Differential clinical associations of BRAF and NRAS mutations among histologic types of cutaneous melanomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20034-e20034
Author(s):  
David Stockman ◽  
Michael T. Tetzlaff ◽  
Tariq Al-Zaid ◽  
Carlos A. Torres-Cabala ◽  
Amanda Dawn Bucheit ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Stage Iv ◽  
Braf V600e ◽  
Nras Mutation ◽  
Braf Mutations ◽  
Mutation Status ◽  
Mutational Status ◽  
Significant Difference ◽  
Clinical Associations ◽  
Histologic Types

e20034 Background: Previous studies have investigated whether BRAF and NRAS mutation status in melanoma correlate with histologic parameters and overall survival (OS), but evaluation of mutation groups irrespective of specific mutation among histologic types of melanoma has led to variability in the reproducibility of results. We tested the hypothesis that different histologic types of melanoma (nodular [NM] and superficial spreading [SSM]) have distinct clinical associations with specific BRAF and NRAS mutations. Methods: Primary tumor histology, BRAF/NRAS mutation status, and clinical outcomes were collected for 195 patients (pts) with stage III or IV disease. Clinical associations with specific mutations were determined separately for patients with NM (n=105) and SSM (n=90) histologic types of primary cutaneous melanomas. Results: Mutational status in NM: 69 BRAF (66%), 19 NRAS (18%), & 17 wild-type (WT;16%). Specific BRAF mutations in NM: V600E 50 (75%), V600K 13 (19%), V600R 4 (6%). Specific NRAS mutations in NM: Q61K 6 (32%), Q61L 2 (11%), Q61R 8 (42%); other 3 (16%). Mutation status in SSM: 45 BRAF (50%), 24 NRAS (27%), 21 WT (23%). Specific BRAF mutations in SSM: V600E 32 (71%), V600K 12 (24%), V600R 0. Specific NRAS mutations in SSM: Q61K 2 (8%), Q61L 5 (21%), Q61R 12 (50%). The distribution of specific BRAF (p=0.21) and NRAS (p=0.29) mutations between NM and SSM was not significantly different. Among NM pts, pts with activating NRAS mutations had shorter OS from the diagnosis of Stage IV melanoma than WT (HR 3.42, p=0.02) and BRAF (HR 2.40, p=0.009). There was no significant difference for BRAF pts vs WT (HR 1.43, p=0.47). Among SSM patients, neither NRAS (HR 1.3, p=0.53) nor BRAF(HR 0.54, p=0.16) were significantly associated with OS compared to WT. Comparison of patients with BRAF V600E vs V600K showed significant association for OS from stage 4 in SSM pts (HR 0.24, p=0.01), but not in NM pts (HR 0.64, p=0.36). Conclusions: The prognostic significance of BRAF and NRAS mutations on OS from stage IV differed for pts with NM and SSM primaries. Further investigation of the histologic types of melanoma with specific BRAF and NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes.

scholarly journals Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: Association with overall survival?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9025-9025 ◽  
Author(s):  
Joanna Mangana ◽  
Simone M. Goldinger ◽  
Katja Schindler ◽  
Sima Rozati ◽  
Anna L. Frauchiger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Wild Type ◽  
Nras Mutation ◽  
Mutation Status ◽  
Mutational Status ◽  
Melanoma Patients

