scholarly journals GENE-01. THE MUTATIONAL LANDSCAPE OF PRIMARY CHORDOMAS AND THEIR SENSITIVE DETECTION IN PLASMA ctDNA BY MULTIPLE NEXT GENERATION SEQUENCING TECHNOLOGIES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Austin Mattox ◽  
Yuchen Jiao ◽  
Cherie Blair ◽  
Nickolas Papadopoulos ◽  
Chetan Bettegowda
Keyword(s):  
Liquid Biopsy ◽  
Clinical Status ◽  
Spinal Column ◽  
Digital Pcr ◽  
Disease Recurrence ◽  
Blood Draw ◽  
Tumor Seeding ◽  
Mutational Landscape ◽  
Sequencing Technologies

Abstract CNS-associated tumors are notoriously difficult to detect in plasma. Chordomas are the most common primary spinal column malignancy, and extensive surgical procedures, along with chemotherapy and radiation are required to reduce recurrence. Currently CT, MRI, and PET are used to monitor for recurrence but are limited by surgical sequalae. In addition, needle biopsy risks tumor seeding along the biopsy track. In the largest cohort of chordomas described thus far, we characterize the mutational landscape of these tumors and show that liquid biopsy is a sensitive method for detecting cancers. 34 patients with a biopsy-confirmed diagnosis of chordoma had blood drawn before surgery, at the time of surgery, and/or at follow up appointments. Mutations in the primary tumor were identified by whole exome sequencing (WES) and droplet digital PCR (ddPCR) and/or Rapid Amplification of cDNA Ends Sequencing (RACE-Seq) was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points. The primary endpoint was detection of mutations in ctDNA in biopsy-confirmed chordoma samples. 87.9% of patients were ctDNA positive at the time of initial blood draw (p < 0.001). Follow up blood draws in twenty of the patients demonstrated that ctDNA levels reflected the clinical status of the disease. Patients with positive ctDNA levels were more likely to undergo radiotherapy (p = 0.004), and the presence of ctDNA may predict response to systemic chemotherapy and/or disease recurrence. Given the significant sequelae of biopsy and spinal surgery, liquid biopsy may be the best tool for detection and monitoring of chordomas.

scholarly journals The mutational landscape of spinal chordomas and their sensitive detection using circulating tumor DNA

2020 ◽  
Author(s):  
Austin K Mattox ◽  
Beibei Yang ◽  
Christopher Douville ◽  
Sheng-fu Lo ◽  
Daniel Sciubba ◽  
...  
Keyword(s):  
Clinical Status ◽  
Spinal Column ◽  
Disease Recurrence ◽  
The United States ◽  
Circulating Tumor Dna ◽  
Blood Draw ◽  
Primary Tumors ◽  
Whole Exome ◽  
Tumor Dna

Abstract Background Chordomas are the most common primary spinal column malignancy in the United States. The aim of this study was to determine whether chordomas may be detected by evaluating mutations in circulating tumor DNA (ctDNA). Methods 32 patients with a biopsy-confirmed diagnosis of chordoma had blood drawn pre-operatively and/or at follow up appointments. Mutations in the primary tumor were identified by whole exome sequencing and liquid biopsy by ddPCR and/or RACE-Seq was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points. Results 87.1% of patients were ctDNA positive at the time of initial blood draw (p < 0.001). Follow up blood draws in twenty of the patients suggest that ctDNA levels may reflect the clinical status of the disease. Patients with positive ctDNA levels were more likely to have greater mutant allele frequencies in their primary tumors (p = 0.004) and undergo radiotherapy (p = 0.02), and the presence of ctDNA may correlate with response to systemic chemotherapy and/or disease recurrence. Conclusions Detection of ctDNA mutations may allow for the detection and monitoring of disease progression for chordomas.

scholarly journals Epigenetic Biomarkers in Cell-Free DNA and Applications in Liquid Biopsy

Genes ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 32 ◽  
Author(s):  
Wanxia Gai ◽  
Kun Sun
Keyword(s):  
Cancer Diagnosis ◽  
Liquid Biopsy ◽  
Prenatal Testing ◽  
Digital Pcr ◽  
Liquid Biopsies ◽  
Sequencing Technologies ◽  
Epigenetic Biomarkers ◽  
Free Circulating Dna ◽  
Epigenetic Biomarker ◽  
Fragmentation Patterns

