Positive BRAF Research Articles

The secretome of highly metastatic cells as a source of biomarkers and metastatic effectors in colorectal cancer patients.

Introduction: Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries, mainly as a consequence of metastatic spread. Secreted proteins are essential to communicate the cancer cells with the tumor- microenvironment, favoring tumor progression and metastasis. The conditioned medium or cellular secretome, including exosomes, has demonstrated to be a rich source of metastatic effectors and biomarkers of metastatization in different tumors. Our goal was to identify proteins altered in the secreted fraction of highly metastatic cells in order to determine altered biological pathways and potential biomarkers of prognosis. Material and methods: A quantitative label-free proteomic analysis was carried out on the secretome of highly and poorly metastatic CRC cell lines from different genetic background. Proteomic results were validated using unbiased transcriptomic analyses. Hazard ratios and long-rank tests for the differentially-secreted proteins were determined in four different external datasets in order to select the proteins with clinical relevance for further analysis. Gene ontology was performed to determine the biological processes altered in highly metastatic cells. Results: 221 differentially-secreted proteins were found to be significantly associated to metastasis. Some corresponding genes were able to predict the overall and progression free survival in stage II and stage III CRC patients. In addition, they showed higher expression in the stem cell-like and CMS4 subtypes of CRC, associated to worse prognosis. These genes were also associated to deficient mismatch repair, CpG-island methylator positive status and BRAF mutation. It is also remarkable that a significant number of altered proteins were involved in cholesterol metabolism, suggesting an enhancement of the LDL uptake and metabolism in highly metastatic cells. Extracellular matrix constituents involved in cell adhesion and migration were also overrepresented in the highly metastatic fraction. Conclusion: Secretome of highly metastatic cells is enriched in proteins involved in essential pathways for metastasis such us adhesion, migration and lipid metabolism. In addition, several proteins with a robust and significant prognosis value were detected howing the value of the fraction as a source of biomarkers.

The Detection of BRAF-V600E Mutation in Hairy Cell Leukaemia by Polymerase Chain Reaction and Study of its associated Clinicohaematological Parameters

Objective: To contemplate the occurrence of a rare mutation (BRAF V600E) in the patients having Hairy cell leukemia in our setting, which wouldserve asuseful analytic and diagnostic criteria.
 Study Design: Analytical cross sectional study.
 Place and Duration of Study: Armed Forces Institute of Pathology Rawalpindi Pakistan, from Oct 2017 to Oct 2018.
 Methodology: A sample of 36 patients with a suspicion of Hairy cell leukemia were included in this investigation. Complete blood counts, bone marrow examination (trephine biopsy and aspiration), cyto-chemistry and staining of the patients suspected to have Hairy cell leukemia was performed. PCR was done for detection of BRAF V600E mutation.
 Results: 29 (80.5%) cases showed a positive BRAF mutational analysis and 7 (19.4%) cases showed a negative result.
 Conclusion: Almost all the cases of classic Hairy cell leukemia had BRAF V600 E mutation.Isolating this mutation can be used as a regular tool in detection of disease and monitoring disease progression and relapse.

Integration of traditional molecular diagnostic tools and targeted next generation sequencing for the precise diagnosis and management of adult gliomas.

e14011 Background: It is known that gliomas represent a wide variety of entities with varying biological features and clinical outcomes (Neuropathol Exp Neurol 2019, 78). Hence, optimal tumor classification that aids in the diagnosis and management of patients and which supports the use of specific treatment modalities is of critical importance in neuro-oncology. Targeted next-generation sequencing (NGS) has proven to be an efficient and reliable tool for identifying prognostic biomarkers for the diagnosis of CNS tumors (Neurooncol Adv 2020, 2). Here, an analysis of the impact of using NGS in addition to traditional molecular tools on tumor classification and therapy selection was analyzed; and the overall concordance was evaluated. Methods: Patients with glial tumors who were seen at our clinic between 2019-2020 and had an NGS analysis in addition to traditional molecular studies were included. All clinical data, histopathological findings and genetic reports were retrieved from the electronic medical record. We retrospectively studied each of the patients’ findings with regards to their clinical diagnosis, grade, anatomic localization; ki67 (%); TP53, IDH and ATRX mutations; as well as microsatellite instability (MSI) and additional mutational studies such as HER2 and BRAF for some patients. The concordance between the genetic and molecular data regarding TP53 and IDH mutations was also analyzed. Results: 9 patients (66.7% male) with grade 3-4 gliomas were identified at our single-center oncology institution. Most patients had a diagnosis of glioblastoma (55.6%), with a median age of 43 years at the time of diagnosis. 22.2% (2/9) had a genetic analysis through FoundationOneCDx. The concordance of the identification of mutations by NGS and immunohistochemistry (IHC) was 77.8% (7/9) for IDH mutations, and 55.6% (5/9) for TP53 mutations. NGS led to the identification of TP53 mutation in 1 patient (11%) which IHC failed to show. NGS also supported the use of targeted therapy [dabrafenib] in 1 patient (11.1%) with BRAF positivity. Conclusions: Traditional molecular diagnostic tools and targeted NGS are not perfectly concordant, but when integrated together can lead to a more comprehensive identification of genetic mutations and potential biomarkers. This can have significant implications on the precise diagnosis and potential use of targeted therapies of adult gliomas in the future.

