scholarly journals ETV6: A Candidate Gene for Predisposition to “Blend Pedigrees”? A Case Report from the NEXT-Famly Clinical Trial

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Simona Bernardi ◽  
Mirko Farina ◽  
Camilla Zanaglio ◽  
Federica Cattina ◽  
Nicola Polverelli ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Hematological Malignancies ◽  
Hematologic Malignancies ◽  
Recent Experience ◽  
Case Presentation ◽  
Noncoding Regions ◽  
Oncologic Patients ◽  
Predisposition Genes ◽  
Hematologic Neoplasia ◽  
Generation Sequencing

Background. The identification of germline mutations in familial leukemia predisposition genes by next generation sequencing is of pivotal importance. Lately, some “blend pedigrees” characterized by both solid and hematologic malignancies have been described. Some genes were recognized as related to this double predisposition, while the involvement of others is still a matter of debate. ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. Case Presentation. We present our recent experience in the identification of an ETV6-mutated “blend pedigree,” suggesting the involvement of ETV6 in the predisposition to both solid and hematologic neoplasia. The pedigree recognition started with a MDS case enrolled in the NEXT-Famly protocol. The patient presented 9 relatives affected by solid tumors and hematological malignancies. Following the clinical trial protocol, the patient underwent NGS analysis, which confirmed the presence of a mutation on the noncoding region of ETV6 both on tumor and on germline DNA. The mutation resulted was shared by the still alive affected relatives. Conclusion. This evidence supports the involvement of ETV6 in the predisposition to both solid and hematologic neoplasia and the importance of the investigation of the noncoding regions of the genes as recently suggested by different expert groups.

Darbepoetin alfa Administered Every 3 Weeks Is Effective in Correcting Hemoglobin and Reducing Transfusion Requirements in Anemic Patients with Hematological Malignancies Receiving Chemotherapy: A Retrospective Observational Study Reflecting Real-World Clinical Practice in Europe.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4085-4085
Author(s):  
Bertrand Coiffier ◽  
David Coeffic ◽  
Frank Strohbach ◽  
Marcus Schweigert ◽  
Hirsh Koyi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Practice ◽  
Real World ◽  
Darbepoetin Alfa ◽  
Hematological Malignancies ◽  
Hematologic Malignancies ◽  
Tumor Type ◽  
Phase 3 ◽  
End Of Treatment ◽  
Hematopoietic Response

Abstract Introduction: Observational research provides valuable comparative information about the use and effect of drugs in a particular patient (pt) population (eg, pts with hematological malignancies) in real-world clinical practice, which may be different from those in controlled clinical studies. Methods: This multicenter study of medical records evaluated use of darbepoetin alfa (DA) 500 mcg every 3 weeks (Q3W) in anemic pts with nonmyeloid malignancies receiving chemotherapy treatment in 7 European countries (Denmark, France, Germany, Greece, Spain, Sweden, and Switzerland). Data were collected on a retrospective basis using medical record review and a standard case report form. Data related to adverse events or other measures of safety were not collected. The analysis included pts who either completed the observational period (≤16 weeks) or stopped treatment but received ≥1 DA dose. Pts had to be ≥18 years old, start DA treatment after 01January2004, and provide informed consent (if needed by country regulations). Descriptive statistics were generated. In this posthoc analysis, a subset analysis was performed by tumor type: hematologic malignancies, solid tumors, and all pts. Percentages of pts with hematopoietic response (hemoglobin [Hb]≥12g/dL and/or 2-g/dL increase from baseline to end of treatment period), transfusion, and Hb ≥11 g/dL were evaluated. Results: 391 pts received DA, of whom 64 (20%) had hematologic malignancies. Overall, most pts were women (60%) and white (97%), with a mean (SD) age of 62.5[11.8] yrs and a mean baseline Hb of 9.7[0.9] g/dL. Most pts received concomitant chemotherapy (99%). No pts discontinued treatment due to side effects. In pts with hematologic malignancies, treatment with DA 500 mcg Q3W increased Hb levels above 11 g/dL in 73% of patients and left 69% of pts transfusion free (Table). These results were similar in pts with other tumor types and in all pts in this study, as well as in pts with lymphoproliferative malignancies enrolled in previously reported phase 3 clinical trial of the DA QW treatment schedule (Table). Table. Outcomes Real-world Study (DA 500mcg Q3W) Phase 3 Study Kaplan Meier proportions of patients (95% Confidence Intervals) # Hematologic Malignancies (n=64) Other Tumors (n=261) All Pts (n=325) DA 2.25 mcg/kg QW (n=174) Placebo (n=170) NR=not reported; #=Based on effectiveness analysis set. Phase 3 Study = Hedenus et al, Brit J Haematol2003;122:394. Hematopoietic response 59%(44–73) 68%(60–75) 66%(59–73) 65%(57–73) 24%(72–81) Hemoglobin ≥11g/dL during study 73%(61–85) 85%(78–92) 78%(71–85) NR NR At least 1 transfusion (week 5 to end of treatment period) 31%(18–44) 22%(16–29) 24%(19–30) 31%(24–38) 48%(41–56) Conclusion: Based on these results, DA 500 mcg Q3W in real-world clinical practice in Europe exhibited similar effectiveness compared with outcomes observed in clinical trial setting. In this study, DA 500 mcg Q3W appeared to be effective in treating anemia in pts receiving chemotherapy, regardless of tumor type.

