuna, NY, United States of America.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219724PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934292PMC
March 2020

OVQUEST - Life after the diagnosis and treatment of ovarian cancer - An international survey of symptoms and concerns in ovarian cancer survivors.

Gynecol Oncol 2019 10 13;155(1):126-134. Epub 2019 Aug 13.

Prince of Wales Clinical School UNSW, and Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia.

Objectives: Our aim was to investigate the prevalence and potential risk factors for persistent and troublesome physical and psychological symptoms following treatment for ovarian cancer (OC).

Methods: OvQuest is an international, internet-based, cross-sectional questionnaire which explored symptom burden and quality of life (QOL) after treatment for OC. Eligible women were aged 18 and over, diagnosed with OC at least 6 months previously and had received chemotherapy. Self-report data were collected including demographics, diagnosis and treatment, and standardised instruments for treatment-related toxicities, QOL, physical activity (PA) and supportive care needs.

Results: The survey included 1360 patients, of whom 421 (31%) had been treated for recurrent OC. 78% reported symptoms of peripheral neuropathy, 60% significant fatigue, 48% mood disturbance and 59% moderate-severe insomnia. Rates of fatigue, mood disorders, neuropathy and insomnia did not differ between women with or without recurrence. The majority of respondents were overweight or obese (high BMI, 59%) and 35% reported low PA. Low PA and high BMI were associated with poorer QOL scores and higher symptom burden across a range of domains.

Conclusion: Women living after a diagnosis of OC report a substantial and ongoing symptom burden which impacts significantly on their quality of life across multiple domains. The reported associations between obesity, physical inactivity and poor QOL warrant prospective evaluation of lifestyle interventions to improve QOL.
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http://dx.doi.org/10.1016/j.ygyno.2019.08.009DOI Listing
October 2019

Physicians' perceptions, expectations, and experiences of clinical pharmacists in Jordan-2017.

Int J Clin Pharm 2019 Oct 3;41(5):1193-1201. Epub 2019 Aug 3.

Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ, USA.

Background A decade ago, clinical pharmacy was a new concept in hospital settings in Jordan, as evidenced in our 2006/2007 study. Changes in the perceptions, expectations, and experiences of physicians regarding the role of clinical pharmacists need to be investigated. Objective To document physicians' perceptions and expectations of, and experiences with, clinical pharmacists in hospital settings in 2017, and to assess differences in these areas between the 2017 and the 2006/2007 samples. Setting: The study was conducted at four hospitals in the north of Jordan. Method Physicians completed a self-administered questionnaire similar to the one used in our 2006/2007 study, which recorded demographics and assessed physicians' perceptions, expectations, and experiences regarding clinical pharmacists. Data of the 2017 sample were analyzed and compared descriptively to those of the 2006/2007 sample. Main outcome measure Physicians' perceptions, expectations, and experiences of pharmacists in hospital settings in 2017. Results Two hundred and ninety-five physicians completed the questionnaire. Physicians in the 2017 sample were most comfortable with pharmacists suggesting the use of prescription medications such as antibiotics (53.6%). Physicians in the 2017 cohort agreed with the eight expectations stated in the questionnaire. Physicians' experiences with clinical pharmacists improved in 2017 from 2006/2007 in all eight areas evaluated. Conclusion Physicians' perceptions, expectations, and experiences towards the professional role of pharmacists have changed over the past 10 years in Jordan.
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http://dx.doi.org/10.1007/s11096-019-00884-6DOI Listing
October 2019

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

Int J Cancer 2019 10 3;145(7):1889-1901. Epub 2019 Apr 3.

Center for Data-Driven Discovery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.
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http://dx.doi.org/10.1002/ijc.32258DOI Listing
October 2019

A report on the Marrakech International Women's Cancer Days: dialogs and implications.

Int J Gynecol Cancer 2019 02 21;29(2):417-421. Epub 2018 Dec 21.

Department of Gynecologic Oncology, Charite Comprehensive Cancer Center, Berlin, Germany.