9025 Background: Ipilimumab and tremelimumab are human monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival with durable-long-term responses for advanced melanoma patients both in first-and second-line setting. Up to date, there is no proven association between the BRAF-V600E mutation and the disease control rate (DCR) in response to Ipilimumab. Moreover, significantly shorter survival rates have been reported in patients harboring an NRAS mutation than in those without. This retrospective analysis was carried out to assess if BRAF (V600) and NRAS mutation status affects the clinical outcome of Ipilimumab-treated melanoma patients. Methods: This is a retrospective multi-center analysisof 71 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The cut-off for the estimation of overall survival was end of November 2012. Results: The median overall survival of BRAFV600/NRAS mutant patients (n=44) was 1,41 years compared with 2.67 years in BRAF/NRAS wild-type patients (n=27). Although this difference was not statistically significant there was a trend for improved survival in wild-type patients. Of the 71 patients analyzed, 56 received chemotherapy prior to Ipilimumab. In the BRAF/NRAS mutant cohort, 12 patients received Ipilimumab following either a BRAF- or a MEK- inhibitor. Of those 12 patients, 8 progressed and were unable to complete Ipilimumab. Of the 4 patients who completed 4 cycles of Ipilimumab, 2 were subsequently treated with a BRAF inhibitor. Furthermore out of the 71 patients, 8 patients received a BRAF or a MEK inhibitor after progression; 5 of them are still alive. Conclusions: This is the first retrospective study to evaluate the association of both BRAF and NRAS mutational status with the overall survival of Ipilimumab-treated patients. There was a trend towards an improved survival in the BRAF/NRAS wild-type subpopulation. Additional patients will be examined to foster these preliminary results.

Analysis of NRAS mutation as poor prognostic indicator and predictor of resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) in metastatic colorectal cancer (mCRC) patients (pts).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3613-3613 ◽  
Author(s):  
Marta Schirripa ◽  
Fotios Loupakis ◽  
Chiara Cremolini ◽  
Manfredi Morvillo ◽  
Francesca Bergamo ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Prognostic Indicator ◽  
Braf V600e ◽  
Nras Mutation ◽  
Braf Mutations ◽  
Mutational Status ◽  
Ras Family ◽  
Predictive Role ◽  
Poor Prognostic Indicator

3613 Background: NRAS belongs to RAS family. NRAS mutations are mutually exclusive with KRAS and BRAF mutations and contribute to the activation of Ras/Raf/MAPK pathway. Previous experiences evaluated the prognostic/predictive role of NRAS mutations suggesting a poorer prognosis and resistance to anti-EGFRs for NRASmutant (mut) mCRC pts. The aim of the present study was to confirm such preliminary findings in a large cohort of mCRC pts. Methods: Data on KRAS (codons 12, 13 and 61) and BRAF-V600E mutational status of mCRC pts referred to our pathology from '09 to '12 were collected. NRAS mutational status (codons 12, 13 and 61) was evaluated in KRAS and BRAF wt pts. OS was calculated from date of diagnosis of metastatic disease. Data on response and PFS according to RECIST were collected for NRASmut irinotecan-refractory pts treated with anti-EGFRs +/- irinotecan. Results: 774 mCRC pts were included. KRAS/BRAF mutations were found in 384 (50%)/69 (9%) cases. NRAS was mut in 47 (15%) out of 318 KRAS and BRAF wt pts. NRAS mut pts had significantly shorter OS in comparison to KRAS-BRAF-NRAS wt pts (HR=0.60 [0.29-0.99] p=0.045). BRAF mut pts had significantly worse OS in comparison to NRAS mut pts (HR=1.75 [1.073-2.87] p=0.03). No difference was observed between NRAS mut and KRAS mut pts (HR=0.86 [0.51-1.43] p=0.61). 18 pts out of 47 NRAS mut pts received anti-EGFRs in advanced lines. 8 pts (7 cetuximab-based, 1 panitumumab monotherapy) were evaluable according to RECIST criteria and therefore eligible for the present analysis. None of them responded and only 1 SD was observed. Pooling our results with available data on anti-EGFRs’ activity in NRASmut pts in advanced lines of treatment (De Roock, 2010; Peeters, 2013; Andrè, 2012), only 1 response is described out of 35 treated pts (2,9%). Conclusions: Our data demonstrate that NRAS mutations have a relevant incidence in KRAS and BRAF wt mCRC pts. Present results are consistent with previous experiences and confirm that NRAS mutations affect prognosis of mCRC patients and predict lack of response to anti-EGFRs. Further insights into NRAS mut mCRC biology and prospective validation are warranted.