Disease Characteristics of Multiple Myeloma Involving BRAF Mutations

Disease Characteristics of Multiple Myeloma Involving BRAF Mutations

BRAF Fusions in Histiocytic Disorders: Frequency and Clinical Characteristics

▪Background: Activation of extracellular-signal regulated kinase (ERK) is almost universal in histiocytic disorders and is driven by genomic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases (PI3K) pathways. While BRAFV600E mutations are well described in histiocytic disorders, less is known about BRAF fusions. The goal of our study is to describe the frequency and clinical characteristics of patients harboring BRAF fusions.Methods: We included patients with a diagnosis of histiocytic disorder seen at our institution from November 2016-June 2021. Only those who had adequate BRAF testing were included. The following were considered adequate BRAF testing: 1) unequivocally positive BRAF V600E immunostain with or without molecular confirmation; 2) successful multigene next generation sequencing (mostly Tempus â or FoundationOne â) if BRAF V600Eimmunostain was equivocal or negative. We also searched the literature for similar cases and compared BRAF fusions found in histiocytic disorders to those found in solid tumors and other hematologic conditions.Results: One hundred and twenty-six patients were included in this study. BRAF fusions were detected in 7 (6%) patients. The median follow-up for these patients was 1.4 years (95% CI: 0.4-not reached). The frequency according to disease subtypes is as follows: Erdheim-Chester disease (ECD; 2/46 [4%]), Langerhans cell histiocytosis (LCH; 1/41 [2%]), adult or juvenile xanthogranuloma (AXG/JXG; 4/7 [57%]), and histiocytic or Langerhans cell sarcoma (HS/LCS; 0/9 [0%]). The median age at diagnosis for our study cohort was 34 years (range, 7-81 years) and 5 were females. The clinical characteristics and nature of BRAF fusions of our 7 patients plus additional 13 cases from the literature are shown in Table 1. For the final cohort of 20 patients with BRAF-fusions, the median age was 16 years (range, 0.5-81 years) and most (56%) were females. The distribution by histiocytic subtypes is as follows: AXG/JXG (45%), LCH (40%), ECD (10%), HS/LCS (5%). Two patients received cobimetinib as frontline treatment in our cohort and achieved partial responses. Of these two patients, one completed 12 cycles (12 months) of cobimetinib and had a sustained PR while the other patient received 2 cycles before having to hold therapy due to intolerable adverse effects despite dose reduction. From literature review, another patient (LR-12) received cobimetinib as second line treatment and achieved complete response. We found 15 unique BRAF gene fusions with 4 being recurrent. Except for AGAP3-BRAF, none of these BRAF fusions in histiocytosis has been reported in solid tumors or hematologic conditions to date.Conclusions: BRAF gene fusions occur rarely (<5%) in histiocytic disorders. The only exception is AXG/JXG where more than half of the patients harbor BRAF gene fusions. These gene fusions are mostly distinct to histiocytosis and not found in solid tumors or other hematologic conditions. [Display omitted] DisclosuresBennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board.

Detection of Circulating Tumor DNA in Patients with Thyroid Nodules.

