Molecular profiling (MP)-selected therapy for the treatment of patients with advanced pancreaticobiliary cancer (PBC).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 195-195
Author(s):  
Ron Epelbaum ◽  
Einat Shacham-Shmueli ◽  
Ravit Geva ◽  
Ayala Hubert
Keyword(s):  
Retrospective Analysis ◽  
Null Hypothesis ◽  
Impact Analysis ◽  
Treatment Decision ◽  
Treatment Selection ◽  
Outcome Analysis ◽  
Sequencing Analysis ◽  
Tissue Samples ◽  
Treatment Regimens ◽  
Guided Therapy

195 Background: For patients (pts) with advanced PBC who are able to pursue additional therapy, treatment selection is often empiric and clinical benefits are usually modest. Our goal was to study clinical outcomes of MP-guided treatment in advanced PBC. Methods: This retrospective analysis included pts with advanced PBC whose tissue samples underwent MP (IHC, microarray [MA], and sequencing analyses) using Target Now (Caris Life Sciences, Irving, TX). These pts received ≥1 lines of therapy for advanced PBC before their treatment was guided by MP. The MP-guided therapy was considered to have clinical benefit if the TTP ratio between the longest TTP on MP-guided therapy and the TTP on the last therapy pre-MP was ≥1.3. Results: Out of 20 pts included in the analysis, 16 had advanced cancer of the pancreas. Median age was 59 yrs (range: 30-81), 85% were male, and 60% had PS of 1. Pts had 1-4 treatment regimens (median: 1) prior to MP. MP identified 1-7 (median: 4) actionable targets per pt. The most commonly identified targets by IHC were: negative or low TS (80%), high TOPO1 (70%), negative or low ERCC1 (52%), and high SPARC (40%). In all 14 pts that had MA results, multiple actionable targets were identified. Of 14 pts with KRAS sequencing analysis, 10 pts (71%) had mutations. Post-MP, pts had 1-4 (median: 1) treatment regimens, most commonly FOLFIRI/XELIRI, FOLFOX/XELOX, capecitabine, and nab-paclitaxel. The total number of regimens post-MP was 33, of which 29 were evaluable for decision impact analysis. In 24 (83%) of cases, treatment decision was modified due to the MP results. Out of the 20 pts, 4 received ≤1 cycle of MP-guided therapy during rapidly progressing disease and were excluded from the clinical outcome analysis. Of the 16 evaluable pts, 6 (37.5%) had a TTP ratio of ≥1.3 (one-sided exact binomial test vs a null hypothesis of ≤15% with TTP ratio ≥1.3, P=0.0056; therefore the null hypothesis is rejected). Conclusions: In our retrospective analysis of a small, yet well-defined, cohort of pts with advanced PBC, MP often influenced treatment decisions and over a third of pts experienced a longer TTP (compared to the last regimen pre-MP), highlighting the promise in MP for treatment selection.

scholarly journals Molecular Profiling-Selected Therapy for Treatment of Advanced Pancreaticobiliary Cancer: A Retrospective Multicenter Study

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Ron Epelbaum ◽  
Einat Shacham-Shmueli ◽  
Baruch Klein ◽  
Abed Agbarya ◽  
Baruch Brenner ◽  
...  
Keyword(s):  
Null Hypothesis ◽  
Impact Analysis ◽  
Treatment Decision ◽  
Treatment Decisions ◽  
Molecular Profiling ◽  
Outcome Analysis ◽  
Multicenter Cohort Study ◽  
Pancreaticobiliary Cancer ◽  
The Impact ◽  
Guided Therapy

