scholarly journals Two Case Reports of Rare BRAF Mutations in Exon 11 and Exon 15 with Discussion of Potential Treatment Options

2016 ◽  
Vol 9 (3) ◽  
pp. 543-546 ◽  
Author(s):  
Georg Richtig ◽  
Ariane Aigelsreiter ◽  
Karl Kashofer ◽  
Emina Talakic ◽  
Romana Kupsa ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Treatment Options ◽  
Mek Inhibitor ◽  
Activity Levels ◽  
Wild Type ◽  
Braf Gene ◽  
Braf Mutations ◽  
Exon 11 ◽  
Increased Activity

BRAF mutations occur in up to 50% of melanomas. Mutations in the BRAF gene directly influence the patient’s treatment because several inhibitors are available that only target BRAFV600 mutations. Herein, we describe two cases of patients with metastatic melanomas, each carrying a ‘nonstandard’ mutation in the BRAF gene: BRAFK601E and BRAFG466E, respectively. The first patient was treated with a MEK inhibitor and the second one with ipilimumab. However, not all BRAF mutations result in increased BRAF kinase activity, and clinical data for ‘nonstandard’ mutations, such as those described in our case report, are sparse. Therefore, treatment with MEK inhibitors can be helpful in cases where BRAF mutations result in increased activity, whereas immune checkpoint inhibitors might be used in cases where the mutations lead to activity levels below those of the wild type.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

scholarly journals Rapid BRAF mutation detection in melanoma patients by immunohistochemistry

2017 ◽  
Vol 4 (1) ◽  
pp. 1-5
Author(s):  
László Fülöp ◽  
Katalin Götzer ◽  
Erzsébet Csernák ◽  
Danyil Szergejevics Kuznyecov ◽  
Erika Tóth
Keyword(s):  
Braf Inhibitor ◽  
Pcr Amplification ◽  
Diagnostic Algorithm ◽  
Braf V600e ◽  
Wild Type ◽  
Braf Gene ◽  
Braf Mutations ◽  
Activating Mutation ◽  
Melanoma Patients ◽  
Braf V600 Mutation

The V600E mutation is the most common (~90%) activating mutation of the BRAF gene. BRAF mutations have been frequently investigated in melanoma, colorectal cancer and papillary thyroid carcinoma. The importance of the detection of BRAF mutations has been rising by the routine use of Braf inhibitor therapy. We evaluated the usefulness of the BRAF V600E mutation-specific monoclonal antibody (VE1) in metastatic melanoma patients. To confirm the results of immunohistochemistry (IHC), we used COBAS 4800 BRAF V600 mutation test and PCR amplification followed by Sanger sequencing.36 of 105 patients have wild-type BRAF gene, 64 have V600E mutation and 5 of 105 have V600K mutation. Predicting the mutation only by IHC using VE1 antibody, all 58 positively scored specimen were V600E mutant. The V600K, the wild-type patients and 7 patients from the V600E mutant group scored as negative. Thus the specificity is 100% and the positive predictive value is 1 of the IHC method. After processing our data we could establish a cheaper diagnostic algorithm for rapid detection ofBRAF mutation.

ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1443-1451 ◽  
Author(s):  
Jordi To-Figueras ◽  
Sarah Ducamp ◽  
Jerome Clayton ◽  
Celia Badenas ◽  
Constance Delaby ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Gene Mutations ◽  
Wild Type ◽  
Aminolevulinate Synthase ◽  
Sequence Variations ◽  
Congenital Erythropoietic Porphyria ◽  
New Type ◽  
Terminal Amino ◽  
Exon 11 ◽  
Increased Activity

AbstractMutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.