Impact of BRAF mutations on prognosis and immunotherapy response in microsatellite instability/mismatch repair deficient metastatic colorectal cancer: A systematic review and meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3557-3557
Author(s):  
Robin Park ◽  
Laércio Lopes da Silva ◽  
Sunggon Lee ◽  
Anwaar Saeed
Keyword(s):  
Colorectal Cancer ◽  
Systematic Review ◽  
Braf Mutation ◽  
Meta Analysis ◽  
Stage Iv ◽  
Stage I ◽  
Prognostic Impact ◽  
Braf Mutations ◽  
Mutation Status ◽  
The Impact

3557 Background: Mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC) defines a molecular subtype with distinct clinicopathologic characteristics including an excellent response to immunotherapy. Although BRAF mutations are established as a negative prognostic marker in CRC, whether they retain their negative prognostic impact in or alter the response to immunotherapy in dMMR/MSI-H CRC remains unknown. Herein, we present a systematic review and meta-analysis of the impact of BRAF mutations on the overall survival (OS) and immune checkpoint inhibitor (ICI) response in dMMR/MSI-H CRC. Methods: Studies published from inception to 26 January 2021 were searched in PubMed, Embase, and major conference proceedings (AACR, ASCO, and ESMO). Eligible studies included the following: 1) observational studies reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients and 2) experimental studies of ICI reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients. A summary hazard ratio (HR) was calculated for OS in BRAF mutated ( BRAFmut) vs. BRAF wild type ( BRAFwt) patients (pts) with the random effects meta-analysis (REM). A summary odds ratio (OR) was calculated for objective response rate (ORR) in BRAFmut vs. BRAFwt pts treated with ICI with the REM. Results: Database search conducted according to PRISMA guidelines found 4221 studies in total. Initial screening identified 30 studies and after full-text review, 9 studies (N = 4158 pts) were included for the meta-analysis of prognosis (analysis A) and 3 studies (N = 178 pts) were included for the meta-analysis of ICI response (analysis B). The outcome measures are summarized in the table below. Analysis A showed that in stage I-IV dMMR/MSI-H CRC pts, BRAFmut was associated with worse OS than BRAFwt (HR 1.57, 1.23-1.99). The heterogeneity was low (I2 = 21%). Subgroup analysis showed no significant difference in the prognostic impact of BRAF mutation status between stage IV only and stage I-IV CRC pts. Analysis B showed no difference in ORR (OR 1.04, 0.48-2.25) between BRAFmut vs. BRAFwt dMMR/MSI-H pts who received ICI. The heterogeneity was low (I2 = 0%). Conclusions: BRAF mutations retain their negative prognostic impact in dMMR/MSI-H stage I-IV and stage IV CRC but are not associated with differential ICI response. Limitations include the following: analysis A was based on retrospective studies; also, the impact of BRAF status on the survival outcome of ICI could not be assessed due to limited number of studies.[Table: see text]

Quality Control and Telemedicine for BRAF V600E Mutations in Papillary Thyroid Carcinomas

2015 ◽  
Vol 4 (2) ◽  
pp. 12-30 ◽  
Author(s):  
Niki Margari ◽  
Abraham Pouliakis ◽  
Aris Spathis ◽  
Emmanouil Mastorakis ◽  
Efthymios Karakostas ◽  
...  
Keyword(s):  
Quality Control ◽  
Braf Mutation ◽  
Image Features ◽  
Classification And Regression Tree ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Cell Nuclei ◽  
Braf Mutations ◽  
Mutation Status ◽  
Thyroid Carcinomas