This multicenter cohort study assessed the impact of molecular profiling (MP) on advanced pancreaticobiliary cancer (PBC). The study included 30 patients treated with MP-guided therapy after failing ≥1 therapy for advanced PBC. Treatment was considered as having benefit for the patient if the ratio between the longest progression-free survival (PFS) on MP-guided therapy and the PFS on the last therapy before MP was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. Overall, ≥1 actionable (i.e., predictive of response to specific therapies) biomarker was identified/patient. Immunohistochemistry (the most commonly used method for guiding treatment decisions) identified 1–6 (median: 4) actionable biomarkers per patient. After MP, patients received 1–4 (median: 1) regimens/patient (most commonly, FOLFIRI/XELIRI). In a decision-impact analysis, of the 27 patients for whom treatment decisions before MP were available, 74.1% experienced a treatment decision change in the first line after MP. Twenty-four patients were evaluable for clinical outcome analysis; in 37.5%, the PFS ratio was ≥1.3. In one-sided exact binomial test versus the null hypothesis,P= 0.0015; therefore, the null hypothesis was rejected. In conclusion, our analysis demonstrated the feasibility, clinical decision impact, and potential clinical benefits of MP-guided therapy in advanced PBC.

scholarly journals Identifying Opportunities and Challenges for Patients With Sarcoma as a Result of Comprehensive Genomic Profiling of Sarcoma Specimens

2020 ◽  
pp. 176-182 ◽  
Author(s):  
Margaret A. Hay ◽  
Eric A. Severson ◽  
Vincent A. Miller ◽  
David A. Liebner ◽  
Jo-Anne Vergilio ◽  
...  
Keyword(s):  
Decision Making ◽  
Bone Biopsy ◽  
Clinical Care ◽  
Soft Tissue Sarcomas ◽  
Treatment Decision ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Treatment Selection ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling

PURPOSE Comprehensive genomic profiling (CGP) of sarcomas is rapidly being integrated into routine clinical care to help refine diagnosis and prognosis and determine treatment. However, little is known about barriers to successful CGP or its clinical utility in sarcoma. We set out to determine whether CGP alters physician treatment decision-making, and whether sarcoma subtypes influence the frequency of successful technical performance of CGP. METHODS A single-institution study evaluated profiling outcomes of 392 samples from patients with sarcoma, using a commercially available CGP panel. Of this group, 34 patients were evaluated prospectively (Decision Impact Trial) to evaluate the utility of CGP in physician decision-making. All cases were retrospectively analyzed to identify causes of CGP failure. RESULTS CGP successfully interrogated 75.3% (n = 295 of 392) of patients with sarcoma. Bone sarcomas had lower passing rates at 65.3% (n = 32 of 49) compared with soft tissue sarcomas at 76.7% (n = 263 of 343; P = .0008). Biopsy location also correlated with profiling efficiency. Bone biopsy specimens had a 52.8% (n = 19 of 36) passing rate versus lung (61.1%; n = 33 of 54) and abdomen (80.1%; n = 109 of 136) specimens. CGP altered physician treatment selection in 25% of evaluable patients (n = 7 of 28) and was associated with improved progression-free survival. CONCLUSION To our knowledge, this is the largest technical evaluation of the performance of CGP in sarcoma. CGP was effectively performed in the vast majority of sarcoma samples and altered physician treatment selection. Tumor location and tissue subtype were key determinants of profiling success and associated with preanalytic variables that affect DNA and RNA quality. These results support standardized biopsy collection protocols to improve profiling outcomes.

scholarly journals Mo1331 RETROSPECTIVE ANALYSIS OF A MODIFIED ENDOSCOPIC ULTRASOUND NEEDLE TO OBTAIN HISTOLOGICAL TISSUE SAMPLES

2018 ◽  
Vol 87 (6) ◽  
pp. AB448-AB449
Author(s):  
Kaartik Soota ◽  
Jagpal S. Klair ◽  
Sarika Gupta ◽  
Arvind R. Murali ◽  
Chris Jensen ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Endoscopic Ultrasound ◽  
Tissue Samples

A Comparative Oncology Analysis of Canine T-Cell Lymphoma (TCL): Immunohistochemical Study and Next Generation Sequencing for Protein Analysis and Genomic Target Discovery

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3883-3883
Author(s):  
Athena Kritharis ◽  
J. Tyson McDonald ◽  
Afshin Beheshti ◽  
Monika Pilichowska ◽  
Kristine Burgess ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Sequencing Analysis ◽  
Type B ◽  
Next Generation ◽  
Comparative Oncology ◽  
Tissue Samples ◽  
Next Generation Dna Sequencing ◽  
Human Antibodies ◽  
Network Analyses ◽  
Variant Type