The temporal evaluation of RAS and BRAF mutation by liquid biopsy at progression after bevacizumab combinations in patients with metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15587-e15587
Author(s):  
Irem Bilgetekin ◽  
Mehmet Dogan ◽  
Cengiz Karacin ◽  
Fatma Bugdayci Basal ◽  
Ece Esin ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Liquid Biopsy ◽  
Treatment Options ◽  
Rank Test ◽  
Wild Type ◽  
Braf Mutations ◽  
Mutant Type ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Significant Difference

e15587 Background: Expanded RAS analysis is essential for the selection of biologic agents in mCRC. RAS mutations indicates anti-EGFR unresponsiveness. In this study, we aimed to investigate RAS and BRAF mutations by liquid biopsy at progression in patients with RAS mutant mCRC. Methods: Sixty patients with mCRC who harbored tissue RAS mutations were prospectively analyzed between July 2019 and April 2020. All the patients treated with chemotherapy plus bevacizumab combinations . The plasma samples of the patients were analyzed after progression of bevacizumab combinations. RAS mutation profile was evaluated in plasma using Idylla PCR-based molecular diagnostics method, which enables rapid detection of common mutations in RAS and BRAF genes in circulating tumor DNA (ctDNA). Kaplan-Meier method was used for survival analysis and log-rank test was performed for comparison of groups. Results: The median age of the patients was 60 years (IQR:35-83 years) and female was (n=23, 38.3%). Primary tumor was located in the left colon in 81.7% of all patients. There were 95.0% KRAS and 5% NRAS mutations in baseline tissue biopsy. As a result of liquid biopsy after progression, 55.0% of the patients had KRAS, 3.3% NRAS and 3.3% had BRAF mutations. The RAS mutation detected in 58.3% of the patients. While there was no significant difference in terms of clinicopathological features between wild type (RAS/BRAF) and mutant type (RAS/BRAF) determined by liquid biopsy, the overall survival (OS) of the wild type group was significantly longer than mutant group (43.8 vs. 20.4 months, p= 0.002). Conclusions: This study demonstrated that there may be changes in RAS/BRAF mutation from plasma analysis after progression in patients with mCRC. Since better survival in the patient group with wild type was detected compared to the RAS concordance group, the evaluation of RAS mutation status at the time of progression may be important in terms of disease prognosis and treatment options.

Chemo-immunotherapy combination after PD-1 inhibitor failure improves clinical outcomes in metastatic melanoma patients.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 138-138
Author(s):  
Jesus Vera Aguilera ◽  
Jonas Paludo ◽  
Jarrett Failing ◽  
Robert R. McWilliams ◽  
Lisa A. Kottschade ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Efficacy And Safety ◽  
Wild Type ◽  
Lung Cancer Patients ◽  
Melanoma Patients

138 Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains challenging and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. In this study, we compared the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We reviewed MM patients seen at Mayo Clinic between Jan, 2012 and Jun, 2018 who failed anti-PD1 therapy and received subsequent CIT, or immune checkpoint inhibitors (ICI) or chemotherapy alone. A total of 60 patients were analyzed, the CIT cohort [n=33 (55%)] treatment consisted of carboplatin/paclitaxel (n=29), nab-paclitaxel (n=2), paclitaxel (n=1), and temozolomide (n=1). In the ICI (n=9) or chemotherapy alone cohort (n=18) [n=27 (45%)], treatment consisted of carboplatin/paclitaxel (n=11), temozolomide (n=4), nab-paclitaxel (n=3), ipilimumab/nivolumab (n=4), pembrolizumab (n=4), or nivolumab (n=1). Results: Patients in the CIT cohort had a median OS of 3.5 years (95% CI: 1.7-NR) compared to 1.8 years (95% CI: 0.9-2) in the ICI or chemotherapy alone cohort, p=0.02. The median EFS following CIT was 7.6 months (95% CI: 6-10) compared to 3.4 months (95% CI: 2.8-4.1) following either ICI or chemotherapy alone, p=0.0005. A trend towards longer median EFS with use of CIT was seen in patients with BRAF wild-type [median 9 months (95% CI: 6-12)] compared to those harboring a BRAF mutation [median 6.5 months (95% CI: 1.8-9.1), p=0.29]. Side effects were similar among both groups. Conclusions: In MM patients who have failed anti-PD-1 therapy, the CIT combination showed favorable clinical outcomes and acceptable safety profile. This regimen should be considered for MM pts in this setting who have limited treatment options. [Table: see text]

scholarly journals Bullous Pemphigoid as an Adverse Reaction to Pembrolizumab: Two Case Reports