Objective Detection of circulating tumor DNA (ctDNA) in cancer patients can potentially serve as a noninvasive, sensitive test of disease status. The purpose of this study was to determine the ability to detect BRAF (V600E) mutations in the plasma of patients with thyroid nodules, with the goal of distinguishing between benign and malignant nodules. Methods Consecutive patients with thyroid nodules who consented for surgery were recruited. Plasma samples were obtained preoperatively and one month postoperatively. Quantitative PCR was used to determine the levels of the BRAF (V600E) mutation preoperatively and postoperatively. Results A total of 109 patients were recruited. On final pathology, 38 (32.8%) patients had benign thyroid nodules, 45 (38.8%) had classical papillary thyroid cancer (PTC), 23 (19.8%) had nonclassical PTC, and 3 (2.6%) had follicular thyroid cancer. 15/109 patients had detectable BRAF (V600E) ctDNA in their preoperative samples—all of them having classical PTC. Higher T-stage and extrathyroidal extension in PTC were associated with positive BRAF (V600E) ctDNA (p < 0.05). Eighty-eight pairs of preoperative and postoperative plasma samples were collected and analyzed. Of these eighty-eight paired samples, a total of 13/88 (14.8%) patients had detectable BRAF (V600E) ctDNA in their preoperative samples—all of them having classical PTC. 12 of these 13 patients had no detectable BRAF (V600E) postoperatively, while one remaining patient had a significant decline in his levels (p < 0.05). ConclusionBRAF (V600E) circulating thyroid tumor DNA can be detected in plasma and is correlated with a final diagnosis of the classical variant of PTC. Given that a postoperative drop in BRAF (V600E) ctDNA levels was observed in all cases suggests its utility as a tumor marker.

BRAF V600E and Mismatch Repair Proteins Expression in Sporadic Young-onset Colorectal Cancer in Kelantan, Malaysia.

ObjectivesWe sought to determine the immunohistochemistry expression of mismatch repair (MMR) and BRAF V600E proteins in sporadic young-onset colorectal cancer (CRC) and their association with clinicopathological features in the Kelantan population.MethodsThis was a cross-sectional study of sporadic young-onset CRC over 11 years from 1 January 2006 to 31 December 2017 in Kelantan. Formalin-fixed paraffin-embedded tissue blocks were immunohistochemically stained with antibodies for MMR (MLH1, MSH2, MSH6, and PMS2) and BRAF V600E. These expressions were correlated with clinicopathological parameters.ResultsOur patient sample included 31 patients with a mean age of 31.5 years. More than half (61.3%) of the patients were women. The majority presented with abdominal pain (41.9%), and 71.0% had a tumor located on the right side of the colon, with 83.9% being moderately differentiated adenocarcinoma. The majority of patients presented at stage IV (54.8%). The most frequent pattern was all MMR protein expressions, which constituted patients in the microsatellite stable group (64.5%). Nine (29.0%) were microsatellite instability (MSI-high), and two (6.5%) were MSI-low. Positive BRAF V600E expression was observed in 83.9% of patients. Only histopathological subtypes revealed a significant association with BRAF V600E positive expression (p = 0.015).ConclusionsThe majority of sporadic young-onset CRC presented with abdominal pain and advanced cancer stage. Most were microsatellite stable, and most cases showed positive expressions in all MMR markers and BRAF V600E by immunohistochemistry method. This finding will pave the way for further research on this disease.

Correlation between US-FNAC with BRAF V600E Mutation Analysis and Central Neck Lymph Node Metastasis in cN0 Papillary Thyroid Cancer.

The aim of this study was to explore the correlation between ultrasound-guided fine-needle aspiration cytology(US-FNAC) combined with BRAF V600E mutation analysis and central neck lymph node metastasis in cN0 papillary thyroid cancer, so as to provide reliable molecular evidence to use it for preoperative evaluation, operation procedure design, and postoperative follow-up planning in clinic. Specimens were obtained from 250 patients with cN0 thyroid cancer (TI-RADS≥4a, highly suspected of PTC by US-FNAC) after bilateral thyroidectomy and central neck lymph node dissection with accessible postoperative pathologic results of PTC and central neck lymph nodes and used for cytological diagnosis by H&E stain and BRAF V600E mutation detection. Single-factor analysis showed that differences between the central neck lymph node metastasis and nonmetastasis groups were statistically significant in gender, BRAF V600E mutation, and extracapsular extension. Logistic multivariate regression analysis showed significant differences in gender, BRAF V600E mutation, and extracapsular extension. Positive BRAF V600E mutations by US-FNAC, extracapsular extension, and male gender are risk factors of central neck lymph node metastasis in cN0 PTC metastatic PTC to central neck lymph node. Patients with those factors should undergo prophylactic central neck lymph node dissection.