Cell-free circulating DNA (cfDNA) in plasma has gained global interest as a diagnostic material for noninvasive prenatal testing and cancer diagnosis, or the so-called “liquid biopsy”. Recent studies have discovered a great number of valuable genetic and epigenetic biomarkers for cfDNA-based liquid biopsy. Considering that the genetic biomarkers, e.g., somatic mutations, usually vary from case to case in most cancer patients, epigenetic biomarkers that are generalizable across various samples thus possess certain advantages. In this study, we reviewed the most recent studies and advances on utilizing epigenetic biomarkers for liquid biopsies. We first reviewed more traditional methods of using tissue/cancer-specific DNA methylation biomarkers and digital PCR or sequencing technologies for cancer diagnosis, as well as tumor origin determination. In the second part, we discussed the emerging novel approaches for exploring the biological basis and clinical applications of cfDNA fragmentation patterns. We further provided our comments and points of view on the future directions on epigenetic biomarker development for cfDNA-based liquid biopsies.

scholarly journals Spinal metastasis: diagnosis, management and follow-up

2019 ◽  
Vol 92 (1103) ◽  
pp. 20190211 ◽  
Author(s):  
Mahmud Mossa-Basha ◽  
Peter C. Gerszten ◽  
Sten Myrehaug ◽  
Nina A. Mayr ◽  
William TC Yuh ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Metastatic Disease ◽  
Spinal Metastasis ◽  
Surgical Techniques ◽  
Spinal Column ◽  
Disease Recurrence ◽  
Current Treatment ◽  
Post Treatment ◽  
Pre Treatment

Spine metastatic disease is an increasingly common occurrence in cancer patients due to improved patient survival. Close proximity of the bony spinal column to the spinal cord limits many conventional treatments for metastatic disease. In the past decade, we have witnessed dramatic advancements in therapies, with improvements in surgical techniques and recent adoption of spine stereotactic radiotherapy techniques leading to improved patient outcomes. Multidisciplinary approaches to patient evaluation, treatment and follow-up are essential. Imaging plays an ever increasing role in disease detection, pre-treatment planning and assessment of patient outcomes. It is important for the radiologist to be familiar with imaging algorithms, best practices for surgery and/or radiotherapy and imaging findings in the post-treatment period that may indicate disease recurrence. In this review, we present a multidisciplinary discussion of spine metastases, with specific focus on pre-treatment imaging, planning, current treatment approaches, and post-treatment assessment.

scholarly journals Inability of immunohistochemistry to predict clinical outcomes of endometrial cancer patients

2004 ◽  
Vol 14 (1) ◽  
pp. 145-151
Author(s):  
D. R. Gossett ◽  
P. Alo ◽  
R. E. Bristow ◽  
M. Galati ◽  
A. Kyshtoobayeva ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Hormone Receptors ◽  
Clinical Status ◽  
Figo Stage ◽  
Disease Recurrence ◽  
Vascular Endothelial ◽  
Cell Cycle Regulatory Proteins ◽  
Endometrial Carcinomas ◽  
Endothelial Growth Factor

IntroductionDespite optimal surgery, some patients with early endometrial carcinoma develop recurrence and die of disease. A number of immunohistochemical (IHC)-identified cell products (markers) have been proposed as predictors of recurrence. This study characterizes a large series of endometrial carcinomas with previously described markers as well as markers that have not been investigated in endometrial carcinoma.Patients and methodsWomen who had undergone surgery for endometrial carcinoma were identified and specimens accessed. Tissue blocks were evaluated for ten IHC markers. Results were correlated with last known clinical status.ResultsMean follow-up was 43 months; complete data were available on 117 patients. Two women died of other causes; of the remaining 115, eight died of disease and six were alive with recurrence at last follow-up (12%). Vascular endothelial growth factor staining independently predicted recurrence and death. However, in multivariate analyses, only FIGO stage predicted outcome.DiscussionOur goal was to identify markers to predict which women with endometrial carcinoma were likely to have disease recurrence. We evaluated cell-cycle regulatory proteins, growth factors, hormone receptors, and angiogenic factors, but did not identify any marker that independently predicted outcome in multivariate analysis. This may reflect the few negative outcomes in our population.