2018 ◽  
Vol 10 (2) ◽  
pp. 154-157 ◽  
Author(s):  
Kenneth Thomsen ◽  
Jon Diernaes ◽  
Trine Heide Øllegaard ◽  
Eva Spaun ◽  
Christian Vestergaard
Keyword(s):  
Adverse Reaction ◽  
Bullous Pemphigoid ◽  
Adverse Reactions ◽  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Treatment Options ◽  
Survival Rates ◽  
Programmed Cell Death 1 ◽  
Different Types ◽  
Promising Treatment

Checkpoint inhibitors are novel and promising treatment options for different types of cancer. Programmed cell death 1 (PD-1) inhibitors, such as pembrolizumab, have been shown to significantly raise the survival rates of disseminated malignant melanoma (MM). Autoimmune adverse reactions are very common in checkpoint inhibitors. We present 2 cases of bullous pemphigoid, as adverse reactions to pembrolizumab-treated MM.

scholarly journals Procedure of Direct Hepatic Artery Puncture for the Treatment of Hepatocellular Carcinoma: Two Case Reports

2020 ◽  
Vol 13 (1) ◽  
pp. 414-418
Author(s):  
Hidetaka Takashima ◽  
Michihisa Moriguchi ◽  
Kohichiroh Yasui ◽  
Natsuko Hayashi ◽  
Kyohei Ikeda ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatic Artery ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Treatment Options ◽  
Intermediate Stage ◽  
Emergency Case ◽  
Ultrasonographic Guidance ◽  
Computed Tomography Image

Recently, treatment options for hepatocellular carcinoma (HCC) have expanded due to the development of the tyrosine kinase inhibitor ramucirumab and immune checkpoint inhibitors. Transcatheter arterial chemoembolization is the standard therapy for intermediate-stage HCC; however, in cases with anatomical problems, normal approaches are not possible. In such rare cases, direct hepatic puncture may be considered as an effective therapy and an indispensable treatment. We report our novel method of direct hepatic artery puncture in this case report. In 2011 and 2017, we reported 2 cases in the journal of the Japan Society of Hepatology in Japanese. This therapy is difficult and is associated with a high risk of complications; however, we succeeded in both cases in a similar way. We believe this method may provide an alternative treatment when standard treatment is not possible or when urgent therapy is required. In case 1, direct hepatic artery puncture was performed under ultrasonographic guidance, and we were able to control the disease with percutaneous lipiodol chemotherapy. Case 2 was an emergency case of ruptured HCC. Direct hepatic puncture successfully stopped tumor bleeding; furthermore, tumor necrosis also occurred, as seen on the enhanced computed tomography image. Our new method requires advanced puncture techniques and is not the treatment of choice if there are other safe alternatives available. However, it can be considered as an option if there are no other viable, effective treatments.

Case of metastatic kaposi sarcoma successfully treated with anti-PD-1 immunotherapy

2021 ◽  
pp. 107815522098558
Author(s):  
E Cesmeci ◽  
DC Guven ◽  
BY Aktas ◽  
S Aksoy
Keyword(s):  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Treatment Options ◽  
Kaposi Sarcoma ◽  
Complete Response ◽  
Punch Biopsy ◽  
Trial Management ◽  
Treatment Algorithms ◽  
Immunotherapy Trial ◽  
And Control