Abstract #1003213: An Interesting Case of Metastatic Malignant Pleural Effusion - Initial Presentation of an Aggressive form of Primary Thyroid Cancer

Papillary thyroid cancer (PTC) is a subtype of differentiated thyroid cancer (DTC) derived from thyroid follicular epithelial cells, which constitutes ∼ 85% of DTC. Out of all variants of PTC, tall cell is more aggressive & accounts for 1% of papillary cancers. Poor prognostic factors are age > 55, gross local invasion, distant metastases and positive BRAF V600E mutation. We have a rare case of PTC presenting as malignant pleural effusion , initially thought due to primary lung cancer, was later noted to have tall cell variant of PTC. Pulmonary metastases in PTC are well known. Previous such reported cases are due to recurrence of PTC, whereas our patient had a rare initial presentation. Indolent thyroid enlargement added to diagnostic challenge.

Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA

IntroductionMalignant melanoma is the third most common primary in the diagnosis of brain metastases. Stereotactic radiosurgery (SRS) is a well-established treatment option in limited brain disease. We analyzed outcomes of SRS with a particular focus on the graded prognostic assessment (GPA, melanoma molGPA), prognostic factors, and toxicity.MethodsWe evaluated 173 brain metastases in 83 patients with malignant melanoma. All were treated with SRS median dose of 20 Gy prescribed to the 80 or 100% isodose line between 2002 and 2019. All patients were followed-up regularly, including contrast‐enhanced brain imaging as well as clinical examination, initially 6 weeks after treatment, then in quarterly follow-up.ResultsThe median age was 61 years (range 27–80); 36 female and 47 male patients were treated. After a median follow-up of 5.7 months, median OS (overall survival) was 9.7 months 95%-KI 4.7–14.7). LC (local control) at 6 months, 12, 24 months was 89%, 86%, and 72%, respectively (median was not reached). Median DBC (distant brain control) was 8.2 months (95%-KI 4.7–11.7). For OS, a KPS ≥ 80%, a positive BRAF mutation status, a small PTV (planning target volume), the absence of extracranial metastases, as well as a GPA and melanoma molGPA > 2 were prognostic factors. In the MVA, a small PTV and a melanoma molGPA > 2 remained significant.ConclusionThe present survival outcomes support the use of the disease-specific melanoma molGPA as reliable prognostic score. Favorable outcomes for SRS compared to other studies were observed. In the treatment of brain metastases of malignant melanoma patients, a multidisciplinary approach consisting of surgery, SRS, chemotherapy, and immunotherapy should be considered.

The Correlation of BRAF V600E Expressions with Histopathological Variant and Lymphocyte Infiltration in Papillary Thyroid Carcinoma

BackgroundPapillary thyroid carcinoma is the most common endocrine gland malignancy that has the highest incidence rate of 60-80%. In papillarythyroid carcinoma BRAF V600E mutation plays an important role in carcinogenesis. BRAF V600E is a RAS-regulated-serine-threoninekinase and activator of the MAPK pathway cascade that functions to regulate cell proliferation, differentiation and survival. BRAFV600E mutations in PTC is associated with a high incidence of recurrence and reduced survival. The purpose of this study is to lookat the relationship of BRAF V600E expression with histopathological variants and lymphocyte infiltration in PTC.MethodsThis research was a retrospective observational cross sectional study with 40 cases of papillary thyroid carcinoma which werediagnosed in 4 Pathology Anatomy Laboratory in West Sumatera. Samples were obtained from paraffin blocks of tissue from surgeryand were reevaluated for histopathological variant and lymphocyte infiltration. Expression of BRAF V600E in tumor cell were analyzedusing immunohistochemistry staining. Bivariate statistical analysis of Chi-Square were used and p value &lt;0,05 were consideredsignificance.ResultsPositive BRAF V600E expression was found in 24 case (60%). Positive BRAF V600E expression was mostly found in classic PTC(50%). Papillary thyroid carcinoma with lymphocyte infiltration mostly found with negative BRAF V600E expression (79.2%). Statisticalanalysis showed no significant correlation between BRAF V600E with histopathological variant (p=0.74) and no significancecorrelation between BRAF V600E expression with lymphocyte infiltration (p=0.12).ConclusionThe conclusion is BRAF V600E expression has no correlation with histological variants in papillary thyroid carcinoma and no significantcorrelation of BRAF V600E expression with lymphocyte infiltration.