The MarrakechInternational Women's Cancer Days showcased a first-time international meeting of healthcare professionals worldwide to discuss, over the course of 3 days, aspects of public health, prevention, and treatment of gynecological cancers in the Arabic region. The focus was particularly on promoting globally sustainable research initiatives. The event was a joint initiative organized by the Gynecological Cancer Intergroup and the Pan-Arabian Research Society of Gynecological Oncology. The first conference day focused on the early diagnosis and screening of cervical cancer and the required action to establish equity within screening programs and improve cancer control strategies in the Euro-Mediterranean region. The second day highlighted current screening, diagnosis, and treatment strategies for ovarian cancer in the Arabic region, with particular discussion on the incidence of germline mutations in Arabic women with ovarian cancer. Centers from the Arabic region such as Jordan, Tunesia, Sudan, and Morocco presented their own data on ovarian cancer patients and local clinical practice, and barriers to treatment. It was highlighted that more support is required in surgical training and medical therapies. On the third day , the focus was on cervical cancer therapies and treatment. Interesting surveys on patient awareness of screening programs and cervical cancer were presented from various centers including Lebanon, Sudan, and the UAE. The conference ended with emphasis on patient education, and quality of life. The meeting provided a first-time platform for sustainable worldwide dialog and exchange on all aspects of gynecological cancers focusing on the Arabic woman and the particular barriers, unchartered territories, and challenges this patient population presents to the global healthcare community.
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http://dx.doi.org/10.1136/ijgc-2018-000059DOI Listing
February 2019

Impact of right upper quadrant cytoreductive techniques with extensive liver mobilization on postoperative hepatic function and risk of liver failure in patients with advanced ovarian cancer.

Gynecol Oncol 2018 12 29;151(3):466-470. Epub 2018 Sep 29.

Department of Gynaecologic Oncology, Imperial College Healthcare NHS Trust, London, United Kingdom. Electronic address:

Objective: Evaluate postoperative hepatic-function in patients with advanced ovarian cancer (OC) who underwent extensive right upper-quadrant (RUQ) cytoreduction in primary, relapsed or interval settings.

Methods: We retrospectively reviewed all patients with OC who underwent liver resection, mobilization and/or diaphragmatic-stripping between 01/2013 and 12/2016. Postoperative liver enzyme function (LFTs), assessed by alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin (Bil), was correlated with postoperative complications.

Results: 132 patients were identified. 81 patients (61%) underwent upfront, 25(19%) interval and 26(20%) secondary cytoreduction. The surgical procedures were right diaphragmatic peritoneal stripping (81/132;61%), full-thickness resection (42/132;32%), liver-capsule resection (85/132;64%), porta-hepatis tumor resection (11/132;8%) and partial hepatectomy (5/132;4%). 74%(98/132) of patients increased their LFTs postoperatively with a peak at 24-hours. Highest ALT median was 1.7-fold of upper normal limit (UNL), with the highest ALT value rising up to 28-fold UNL on the 1st postoperative day (PoD)(range 6-1792 IU/L). Median value of highest ALP was within normal, with the highest ALP value rising up to 4-fold UNL on PoD 5(range 22-512 IU/L). Median value of highest Bilirubin level was also within normal, with highest Bilirubin level rising up to 6-fold UNL on PoD 5(range: 2-120 μmol/L). Mean LFT-normalization time was 7 days (range: 3-14 days). No significant morbidity was directly linked to LFT deterioration, apart from one case (0.8%) of fatal fulminant hepatic-failure.

Conclusion: RUQ-cytoreduction is almost always associated with a transient LFT-increase, with no significant clinical implications and spontaneous normalization within the first postoperative week. Due to the existing risk of fulminant liver failure, albeit rare and difficult to predict, postoperatively elevated LFTs should be monitored, until normalization. Large prospective studies are required to assess the predictive value of LFTs and other risk factors for postoperative hepatic failure in patients with OC undergoing extensive RUQ-cytoreduction.
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http://dx.doi.org/10.1016/j.ygyno.2018.09.028DOI Listing
December 2018

Checkpoint-inhibition in ovarian cancer: rising star or just a dream?

J Gynecol Oncol 2018 Nov;29(6):e93

Department of Gynecology, European Competence Center for Ovarian Cancer (EKZE), Charité-University Medicine of Berlin, Campus Virchow Klinikum, Berlin, Germany.

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.
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http://dx.doi.org/10.3802/jgo.2018.29.e93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189441PMC
November 2018

Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma.

Clin Cancer Res 2018 01 26;24(2):295-305. Epub 2017 Oct 26.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.

Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma. We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome sequencing and tumor RNA sequencing were performed to identify molecular targets for potential matched therapy. A multidisciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood-brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed. Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome sequencing was completed for all patients, and RNA sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression free 21 months after surgery, 3 times longer than the patient's previous time to progression. Analysis of matched nonenhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations. Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516926PMC
January 2018

A Review of Thoracic and Mediastinal Cytoreductive Techniques in Advanced Ovarian Cancer: Extending the Boundaries.