scholarly journals Severe pneumonia caused by Parvimonas micra: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qing Yu ◽  
Lingling Sun ◽  
Zuqing Xu ◽  
Lumei Fan ◽  
Yunbo Du
Keyword(s):  
Bronchoalveolar Lavage Fluid ◽  
Case Reports ◽  
Severe Pneumonia ◽  
Lavage Fluid ◽  
Due Date ◽  
Case Presentation ◽  
Abdominal Abscesses ◽  
Parvimonas Micra ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Parvimonas micra (P. micra) is a gram-positive anaerobic coccus that is detected widely on the skin, in the oral mucosa and in the gastrointestinal tract. In certain circumstances, P. micra can cause abdominal abscesses, bacteraemia and other infections. To the best of our knowledge, there have been no case reports describing the biological characteristics of P. micra-related pneumonia. These bacteria do not always multiply in an aerobic organ, such as the lung, and they could be easily overlooked because of the clinical mindset. Case presentation A 35-year-old pregnant woman was admitted to the emergency department 4 weeks prior to her due date who was exhibiting 5 points on the Glasgow coma scale. A computed tomography (CT) scan showed a massive haemorrhage in her left basal ganglia. She underwent a caesarean section and brain surgery before being admitted to the ICU. She soon developed severe pneumonia and hypoxemia. Given that multiple sputum cultures were negative, the patient’s bronchoalveolar lavage fluid was submitted for next-generation sequencing (NGS) to determine the pathogen responsible for the pneumonia; as a result, P. micra was determined to be the causative pathogen. Accordingly the antibiotic therapy was altered and the pneumonia improved. Conclusion In this case, we demonstrated severe pneumonia caused by the anaerobic organism P. micra, and the patient benefited from receiving the correct antibiotic. NGS was used as a method of quick diagnosis when sputum culture failed to distinguish the pathogen.

scholarly journals Myxofibrosarcoma Mimicking Inflammatory Lesion of Temporomandibular Joint—Case Presentation

2021 ◽  
Vol 11 (10) ◽  
pp. 4373
Author(s):  
Dawid Zagacki ◽  
Krzysztof Sztychny ◽  
Marta Tyndorf ◽  
Robert Bibik ◽  
Dominik Sygut ◽  
...  
Keyword(s):  
Temporomandibular Joint ◽  
Inflammatory Lesion ◽  
Maxillofacial Region ◽  
Case Presentation ◽  
Oncologic Patients ◽  
And Function ◽  
Ultra High Molecular Weight ◽  
Methods Of Reconstruction ◽  
Disease Free