The assessment of BRAF V600E mutations is important for prognosis and treatment of Papillary Thyroid Carcinomas (PTC), the standard methods for their identification are molecular biology techniques. In this study, the potential of image morphometry applied to cell nuclei and sequentially the use of a Classification And Regression Tree (CART) is investigated, in order to: identify morphometric features useful to characterize BRAF mutations, and to eventually produce an algorithm identifying BRAF mutation status. The 140 studied cases had histological confirmation and known BRAF mutation status identified via real-time PCR. The analysis revealed that nuclear features contributing to BRAF mutation status identification via the CART model are related mostly to nuclear color. According to the results there is evidence that BRAF V600E mutations can be identified by measurable image features. Therefore, the proposed method is useful for quality control of BRAF V600E mutations on cytological slides, can serve as alternative to PCR method and may be used for remote assessment.

scholarly journals 7 Assessing melanoma BRAF status through ddPCR of cfDNA

2019 ◽  
Vol 95 (1130) ◽  
pp. 686.4-687
Author(s):  
Lauren Passy ◽  
Shobha Silva ◽  
Ian Brock ◽  
Greg Wells ◽  
Angela Cox ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Limit Of Detection ◽  
Wild Type ◽  
Braf Mutations ◽  
Mutation Status ◽  
Gapdh Gene ◽  
Fractional Abundance ◽  
Significant Difference ◽  
Tissue Specimens ◽  
Braf Mutant

IntroductionTreatment of recurrent and metastatic melanoma has been revolutionised by targeted therapy. Inhibitors of mutant BRAF are a systemic treatment offered for patients with stage III/IV melanoma who are known to carry a mutation in BRAF. Currently patients’ BRAF mutation status is assessed through molecular analysis of tissue specimens.Cell-free DNA (cfDNA) released from tumours can be used to non-invasively detect active disease and predict survival in melanoma. cfDNA also provides a method for detecting BRAF mutations. This project aimed to ascertain BRAF mutation status in cfDNA through digital droplet PCR (ddPCR) of plasma samples from patients with melanoma. We aimed to assess the relationship between cfDNA BRAF positivity and disease relapse and progression.MethodsPlasma from 100 patients with active or recently resected melanoma was obtained during previous work. 85 samples had cfDNA extracted. Tissue BRAF status was known for 57 samples. cfDNA was extracted from 1–2 ml plasma with the QIAamp circulating nucleic acid kit (QIAGEN®) following manufacturer protocol, eluting cfDNA into 100µL. cfDNA was quantified with SYBR green quantitative real-time PCR (Life Technologies), based on an 87bp GAPDH gene amplicon. ddPCR™ was performed using the Bio-Rad QX200 Droplet Generator™ and Droplet Reader as per manufacturer protocol. Analysis was performed with Bio-Rad QuantaSoft Version 1.7.4.ResultsMedian yield of cfDNA extracted from 85 samples was 1.97 ng/ml when eluted into 100µL. This was well-correlated with previous cfDNA extraction yields from this sample set (Pearson’s r=0.6687, p<0.0005), where a 200µL elution volume was used. 74 samples yielded >10,000 droplets and were included for analysis. 12 samples contained BRAF mutant positive droplets. A 74% concordance rate between tissue BRAF mutation status and the presence/absence of cfDNA BRAF mutant positive droplets was found. 7/18 tissue BRAF mutant samples contained BRAF mutant droplets, in comparison to 2/32 tissue BRAF wild-type samples. The presence of BRAF mutant positive droplets was significantly different between the tissue BRAF mutant and tissue BRAF wild-type groups (χ2 8.3145, p=0.004).Fractional abundance of BRAF mutant droplets in the samples containing mutant droplets ranged from 0.07–0.74%. When comparing BRAF mutant droplet-containing samples and samples without BRAF mutant droplets, there was no significant difference in rate of relapse (χ2 0.0948, p=0.758), nor mortality rate (χ2 3.3959, p=0.654).Conclusion cfDNA provides a non-invasive snapshot of the tumour genome and any potential therapeutic targets held within. This work demonstrates that a very low volume of cfDNA can be used to detect BRAF mutations in patients with melanoma through ddPCR.Previous work assessing BRAF status in cfDNA has used larger volumes of cfDNA. Though our concordance rates are comparable with other studies, it is possible that using a smaller amount of cfDNA in our ddPCR has resulted in some samples being below the limit of detection for ddPCR.Longitudinal study is warranted to monitor cfDNA BRAF status and mutant fractional abundance, and whether this better correlates with relapse of disease and disease progression.