Abstract Background: TCLs are an uncommon, heterogeneous group of neoplasms with no consensus on optimal treatment and human 5-year survival rates <20-30%. The canine provides a potentially attractive model to study TCL in part given their spontaneously occurring cancers, intact immune system, and phylogenetic resemblance to humans. Furthermore, approximately 1/3 of all lymphomas in canine are TCL (cTCL). Previous research from our group (ASH 2014, #74755) identified 118 differentially expressed genes by RNA seq analyses comparing canine PTCL with normal canine lymph node, and PI3K, GATA3, GRB2 and PPARG as candidate biomarker genes by canonical pathway and network analyses. We aimed to further interrogate the canine as a model by histologic review and detailed genomic examination of cTCL. Methods: We evaluated de novo cTCL with immunohistochemistry (IHC) and next generation DNA sequencing for a priori genes. IHC on canine TCL was evaluated with human antibodies against CD5, CD79a, Ki67, CD3, CD4, CD8 and CD30. Canine DNA was extracted from 14 fresh frozen tissue samples and 2 paraffin embedded blocks using the QIAamp DNA Mini Kit. Utilizing the human Cancer Hotspot Panel v2 (hCHPv2), a custom expanded panel of 68 genes actively expressed in lymphoma tumor cells was created to screen cTCL for mutations. COSMIC database and PubMed was used to identify common variants expected to be present. Targets from the hCHPv2 were converted from the human genome (hg19) to positions in the canine genome (canFam3) using liftOver (UCSC Genome Browser). Following targeted amplification using the custom canine library, DNA sequencing was performed with the Ion Personal Genome Machine resulting in 4,527,638 total reads with an average length of 229 bases and 708x coverage per sample. Results: For IHC, we examined 10 primary cTCL cases utilizing human antibodies. The cTCL cases staining patterns included: 100% were CD79a negative; 80% were CD5+; Ki67 was variable; while the remaining multiple markers did not react to human antibodies. We subsequently evaluated 16 primary cTCL tumor tissue samples using DNA sequencing. There were 331 unique variants and 1474 total variants; each sample had an average of 92 variants. The most prevalent coding consequences mutations were intron variations (68%), followed by synonymous (14%) and missense variations (9%) (Fig. 1A). The most prevalent mutations were found in ATM, KIT, ERBB4, TNFAIP3, and TET2 (Fig. 1B). ATM has been implicated as a tumor suppressor and mutations have been described on a case basis in human thymic and mantle cell lymphomas, however, not in TCL. Furthermore, the majority of ATM variants identified in our analysis were non-coding or synonymous. In ATM, there were 22 mutations with 17 found as introns. The 5 coding mutations had only one of which was missense (M1758T), the others were silent (Fig. 1C). Conversely, the most prevalent variants found in the coding region were found in SMO, TP53, TNFAIP3, and TET2. Of all coding variants, 15 missense variants in TNFAIP3, JAK2, MYC, MET, SMO, DNMT3A, RB1, PIK3CA, TP53, and ERBB2 appeared to be deleterious through bioinformatics analysis. Additionally, a frameshift variant in CDH1 resulted in a 3 bp deletion that has not been described in dbSNP. Finally, mutations in KIT, TNFAIP3 and TET2 have been described in canine and human TCL with varying frequency. Conclusion: To the best of our knowledge, this represents one of the first genomic comparative oncology analyses conducted in TCL. Collectively, the DNA sequencing analysis in cTCL identified genomic similarities and novel mutations that may help unearth new oncogenic pathways in human TCL (e.g., ATM). Furthermore, the deleterious frameshift and missense mutations identified in this study as from TNFAIP3 and CDH1 are novel, of which has not been described in prior research. Continued investigation is needed towards the enhanced delineation of protein expression of cTCL and examination of the functional impact of genomic perturbations identified in cTCL in comparison to human TCL. Figure 1. Next generation DNA sequencing of canine TCL . A. Coding consequences by variant type. B. All gene variations by frequency C. Mutation map of ATM. Figure 1. Next generation DNA sequencing of canine TCL . A. Coding consequences by variant type. B. All gene variations by frequency C. Mutation map of ATM. Disclosures No relevant conflicts of interest to declare.