scholarly journals Liquid Biopsy Detects Relapse Five Months Earlier than Regular Clinical Follow-Up and Guides Targeted Treatment in Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Fiona Tsui-Fen Cheng ◽  
Nina Lapke ◽  
Chin-Chu Wu ◽  
Yen-Jung Lu ◽  
Shu-Jen Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Detection ◽  
Liquid Biopsy ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Targeted Treatment ◽  
Breast Cancer Patients ◽  
Ctdna Analysis

Genetic alterations in circulating tumor DNA (ctDNA) are an emerging biomarker for the early detection of relapse and have the potential to guide targeted treatment. ctDNA analysis is often performed by droplet digital PCR; however, next-generation sequencing (NGS) allows multigene testing without having to access a tumor sample to identify target alterations. Here, we report the case of a stage III hormone receptor-positive breast cancer patient who remained symptomless after receiving surgery and adjuvant chemotherapy. Liquid biopsy analysis by NGS revealed the presence of a ctDNA PIK3CA N345K mutation five months before the detection of relapse with multiple liver metastases by regular clinical follow-up. To date, clinical implications of the PIK3CA N345K variant remain insufficiently investigated; however, everolimus treatment resulted in the shrinkage of tumor lesions and decreased the levels of tumor markers. Four months after treatment initiation, a second ctDNA analysis suggested a relapse, and the patient clinically progressed after five months of everolimus therapy. This case report demonstrates the value of ctDNA analysis by NGS for the early detection of relapse in breast cancer patients. The study further indicates its usefulness for the choice of targeted treatments, suggesting that the variant PIK3CA N345K might be associated with everolimus sensitivity.

scholarly journals Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
L. Warburton ◽  
T. M. Meniawy ◽  
L. Calapre ◽  
M. Pereira ◽  
A. McEvoy ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Residual Disease ◽  
Complete Response ◽  
Digital Pcr ◽  
Disease Recurrence ◽  
Prolonged Treatment ◽  
Durable Response ◽  
Longitudinal Plasma ◽  
Melanoma Patients

Abstract BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/− MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20–74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8–36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.

Liquid Biopsy: General Concepts

2019 ◽  
Vol 63 (6) ◽  
pp. 449-455 ◽  
Author(s):  
Geoffroy Poulet ◽  
Joséphine Massias ◽  
Valerie Taly
Keyword(s):  
Liquid Biopsy ◽  
Tumor Heterogeneity ◽  
Invasive Procedure ◽  
Digital Pcr ◽  
Cancer Tissue ◽  
Minimally Invasive Procedure ◽  
Cancer Evolution ◽  
Sequencing Technologies ◽  
Standardization Of Procedures ◽  
Generation Sequencing

Liquid biopsy provides the opportunity of detecting, analyzing and monitoring cancer in various body effluents such as blood or urine instead of a fragment of cancer tissue. It is composed of different biological matrices such as circulating tumor cells (CTCs), cell free nucleic acids, exosomes or tumors “educated platelets.” In addition to representing a non- or minimally invasive procedure, it should represent a better view of tumor heterogeneity and allows for real-time monitoring of cancer evolution. Recent technological and molecular advances, greatly facilitated by the use of microfluidics in many cases, have permitted large progresses both in our ability to purify and analyze liquid biopsy components. In particular, the great developments of droplet-based digital PCR and the various optimizations of next generation sequencing technologies are central to the several validations of CTC-free DNA as a strong cancer biomarker. However, complete adoption of liquid biopsy in clinics will require pursuing recent efforts in the standardization of procedures both on the pre-analytical and analytical aspects.

scholarly journals When less is more: a daring conservative approach to postpneumonectomy oesophago-pleural fistula