Introduction Kaposi sarcoma (KS) is an angioproliferative malignancy associated with HHV-8. It is mostly observed in patients affected by HIV and/or chronic immunosuppression, while classic KS without underlying immunosuppression are relatively rare. Systemic chemotherapy is used for advanced diseases, although there is no consensus in treatment algorithms. With the demonstration of PD-1 expression in KS, immune-checkpoint-inhibitors (ICI) emerged as possible treatment options. Notwithstanding, the data of ICIs is limited to case reports/series. Herein, we present a case of advanced classic KS, which has been treated successfully with nivolumab. Case report 82-year-old male patient was investigated for erythematous lesions on thigh. Punch biopsy lead to KS diagnosis. Abdominal CT showed lymphadenopathies in the inguinal region. After radiotherapy follow-up, patient had shown vertebral & gastric metastases. Because of the PSA elevation patient was diagnosed with prostatic adenocarcinoma. Metastases were investigated for origin. The lesions showed no uptake in Ga-68 PET-CT, therefore accepted as KS metastases. Patient rejected chemotherapy options and consented to immunotherapy trial. Management and outcome: Nivolumab was initiated 3 mg/kg bi-weekly with 12-dose protocol. After nivolumab patient wellbeing is improved and control endoscopy shown no metastases. With these findings patient has been assessed as complete response. Discussion ICI on KS is still a blurred option to be included in standard regimens; but progressive understanding of PD-1 expression and its role in disease progression may be a milestone for further treatment algorithms on KS. Besides good efficacy, tolerability of ICIs could be helpful patients with comorbidities precluding the use of chemotherapy.

scholarly journals Landscape of Current Targeted Therapies for Advanced Colorectal Cancer

2021 ◽  
Author(s):  
Ana João Pissarra ◽  
Catarina Abreu ◽  
André Mansinho ◽  
Ana Lúcia Costa ◽  
Sara Dâmaso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Disease ◽  
Targeted Therapies ◽  
High Throughput Sequencing ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Her2 Overexpression ◽  
Braf Mutations ◽  
Therapeutic Landscape ◽  
Cancer Types

Colorectal cancer (CRC) is one of the most frequent and lethal cancer types worldwide. While surgery with chemotherapy and radiotherapy remains the only curative approach for localized CRC, for metastatic disease the therapeutic landscape has significantly evolved over the last years. Development and approval of novel targeted therapies, such as monoclonal antibodies against EGFR and VEGF, have significantly increased the median survival of patients with metastatic disease, with some trials reporting a benefit over 40 months. Increasing accessibility of high throughput sequencing has unraveled several new therapeutic targets. Actionable alterations, such as HER2 overexpression, BRAF mutations, and NTRK fusions, are currently available in metastatic disease, providing significant therapeutic opportunities for these patients, while new emerging agents, as immune checkpoint inhibitors, promise better treatment options in the near future. In this chapter, an overview of established and future CRC targeted therapies in the clinical setting is provided, as well as their mechanism of action, limitations, and future applicability.

scholarly journals P.057 Distal hereditary motor neuropathy type I due to the GARS: c.1415A>G, p.His472Arg mutation

2016 ◽  
Vol 43 (S2) ◽  
pp. S34-S34
Author(s):  
AG Florendo-Cumbermack ◽  
K Kimpinski ◽  
S Venance
Keyword(s):  
Genetic Characterization ◽  
Case Reports ◽  
Treatment Options ◽  
Type I ◽  
Motor Neuropathy ◽  
Juvenile Onset ◽  
Hereditary Motor ◽  
Clinical Presentations ◽  
Hereditary Motor Neuropathy ◽  
Exon 11

Background: The distal hereditary motor neuropathies (dHMN) have been characterized through case reports and family studies. Their genetic characterization remains a work in progress. An appreciation of the genetic underpinnings may lead to treatment options in the future. Hence reports, like this one, which add to this understanding, remain extremely important. Methods: The clinical presentations, electrophysiology and genetics of two patients with the dHMN I phenotype are described. Results: A mother and son presented with slowly progressive distal weakness of the lower extremities with onset in the first and second decades. Distal weakness of the upper extremities developed later. Examination 20 and 50 years after onset revealed wasting and weakness of distal upper and lower extremity muscles with absent distal and preserved proximal deep tendon reflexes. Sensory examination was normal. Electrodiagnostic studies demonstrated a motor axonopathy. Genetics testing revealed a missense mutation on chromosome 7, exon 11 of the GARS gene: c.1415A>G (p.His472Arg). Conclusions: GARS mutations have been identified in patients with the dHMN I (juvenile onset distal weakness and wasting) and dHMN V (upper limb predominant) phenotypes. However, this mutation has not previously been directly linked to the dHMN I phenotype.

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