The influence of age plus standard clinical approach with or without comprehensive geriatric assessment (CGA) on treatment decisions in older cancer patients: Final results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9035-9035
Author(s):  
Lore Decoster ◽  
Cindy Kenis ◽  
Katrien Van Puyvelde ◽  
Jacques De Greve ◽  
Godelieve Conings ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Prospective Trial ◽  
Treatment Decision ◽  
Treatment Decisions ◽  
Clinical Approach ◽  
University Hospitals ◽  
Oncological Treatment ◽  
Treatment Regimens ◽  
Reduced Dose ◽  
Older Cancer Patients

9035 Background: The aim of this prospective study was to examine how age and standard clinical approach with and without CGA results determine treatment decisions in older cancer patients (pts). Methods: This study,conducted in 2 Belgian university hospitals, included pts ≥ 70 years with a malignant tumor (breast, colorectal, ovarian, lung, prostate and hematological) if a new cancer therapy was considered. All pts underwent a uniform CGA. Results were communicated to the treating physician. After the treatment decision, an interview with the treating physician was performed, using a predefined questionnaire: 1/ What would be your oncological treatment proposal in case the pt was 55y without other comorbidity? 2/ Is this different from your treatment proposal for this pt according to age and standard clinical approach without CGA results? 3/ Is this different from your treatment proposal for this pt with CGA results? Results: From October 2009 till July 2011, 937 pts were included in the study. Median age was 76y (range 70-95) and 63.5% was female. A total of 902 (96.3%) questionnaires were completed and 56.2% of the physicians were aware of the CGA results at treatment decision. In 381 pts (42.2%; 95%CI 39.0-45.5) age and standard clinical approach led to a different treatment decision compared to younger pts without comorbidity. This influence was most prominent for chemotherapy decisions: 309 patients did not receive standard chemotherapy (reduced dose (13), less toxic regimen (163), less toxic regimen at reduced dose (5) or no chemotherapy (128)). When the physician was aware of the CGA, these results influenced their treatment in 6.7% (95%CI: 4.5-8.9), mostly concerning chemotherapy. In 8 pts CGA results encouraged the treating physician to choose a more aggressive chemotherapy regimen and in 11 pts CGA results led to a decision of palliative care. Conclusions: Based on this prospective trial, we conclude that physicians use adapted treatment regimens in older versus younger pts, only based on age and standard clinical approach. CGA results change the treatment decision in 6.7% and sometimes trigger the use of a more aggressive treatment.

RNA sequencing analysis for profiling activation of cancer-associated molecular pathways.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13032-e13032 ◽  
Author(s):  
Anton Buzdin ◽  
Andrew Garazha ◽  
Maxim Sorokin ◽  
Alex Glusker ◽  
Alexey Aleshin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Original Data ◽  
Tissue Expression ◽  
Molecular Pathways ◽  
Sequencing Analysis ◽  
Rna Seq ◽  
Sequencing Data ◽  
Healthy Human ◽  
Tissue Samples ◽  
Normal Tissues

e13032 Background: Intracellular molecular pathways (IMPs) control all major events in the living cell. They are considered hotspots in contemporary oncology because knowledge of IMPs activation is essential for understanding mechanisms of molecular pathogenesis in oncology. Profiling IMPs requires RNA-seq data for tumors and for a collection of reference normal tissues. However, there is a shortage now in such profiles for normal tissues from healthy human donors, uniformly profiled in a single series of experiments. Access to the largest dataset of normal profiles GTEx is only partly available through the dbGaP. In TCGA database, norms are adjacent to surgically removed tumors and may be affected by tumor-linked growth factors, inflammation and altered vascularization. ENCODE datasets were for the autopsies of normal tissues, but they can’t form statistically significant reference groups. Methods: Tissue samples representing 20 organs were taken from post-mortal human healthy donors killed in road accidents no later than 36 hours after death, blood samples were taken from healthy volunteers. Gene expression was profiled in RNA-seq experiments using the same reagents, equipment and protocols. Bioinformatic algorithms for IMP analysis were developed and validated using experimental and public gene expression datasets. Results: From original sequencing data we constructed the biggest fully open reference expression database of normal human tissues including 465 profiles termed Oncobox Atlas of Normal Tissue Expression (ANTE, original data: GSE120795). We next developed a method termed Oncobox for interrogating activation of IMPs in human cancers. It includes modules of expression data harmonization and comparison and an algorithm for automatic annotation of molecular pathways. The Oncobox system enables accurate scoring of thousands molecular pathways using RNA-seq data. Oncobox pathway analysis is also applicable for quantitative proteomics and microRNA data in oncology. Conclusions: The Oncobox system can be used for a plethora of applications in cancer research including finding differentially regulated genes and IMPs, and for discovery of new pathway-related diagnostic and prognostic biomarkers.