Ann Surg Oncol 2017 Nov 31;24(12):3700-3705. Epub 2017 Aug 31.

NHS Trust, West London Gynecological Cancer Centre, Imperial College, London, UK.

The aim of this study was to review the surgical and clinical outcomes of intrathoracic and mediastinal surgical cytoreduction in stage IV epithelial ovarian cancer (EOC). Relevant articles were identified from MEDLINE and EMBASE. Only analyses or reports that described actual intrathoracic cytoreduction via pleurectomy and/or resection of cardiophrenic/mediastinal lymph nodes were included. Imaging articles that merely described thoracic tumor patterns were excluded. A total of nine studies were identified, the oldest originating in 2007. Procedures described were transdiaphragmatic resection of cardiophrenic lymph nodes and pleural disease (n = 5) and video-assisted thoracoscopic and mediastinal tumorectomies including pleurectomy (n = 4). The number of operated patients ranged between 1 and 30 with complete cytoreduction rates ranging between 68 and 100%. No surgical deaths directly related to the thoracic cytoreduction were reported and only one patient (1/30) experienced a postoperative complication in terms of a pneumothorax. None of the studies presented a direct comparison of survival to patients with thoracic disease who did not undergo thoracic cytoreduction, and therefore the survival benefit of thoracic cytoreduction could not be quantified. In conclusion, thoracic cytoreduction in advanced EOC seems feasible and with acceptable morbidity while offering a better understanding of the extent of disease and hence allowing the tailoring of intraabdominal resections. Nevertheless, its direct impact on patients' survival by a potential overruling of a more adverse tumor biology remains to be established in larger-scale prospective and ideally randomized trials.
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http://dx.doi.org/10.1245/s10434-017-6051-8DOI Listing
November 2017

Integrated genomic analyses reveal frequent aberrations in acral melanoma.

Genome Res 2017 04;27(4):524-532

Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.

Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver mutations. In contrast with CM, we observed copy gains in 15% of patients, and somatic translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.
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http://dx.doi.org/10.1101/gr.213348.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378171PMC
April 2017

Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers.

Sci Rep 2016 12 23;6(1):25. Epub 2016 Dec 23.

Translational Genomics Research Institute, Phoenix, AZ, USA.

DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1-3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.
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http://dx.doi.org/10.1038/s41598-016-0021-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431338PMC
December 2016

Feasibility and Safety of Laparoscopic Total Mesometrial Resection in Early-stage Cervical Cancer.

Anticancer Res 2016 09;36(9):4903-7

Department of Gynecology, Campus Virchow-Klinikum, Charité Medical University, Berlin, Germany

Aim: In this study we aimed to analyze the safety and feasibility of total mesometrial resection (TMMR) using the laparoscopic approach.

Patients And Methods: Laparoscopic TMMR and pelvic lymphadenectomy (LNE) was carried out in 34 patients with cervical cancer FIGO IA-IIB from April 2012-April 2016 at our tertiary center. Para-aortic LNE was performed when indicated. The main outcomes included surgical margins, a number of retrieved lymph node, intra- and post-operative complications, and recurrence rates.

Results: Complete microscopic tumor resection was confirmed in 33/34 (97%) patients. No conversion to open surgery was necessary. Mean intra-operative blood loss was only 65.2 ml with no blood transfusions required. Intra-operative complications occurred in 4/34 (11.8%) cases (2 bladder injuries and 2 ureteric injuries). Post-operative complications were observed in 10/35 (29.4%) cases. Only one complication occurred after 30 days (vesico-vaginal fistula). There was a loco-regional recurrence within a mean follow-up time of 25.9 months.

Conclusion: Laparoscopic TMMR appears to be feasible and safe in the treatment of early-stage cervical cancer. Further large-scale studies are required.
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http://dx.doi.org/10.21873/anticanres.11055DOI Listing
September 2016

A somatic reference standard for cancer genome sequencing.

Sci Rep 2016 Apr 20;6:24607. Epub 2016 Apr 20.

Translational Genomics Research Institute, Phoenix, Arizona, USA.