Strikingly Homologous Immunoglobulin Gene Rearrangements and Poor Outcome in VH3-21-Utilizing Chronic Lymphocytic Leukemia Independent of Geographical Origin and Mutational Status.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 175-175
Author(s):  
Fiona Murray ◽  
Mia Thorselius ◽  
Alexander Krober ◽  
Ulf Thunberg ◽  
Gerard Tobin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Light Chain ◽  
Geographical Origin ◽  
Lymphocytic Leukemia ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Mutation Status ◽  
Mutational Status ◽  
Significant Difference ◽  
Vh Genes

Abstract We recently reported that Swedish VH3-21-utilizing chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite VH mutation status. To investigate whether VH3-21+ CLLs have similar characteristics in different parts of the world, we analyzed the VH and VL gene rearrangements in 90 patients from Sweden, Germany, Italy, USA, Finland and Australia and correlated these data with survival. Sixty-three percent of cases exhibited mutated VH genes and 37% had unmutated VH genes. Fifty patients (56%) displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif, DANGMDV. Also, a highly biased Vλ2-14 usage was evident in 73% of patients with a restricted light-chain CDR3, QVWDS(S/G)SDHPWV. Combined restricted heavy- and light-chain CDR3s were found in patients from all included countries. Although VH3-21+ CLLs have a remarkably predominant λ-expression, analyses of kappa deleting element showed a conserved rearrangement order of the light-chain loci. The overall survival was poor in the VH3-21+ cohort (median survival 88 months) with no significant difference in relation to mutation status or homologous/non-homologous CDR3. In summary, highly restricted B-cell receptors and worse outcome characterize VH3-21+ CLLs independent of geographical origin and mutation status. VH3-21 usage should now be included in prognostic stratification of CLL when assessing mutation status.

BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis

2019 ◽  
Vol 22 (5) ◽  
pp. 449-455 ◽  
Author(s):  
Erdener Ozer ◽  
Akin Sevinc ◽  
Dilek Ince ◽  
Resmiye Yuzuguldu ◽  
Nur Olgun
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Erk Pathway ◽  
Disease Relapse ◽  
Multisystem Disease ◽  
Mutational Status

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.

Differential Prognostic Impact Of Peripheral Blood Blast Clearance In AML Based On Type Of Therapy and FLT3 Mutation Status

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2584-2584
Author(s):  
Christopher B. Benton ◽  
Lisa Gu ◽  
Hagop M. Kantarjian ◽  
Peng Qiu ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Specific Treatment ◽  
Rank Test ◽  
P Value ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Mutational Status