scholarly journals Next Generation Sequencing Analysis of Biofilms from Three Dogs with Postoperative Surgical Site Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
L. M. König ◽  
R. Klopfleisch ◽  
D. Höper ◽  
A. D. Gruber
Keyword(s):  
Next Generation Sequencing ◽  
Sequencing Analysis ◽  
Next Generation ◽  
Bacterial Composition ◽  
Tissue Samples ◽  
Next Generation Sequencing Analysis ◽  
Total Dna ◽  
Chronic Wound Infections ◽  
Generation Sequencing ◽  
Formalin Fixed

The composition of biofilms in chronic wound infections of dogs is unclear. In the present study, histologically identified biofilms attached to sutures in chronically infected wounds of three dogs were examined by next generation sequencing of total DNA extracted from formalin-fixed and paraffin-embedded tissue samples. The analysis identified an inhomogeneous bacterial composition in three tissues containing biofilms. Some of the identified bacterial families such as Staphylococci and Streptococci have been found before in biofilms associated with human and canine wounds but in this study were quantitatively in the minority. The majority of the reads classified as bacterial sequences had the highest identity with sequences belonging to the Porphyromonadaceae, Deinococcaceae, Methylococcaceae, Nocardiaceae, Alteromonadaceae, and Propionibacteriaceae and thus taxons of so far minor relevance in veterinary medicine.

scholarly journals Found in Transcription: Gene fusions arise through defects in RNA processing in the absence of chromosomal rearrangements

2019 ◽  
Author(s):  
Yue Jiang ◽  
Michael J. Apostolides ◽  
Mia Husić ◽  
Robert Siddaway ◽  
Man Yu ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Chromosomal Rearrangements ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Sequencing Analysis ◽  
Tissue Samples ◽  
Complete Representation ◽  
Normal Tissues ◽  
Gene Dysregulation ◽  
Definition Of

AbstractRecent advancements in high throughput sequencing analysis have enabled the characterization of cancer-driving fusions, improving our understanding of cancer development. Most fusion calling methods, however, examine either RNA or DNA information alone and are limited to a rigid definition of what constitutes a fusion. For this study we developed a pipeline that incorporates several fusion calling methods and considers both RNA and DNA to capture a more complete representation of the tumour fusion landscape. Interestingly, most of the fusions we identified were specific to RNA, with no evidence of corresponding genomic restructuring. Further, while the average total number of fusions in tumour and normal brain tissue samples is comparable, their overall fusion profiles vary significantly. Tumours have an over-representation of fusions occurring between coding genes, whereas fusions involving intergenic or non-coding regions comprised the vast majority of those in normals. Tumours were also more abundant in unique, sample-specific fusions compared to normals, though several fusions exhibited strong recurrence in the tumour type examined (diffuse intrinsic pontine glioma; DIPG) and were absent from both normal tissues and other cancers. Intriguingly, tumours also show broad up- or down-regulation of spliceosomal gene expression, which significantly correlates with fusion number (p=0.007). Our results show that RNA-specific fusions are abundant in both tumour and normal tissue and are associated with spliceosomal gene dysregulation. RNA-specific fusions should be considered as a potential mechanism that may contribute to cancer formation initiation and maintenance alongside more traditional structural events.

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