Large-scale multiplexed identification of somatic alterations in cancer has become feasible with next generation sequencing (NGS). However, calibration of NGS somatic analysis tools has been hampered by a lack of tumor/normal reference standards. We thus performed paired PCR-free whole genome sequencing of a matched metastatic melanoma cell line (COLO829) and normal across three lineages and across separate institutions, with independent library preparations, sequencing, and analysis. We generated mean mapped coverages of 99X for COLO829 and 103X for the paired normal across three institutions. Results were combined with previously generated data allowing for comparison to a fourth lineage on earlier NGS technology. Aggregate variant detection led to the identification of consensus variants, including key events that represent hallmark mutation types including amplified BRAF V600E, a CDK2NA small deletion, a 12 kb PTEN deletion, and a dinucleotide TERT promoter substitution. Overall, common events include >35,000 point mutations, 446 small insertion/deletions, and >6,000 genes affected by copy number changes. We present this reference to the community as an initial standard for enabling quantitative evaluation of somatic mutation pipelines across institutions.
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http://dx.doi.org/10.1038/srep24607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837349PMC
April 2016

AGO Score As a Predictor of Surgical Outcome at Secondary Cytoreduction in Patients with Ovarian Cancer.

Anticancer Res 2015 Jun;35(6):3423-9

Department of Gynecology, Virchow Campus Clinic, Charité Medical University, Berlin, Germany.

Aim: The present study aimed to compare the outcome of secondary cytoreductive surgery retrospectively in patients with positive and negative Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score that were operated on at the Department of Gynecology, Charité Comprehensive Cancer Center, Medical University, between 2006 and 2013.

Patients And Methods: A total of 209 consecutive patients presenting a first recurrence of epithelial ovarian cancer were enrolled: 139 patients had a positive AGO score, and 70 patients had at least one negative criterion of the AGO score. All patients underwent secondary cytoreductive surgery and data were evaluated retrospectively.

Results: Total macroscopic tumor resection was obtained during secondary cytoreductive surgery in 127 patients (61%), 93 (67%) in the AGO-positive group and 34 (48.5%) in the AGO-negative group. Overall (OS) and progression-free survival (PFS) were identical in both groups of patients when secondary cytoreductive surgery succeeded in achieving complete tumor resection. PFS was 22 months in AGO-positive patients who were tumor-free after secondary cytoreductive surgery and 21 months in AGO-negative patients with complete resection after secondary cytoreductive surgery. There were no significant differences in morbidity and mortality rates for both groups.

Conclusion: AGO score is a useful predictor for operability in patients with a first recurrence of ovarian cancer. Patients with negative scores may still have a 50% chance of achieving optimal tumor resection after secondary cytoreductive surgery. This will be a pivotal factor when counseling patients with recurrent disease regarding further management options.
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June 2015

An integrated framework for reporting clinically relevant biomarkers from paired tumor/normal genomic and transcriptomic sequencing data in support of clinical trials in personalized medicine.

Pac Symp Biocomput 2015 :56-67

Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.

The ability to rapidly sequence the tumor and germline DNA of an individual holds the eventual promise of revolutionizing our ability to match targeted therapies to tumors harboring the associated genetic biomarkers. Analyzing high throughput genomic data consisting of millions of base pairs and discovering alterations in clinically actionable genes in a structured and real time manner is at the crux of personalized testing. This requires a computational architecture that can monitor and track a system within a regulated environment as terabytes of data are reduced to a small number of therapeutically relevant variants, delivered as a diagnostic laboratory developed test. These high complexity assays require data structures that enable real-time and retrospective ad-hoc analysis, with a capability of updating to keep up with the rapidly changing genomic and therapeutic options, all under a regulated environment that is relevant under both CMS and FDA depending on application. We describe a flexible computational framework that uses a paired tumor/normal sample allowing for complete analysis and reporting in approximately 24 hours, providing identification of single nucleotide changes, small insertions and deletions, chromosomal rearrangements, gene fusions and gene expression with positive predictive values over 90%. In this paper we present the challenges in integrating clinical, genomic and annotation databases to provide interpreted draft reports which we utilize within ongoing clinical research protocols. We demonstrate the need to retire from existing performance measurements of accuracy and specificity and measure metrics that are meaningful to a genomic diagnostic environment. This paper presents a three-tier infrastructure that is currently being used to analyze an individual genome and provide available therapeutic options via a clinical report. Our framework utilizes a non-relational variant-centric database that is scaleable to a large amount of data and addresses the challenges and limitations of a relational database system. Our system is continuously monitored via multiple trackers each catering differently to the diversity of users involved in this process. These trackers designed in analytics web-app framework provide status updates for an individual sample accurate to a few minutes. In this paper, we also present our outcome delivery process that is designed and delivered adhering to the standards defined by various regulation agencies involved in clinical genomic testing.
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April 2016

A rare case of ovarian cancer in pregnancy complicated by pulmonary embolus and myocardial infarction: management dilemmas.