Treating oncologic patients remains a challenge for surgeons aiming to provide patients with safe margins of resection while maintaining the highest possible quality of life. The latter, in the case of malignancies, requires using sophisticated methods of reconstruction. Thus, we present a case of a 75-year-old patient treated in our department with a rare neoplasm in the region of the temporomandibular joint—a myxofibrosarcoma that was mimicking an inflammatory lesion. The patient underwent two surgeries—firstly alloplasty of the TMJ due to the suspicion of an inflammatory lesion, lately extended to the resection of glenoid fossa and subtemporal fossa contents when the mandible was reconstructed using UHMW-PE (ultra-high molecular weight polyethylene). The patient was also referred for adjuvant radiotherapy and has remained disease-free for over 96 months with very good aesthetics and function of the mandible. The presented case highlights not only the need for increased oncologic awareness but also the possible use of UHMW-PE as a reconstruction material in the broad resection of the maxillofacial region.

scholarly journals Clinical Application of Metagenomic Next-Generation Sequencing in Patients with Hematologic Malignancies Suffering from Sepsis

2021 ◽  
Vol 9 (11) ◽  
pp. 2309
Author(s):  
Wang-Da Liu ◽  
Ting-Yu Yen ◽  
Po-Yo Liu ◽  
Un-In Wu ◽  
Prerana Bhan ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Hematologic Malignancies ◽  
Blood Cultures ◽  
Diagnostic Methods ◽  
Next Generation ◽  
Viral Loads ◽  
A Prospective Study ◽  
Positive Results ◽  
Serology Testing ◽  
Generation Sequencing

Background: Sepsis remains a common but fatal complication among patients with immune suppression. We aimed to investigate the performance of metagenomic next-generation sequencing (mNGS) compared with standard microbiological diagnostics in patients with hematologic malignancies. Methods: We performed a prospective study from June 2019 to December 2019. Adult patients with hematologic malignancies and a clinical diagnosis of sepsis were enrolled. Conventional diagnostic methods included blood cultures, serum galactomannan for Aspergillus, cryptococcal antigen and cytomegalovirus (CMV) viral loads. Blood samples for mNGS were collected within 24 h after hypotension developed. Results: Of 24 patients enrolled, mNGS and conventional diagnostic methods (blood cultures, serology testing and virus RT-PCR) reached comparable positive results in 9 cases. Of ten patients, mNGS was able to identify additional pathogens compared with conventional methods; most of the pathogens were virus. Conclusion: Our results show that mNGS may serve as adjunctive diagnostic tool for the identification of pathogens of hematologic patients with clinically sepsis.

scholarly journals Diagnosing Inherited Platelet Disorders: Modalities and Consequences

2021 ◽  
Author(s):  
Carlo Zaninetti ◽  
Martina Wolff ◽  
Andreas Greinacher
Keyword(s):  
Hematological Malignancies ◽  
Ethical Issues ◽  
Diagnostic Delay ◽  
Bleeding Tendency ◽  
Platelet Morphology ◽  
Laboratory Characterization ◽  
Platelet Disorders ◽  
And Function ◽  
Generation Sequencing

AbstractInherited platelet disorders (IPDs) are a group of rare conditions featured by reduced circulating platelets and/or impaired platelet function causing variable bleeding tendency. Additional hematological or non hematological features, which can be congenital or acquired, distinctively mark the clinical picture of a subgroup of patients. Recognizing an IPD is challenging, and diagnostic delay or mistakes are frequent. Despite the increasing availability of next-generation sequencing, a careful phenotyping of suspected patients—concerning the general clinical features, platelet morphology, and function—is still demanded. The cornerstones of IPD diagnosis are clinical evaluation, laboratory characterization, and genetic testing. Achieving a diagnosis of IPD is desirable for several reasons, including the possibility of tailored therapeutic strategies and individual follow-up programs. However, detailed investigations can also open complex scenarios raising ethical issues in case of IPDs predisposing to hematological malignancies. This review offers an overview of IPD diagnostic workup, from the interview with the proband to the molecular confirmation of the suspected disorder. The main implications of an IPD diagnosis are also discussed.