Abstract Background The day of clearance of peripheral blood blast cells (PBBC) is a prognostic marker in patients with acute myeloid leukemia (AML) treated with induction chemotherapy with cytarabine (ara-C) plus idarubicin (AI regimen: ara-C 1.5g/m2 x 4 days, idarubicin 12mg/m2 x 3 days). Earlier PBBC clearance correlates with improved overall survival (OS). We extended this observation to subsets of patients receiving the AI regimen in combination with a targeted agent such as the FLT3 inhibitor sorafenib (AI regimen plus sorafenib 400mg orally twice daily x 7 days) and vorinostat (vorinostat 500mg three times daily x 3 days followed by AI regimen), and examined the interaction of FLT3 mutational status and PBBC clearance. Patients and Methods PBBC clearance (defined as PBBC=0% by CBC differential) was examined for patients with non-APL AML undergoing AI alone (n=168), AI+sorafenib (n=75), and AI+vorinostat (n=102). Patient characteristics for all patients (n=345) were as follows: median age 54 years (range, 18-72), FLT3-mutated (FLT3+, includes FLT3-ITD and FLT3-D385) (95, 28%), wild-type FLT3 (FLT3-neg) (207, 60%), median WBC 5.0x109/dL (range, 0-229), median PBBC 17% (range, 0-99), median BM blasts 46% (range, 1-98). Patients for each cohort were divided based on day of PBBC clearance and survival evaluated by Kaplan-Meier curves. Comparisons of curves were carried out using a log-rank test. Results The overall response rates (ORR=CR+CRp) for the AI, AI+sorafenib, and AI+vorinostat induction cohorts were 63%, 79%, and 76% respectively. We evaluated OS for each of the three cohorts individually. In our first analysis, we divided patients into 5 groups according to PBBC clearance day: group A (0-1 days), B (2-3 days), C (4-5 days), D (6-8 days), and E (>8 days). We found that OS for patients in groups A-E was significantly different only in the AI therapy cohort (p-value<0.01), and not in the AI+sorafenib (p-value=0.15) or AI+vorinostat (p-value=0.1) cohorts. Noting that earlier blast clearance generally correlated with improved OS, we simplified our analysis by dividing patients into only two groups based on blast clearance. We performed two separate analyses using a 3-day cutoff (0-3 days vs. >3 days) or a 5-day cutoff (0-5 days vs. >5 days). For a blast clearance cutoff of 3 days, OS was significantly different in the AI+vorinostat cohort (p-value=0.02) and not in the AI alone (p-value=0.27) or AI+sorafenib (p-value=0.1) cohorts. For a 5-day cutoff, OS was significantly different in the AI (p-value<0.001) and AI+vorinostat (p-value=0.04) cohorts, but not the AI+sorafenib (p-value=0.13) cohort. We next evaluated FLT3+ and FLT3-neg patients individually for all three cohorts. Using a 3-day cutoff for blast clearance, the prognosis of FLT3+ patients could be significantly differentiated for patients treated with the FLT3 targeted regimen AI+sorafenib (p-value=0.04), but not AI alone (p-value=0.64) or AI+vorinostat (p-value=0.48). In distinction, FLT3-neg patients receiving AI+vorinostat could be well differentiated (p-value=0.06), but not FLT3-neg patients receiving AI alone (p-value=0.21) or AI+sorafenib (p-value=0.6). Conclusions The prognostic significance of the day of PBBC clearance during induction chemotherapy in AML is dependent on the specific treatment used and the mutation status of the patients being treated. For patients treated with AI alone, disappearance of blasts within 5 days of induction strongly predicts superior survival compared to patients who clear blasts after 5 days. For patients treated with AI+sorafenib, there is not a strong correlation between day of blast clearance and prognosis, unless FLT3+ patients are investigated alone, where there is a significant correlation between clearing blasts within 3 days of induction and prognosis. For patients treated with AI+vorinostat, disappearance of blasts within 3 days suggests a better survival in FLT3-neg but not FLT3+ patients. Additional approaches are needed to evaluate the prognostic value of clearance of PBBC in AML in the context of targeted therapy and mutational status of disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

2020 ◽  
Vol 9 (3) ◽  
pp. 690 ◽  
Author(s):  
Takamichi Ito ◽  
Yumiko Kaku-Ito ◽  
Maho Murata ◽  
Kazuhisa Furue ◽  
Che-Hung Shen ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Cutaneous Melanoma ◽  
Immunohistochemical Staining ◽  
Staining Pattern ◽  
Braf V600e ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Different Genetic Background

Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan–Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.

scholarly journals TERT promoter mutation is an objective clinical marker for disease progression in chondrosarcoma

2021 ◽  
Author(s):  
Yifan Zhang ◽  
Yi Chen ◽  
Chen Yang ◽  
Nelly Seger ◽  
Asle C. Hesla ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Tumor Grade ◽  
Promoter Mutation ◽  
Primary Tumors ◽  
Mutation Status ◽  
Free Survival ◽  
Metastatic Lesions ◽  
Mutational Status ◽  
Future Potential ◽  
Promoter Mutations

AbstractChondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994–2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at −124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.

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