J Surg Case Rep 2014 Oct 13;2014(10). Epub 2014 Oct 13.

Department of Gynaecological Oncology Charite Comprehensive Cancer Centre, Charite - Universitaetsmedizin Berlin, Berlin, Germany.

Malignant ovarian neoplasms diagnosed during pregnancy at advanced stages are very rare. The clinical course and prognosis of pregnant patients diagnosed with epithelial ovarian cancer is similar to that of non-pregnant patients. We describe our management of a woman diagnosed with FIGO IIIc ovarian cancer at Caesarean section. Immediately after surgery she suffered a pulmonary embolus and a myocardial infarction. She showed signs of a severe pulmonary hypertension (59 mmHg). Four weeks later the pulmonary hypertension was still moderate but, despite her critical status, she underwent primary debulking surgery (PDS). This was performed under extensive anaesthesiological monitoring. Through this rare case, we show that despite the complex initial status of a critically ill patient, PDS can still remain the mainstay of treatment in patients with advanced ovarian cancer as most patients are able to tolerate even extensive debulking surgery without the need for neoadjuvant chemotherapy.
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http://dx.doi.org/10.1093/jscr/rju099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194630PMC
October 2014

Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate.

PLoS Genet 2014 Mar 13;10(3):e1004229. Epub 2014 Mar 13.

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.
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http://dx.doi.org/10.1371/journal.pgen.1004229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953017PMC
March 2014

Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

PLoS Genet 2014 Feb 13;10(2):e1004135. Epub 2014 Feb 13.

Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.
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http://dx.doi.org/10.1371/journal.pgen.1004135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923676PMC
February 2014

Integrated genomic and epigenomic analysis of breast cancer brain metastasis.

PLoS One 2014 29;9(1):e85448. Epub 2014 Jan 29.

Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085448PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906004PMC
September 2014

Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing.

Int J Gynecol Cancer 2014 Feb;24(2):329-38

*Translational Genomics Research Institute; †Comprehensive Cancer Care, St Joseph's Hospital and Medical Center, Phoenix; ‡Mayo Clinic, Scottsdale; §Department of Obstetrics and Gynecology, St Joseph's Hospital and Medical Center, and ∥Division of Gynecologic Oncology, Creighton University School of Medicine, St Joseph's Hospital and Medical Center, University of Arizona Cancer Center, Phoenix, AZ.

Objective: Integration of carcinogenic human papillomaviruses (HPVs) into the host genome is a significant tumorigenic factor in specific cancers including cervical carcinoma. Although major strides have been made with respect to HPV diagnosis and prevention, identification and development of efficacious treatments for cervical cancer patients remains a goal and thus requires additional detailed characterization of both somatic events and HPV integration. Given this need, the goal of this study was to use the next generation sequencing to simultaneously evaluate somatic alterations and expression changes in a patient's cervical squamous carcinoma lesion metastatic to the lung and to detect and analyze HPV infection in the same sample.

Materials And Methods: We performed tumor and normal exome, tumor and normal shallow whole-genome sequencing, and RNA sequencing of the patient's lung metastasis.

Results: We generated over 1.2 billion mapped reads and identified 130 somatic point mutations and indels, 21 genic translocations, 16 coding regions demonstrating copy number changes, and over 36 genes demonstrating altered expression in the tumor (corrected P < 0.05). Sequencing also revealed the HPV type 18 (HPV-18) integration in the metastasis. Using both DNA and RNA reads, we pinpointed 3 major events indicating HPV-18 integration into an intronic region of chromosome 6p25.1 in the patient's tumor and validated these events with Sanger sequencing. This integration site has not been reported for HPV-18.

Conclusions: We demonstrate that DNA and RNA sequencing can be used to concurrently characterize somatic alterations and expression changes in a biopsy and delineate HPV integration at base resolution in cervical cancer. Further sequencing will allow us to better understand the molecular basis of cervical cancer pathogenesis.
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http://dx.doi.org/10.1097/IGC.0000000000000049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921261PMC
February 2014
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