scholarly journals The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data

2017 ◽  
Vol 2 ◽  
pp. 35 ◽  
Author(s):  
Shazia Mahamdallie ◽  
Elise Ruark ◽  
Shawn Yost ◽  
Emma Ramsay ◽  
Imran Uddin ◽  
...  
Keyword(s):  
Sequencing Data ◽  
Targeted Next Generation Sequencing ◽  
Negative Results ◽  
Targeted Ngs ◽  
Predisposition Genes ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Validation Series ◽  
Generation Sequencing ◽  
Dependent Probe

Detection of deletions and duplications of whole exons (exon CNVs) is a key requirement of genetic testing. Accurate detection of this variant type has proved very challenging in targeted next-generation sequencing (NGS) data, particularly if only a single exon is involved. Many different NGS exon CNV calling methods have been developed over the last five years. Such methods are usually evaluated using simulated and/or in-house data due to a lack of publicly-available datasets with orthogonally generated results. This hinders tool comparisons, transparency and reproducibility. To provide a community resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM or PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs, the most difficult type of exon CNV to detect. The FASTQ files for the ICR96 exon CNV validation series can be accessed through the European-Genome phenome Archive (EGA) under the accession number EGAS00001002428.

scholarly journals Identification of Genetic Hereditary Predisposition to Hematologic Malignancies By Clinical Next-Generation Sequencing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3854-3854 ◽  
Author(s):  
Amy E Knight Johnson ◽  
Lucia Guidugli ◽  
Kelly Arndt ◽  
Gorka Alkorta-Aranburu ◽  
Viswateja Nelakuditi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Sanger Sequencing ◽  
Family Members ◽  
Hematologic Malignancies ◽  
Dyskeratosis Congenita ◽  
Molecular Diagnostic ◽  
Next Generation ◽  
Hereditary Predisposition ◽  
Ngs Data ◽  
Generation Sequencing

Abstract Introduction: Myelodysplastic syndrome (MDS) and acute leukemia (AL) are a clinically diverse and genetically heterogeneous group of hematologic malignancies. Familial forms of MDS/AL have been increasingly recognized in recent years, and can occur as a primary event or secondary to genetic syndromes, such as inherited bone marrow failure syndromes (IBMFS). It is critical to confirm a genetic diagnosis in patients with hereditary predisposition to hematologic malignancies in order to provide prognostic information and cancer risk assessment, and to aid in identification of at-risk or affected family members. In addition, a molecular diagnosis can help tailor medical management including informing the selection of family members for allogeneic stem cell transplantation donors. Until recently, clinical testing options for this diverse group of hematologic malignancy predisposition genes were limited to the evaluation of single genes by Sanger sequencing, which is a time consuming and expensive process. To improve the diagnosis of hereditary predisposition to hematologic malignancies, our CLIA-licensed laboratory has recently developed Next-Generation Sequencing (NGS) panel-based testing for these genes. Methods: Thirty six patients with personal and/or family history of aplastic anemia, MDS or AL were referred for clinical diagnostic testing. DNA from the referred patients was obtained from cultured skin fibroblasts or peripheral blood and was utilized for preparing libraries with the SureSelectXT Enrichment System. Libraries were sequenced on an Illumina MiSeq instrument and the NGS data was analyzed with a custom bioinformatic pipeline, targeting a panel of 76 genes associated with IBMFS and/or familial MDS/AL. Results: Pathogenic and highly likely pathogenic variants were identified in 7 out of 36 patients analyzed, providing a positive molecular diagnostic rate of 20%. Overall, 6 out of the 7 pathogenic changes identified were novel. In 2 unrelated patients with MDS, heterozygous pathogenic sequence changes were identified in the GATA2 gene. Heterozygous pathogenic changes in the following autosomal dominant genes were each identified in a single patient: RPS26 (Diamond-Blackfan anemia 10), RUNX1 (familial platelet disorder with propensity to myeloid malignancy), TERT (dyskeratosis congenita 4) and TINF2 (dyskeratosis congenita 3). In addition, one novel heterozygous sequence change (c.826+5_826+9del, p.?) in the Fanconi anemia associated gene FANCA was identified. . The RNA analysis demonstrated this variant causes skipping of exon 9 and results in a premature stop codon in exon 10. Further review of the NGS data provided evidence of an additional large heterozygous multi-exon deletion in FANCA in the same patient. This large deletion was confirmed using array-CGH (comparative genomic hybridization). Conclusions: This study demonstrates the effectiveness of using NGS technology to identify patients with a hereditary predisposition to hematologic malignancies. As many of the genes associated with hereditary predisposition to hematologic malignancies have similar or overlapping clinical presentations, analysis of a diverse panel of genes is an efficient and cost-effective approach to molecular diagnostics for these disorders. Unlike Sanger sequencing, NGS technology also has the potential to identify large exonic deletions and duplications. In addition, RNA splicing assay has proven to be helpful in clarifying the pathogenicity of variants suspected to affect splicing. This approach will also allow for identification of a molecular defect in patients who may have atypical presentation of disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals The First Livebirth Using Warmed Oocytes by a Semi-Automated Vitrification Procedure