2019 ◽  
Vol 30 (1) ◽  
pp. 146-148
Author(s):  
Lara Girelli ◽  
Elena Prisciandaro ◽  
Niccolò Filippi ◽  
Lorenzo Spaggiari
Keyword(s):  
Clinical Presentation ◽  
Clinical Status ◽  
High Morbidity ◽  
Conservative Approach ◽  
Chronic Fistula ◽  
Less Is More ◽  
Primary Surgery ◽  
History Of ◽  
Uncommon Complication

Abstract Oesophago-pleural fistula is an uncommon complication after pneumonectomy, usually related to high morbidity and mortality. Due to its rarity and heterogeneous clinical presentation, its diagnosis and management are challenging issues. Here, we report the case of a patient with a history of pneumonectomy for a tracheal tumour, who developed an asymptomatic oesophago-pleural fistula 7 years after primary surgery. In consideration of the patient’s good clinical status and after verifying the preservation of respiratory and digestive functions, a bold conservative approach was adopted. Five-year follow-up computed tomography did not disclose any sign of recurrence of disease and showed a stable, chronic fistula.

scholarly journals Circulating tumor DNA is detectable in canine histiocytic sarcoma, oral malignant melanoma, and multicentric lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anaïs Prouteau ◽  
Jérôme Alexandre Denis ◽  
Pauline De Fornel ◽  
Edouard Cadieu ◽  
Thomas Derrien ◽  
...  
Keyword(s):  
Residual Disease ◽  
Specific Antigen ◽  
Point Mutations ◽  
Antigen Receptor ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Histiocytic Sarcoma ◽  
Oncology Research ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) has become an attractive biomarker in human oncology, and its use may be informative in canine cancer. Thus, we used droplet digital PCR or PCR for antigen receptor rearrangement, to explore tumor-specific point mutations, copy number alterations, and chromosomal rearrangements in the plasma of cancer-affected dogs. We detected ctDNA in 21/23 (91.3%) of histiocytic sarcoma (HS), 2/8 (25%) of oral melanoma, and 12/13 (92.3%) of lymphoma cases. The utility of ctDNA in diagnosing HS was explored in 133 dogs, including 49 with HS, and the screening of recurrent PTPN11 mutations in plasma had a specificity of 98.8% and a sensitivity between 42.8 and 77% according to the clinical presentation of HS. Sensitivity was greater in visceral forms and especially related to pulmonary location. Follow-up of four dogs by targeting lymphoma-specific antigen receptor rearrangement in plasma showed that minimal residual disease detection was concordant with clinical evaluation and treatment response. Thus, our study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up. ctDNA detection appears to be useful in comparative oncology research due to growing interest in the study of natural canine tumors and exploration of new therapies.

scholarly journals Longitudinal Circulating Levels of miR-23b-3p, miR-126-3p and lncRNA GAS5 in HCC Patients Treated with Sorafenib

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 813
Author(s):  
Michele Manganelli ◽  
Ilaria Grossi ◽  
Manuela Ferracin ◽  
Paola Guerriero ◽  
Massimo Negrini ◽  
...  
Keyword(s):  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Healthy Individuals ◽  
Roc Curve Analysis ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
The Third ◽  
Circulating Levels ◽  
Systemic Drug

Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The multikinase inhibitor sorafenib is a systemic drug for unresectable HCC. The identification of molecular biomarkers for the early diagnosis of HCC and responsiveness to treatment are needed. In this work, we performed an exploratory study to investigate the longitudinal levels of cell-free long ncRNA GAS5 and microRNAs miR-126-3p and -23b-3p in a cohort of 7 patients during the period of treatment with sorafenib. We used qPCR to measure the amounts of GAS5 and miR-126-3p and droplet digital PCR (ddPCR) to measure the levels of miR-23b-3p. Patients treated with sorafenib displayed variable levels of GAS5, miR-126-3p and miR-23b-3p at different time-points of follow-up. miR-23b-3p was further measured by ddPCR in 37 healthy individuals and 25 untreated HCC patients. The amount of miR-23b-3p in the plasma of untreated HCC patients was significantly downregulated if compared to healthy individuals. The ROC curve analysis underlined its diagnostic relevance. In conclusion, our results highlight a potential clinical significance of circulating miR-23b-3p and an exploratory observation on the longitudinal plasmatic levels of GAS5, miR-126-3p and miR-23b-3p during sorafenib treatment.

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