2020 ◽  
Author(s):  
Xavier Orriols Brunetti ◽  
Suzanne Cawood ◽  
Matthew Gaunt ◽  
Wael Saab ◽  
Paul Serhal ◽  
...  
Keyword(s):  
Blastocyst Stage ◽  
Frozen Embryo Transfer ◽  
Automated System ◽  
Standard Laboratory ◽  
Laboratory Procedure ◽  
Case Presentation ◽  
Laboratory Procedures ◽  
Donor Oocytes ◽  
Generation Sequencing ◽  
Laboratory Time

Background: The first successful livebirth using warmed oocytes (vitrified by the GAVITM system) is reported in this paper. Embryologists throughout the world have vitrified oocytes using a manual technique which is susceptible to error and variation. In this era of automated laboratory procedures, vitrification was made semi-automatic by using the GAVITM system. Case Presentation: Donor oocytes were initially vitrified using the GAVITM system. They remained in the clinic’s oocyte bank until they were allocated to the patient. Donor oocytes were warmed as per Genea BIOMEDX protocol and inseminated to create embryos. Resulting embryos for the 42-year-old patient were cultured to the blastocyst stage, biopsied to perform PGT-A, using next generation sequencing and subsequently vitrified. The patient underwent a single euploid transfer in a frozen embryo transfer cycle which resulted in a healthy livebirth. Conclusion: The introduction of a semi-automated system should minimize the risk to the oocytes, standardize the procedure worldwide and potentially reduce the laboratory time taken by the embryologists. This case report demonstrates the safety of the technology used for vitrification, but larger randomized studies need to be performed to demonstrate the safety and efficacy of newer technologies like the GAVITM system before adopting it as a standard laboratory procedure.

scholarly journals PATH-03. CLINICAL UTILITY OF NEXT GENERATION SEQUENCING IN IDH-WILDTYPE GLIOBLASTOMA: THE DANA-FARBER CANCER INSTITUTE EXPERIENCE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii164-ii164
Author(s):  
Mary Jane Lim-Fat ◽  
Gilbert Youssef ◽  
Mehdi Touat ◽  
Bryan Iorgulescu ◽  
Eleanor Woodward ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Immune Checkpoint Blockade ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Dana Farber Cancer Institute ◽  
Clinical Records ◽  
Ngs Data ◽  
Generation Sequencing

Abstract BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.

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