Serum CYFRA 21.1 Level Predicts Disease Course in Thyroid Cancer with Distant Metastasis.

Simple SummaryThe role of serum Cyfra 21.1 as a biomarker in thyroid cancer has yet to be validated. This study investigated the diagnostic or prognostic role of serum Cyfra 21.1 in thyroid cancer. In the present analysis, we found that serum Cyfra 21.1 was increased in thyroid cancer with distant metastasis compared with thyroid cancer without metastasis. Furthermore, in progressive disease when thyroglobulin was undetectable or thyroglobulin monitoring was useless because of thyroglobulin antibody, serial follow-up based on serum Cyfra 21.1 levels might be used as an alternative biomarker for disease monitoring.Background: Serum Cyfra 21.1, the soluble fragment of CK19, has been used as a prognostic tumor marker in various cancers, indicating poor tumor differentiation and increased metastasis. Methods: We analyzed the serum Cyfra 21.1 level in 51 consecutive patients with thyroid cancer manifesting distant metastasis treated with prior total thyroidectomy. Serum Cyfra 21.1 levels of 26 thyroid cancer patients without metastasis and 50 healthy individuals were used for comparison. Results: Higher serum Cyfra 21.1 levels were detected in thyroid cancer patients with distant metastasis compared with healthy subjects and thyroid cancer patients without metastasis (p = 0.012). Serum Cyfra 21.1 levels were significantly increased in patients with positive BRAF V600E mutation (p = 0.019), undergoing Tyrosine Kinase Inhibitor (TKI) therapy (p = 0.008), with radioiodine-refractory status (p = 0.047), and in disease progression compared with those manifesting stable disease (p = 0.007). In progressive disease with undetectable or unmonitored thyroglobulin because of thyroglobulin antibody, serum Cyfra 21.1 was useful as a biomarker for follow-up of disease course. Conclusion: Serum Cyfra 21.1 in thyroid cancer patients might represent an alternative biomarker predicting tumor progression, especially in cases not associated with serum Tg levels.

BRAF V600E Immunoexpression in Papillary Thyroid Carcinoma and Its Association with Prognostic Factors and Histopathologic Variant

&lt;p&gt;&lt;strong&gt;Aim: &lt;/strong&gt;to provide additional information regarding the clinicopathological characteristics of Papillary Thyroid Carcinoma (PTC). Methods: Fifty patient with PTC were reviewed to determine prognostic factors such as age, gender, size of tumor and histologic variant. BRAF V600E mutation was detected by immunohistochemical staining and assessed with H score. Result: BRAF V600E mutations were detected in 17 (34%) cases. There were seven cases with extrathyroidal extension (ETE) p 0,04, 11 cases with lymph node metastasis (LNM) p &amp;lt; 0,001, and 8 cases with tall cell variant p 0,047.The cases with positive BRAF V600E mutation had mean age of 44.71 years, and the size of the tumor between 0.1-4cm. Six cases of them are male and 11 female.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; There were significant relationships between BRAF V600E mutation with ETE, LNM, and tall cell variant. There was no significant relationship between BRAF V600E mutation, either with age, gender, or size of the tumor. BRAF V600E immunohistochemical examination can be performed as additional investigation for PTC patients.&lt;/p&gt;

Metastatic Ovarian Tumor of Vulvar Malignant Melanoma in a 43-Year-Old Woman: A Case Report and Literature Review

An ovarian malignant melanoma sometimes occurs from ovarian teratoma. Ovarian metastatic malignant melanoma is extremely rare. We describe a patient in whom vulvar melanoma (previously resected) metastasized to the ovary, making ovarian metastatic malignant melanoma. A 43-year-old Japanese woman was referred to us because of left ovarian tumor. She had undergone resection for malignant melanoma on the right labia minora with inguinal lymph node metastasis (pT1bN1aM0, stage IIIA, FIGO 2008). Eighteen months after this surgery, CT scans revealed left ovarian tumor and swelled pelvic lymph nodes, with a pelvic examination disclosing a left adnexal solid mass, with normal serum CA125 level (21.7 U/mL). Laparotomy revealed a left solid ovarian tumor measuring 4 cm, which was covered with a smooth grayish capsule. The right ovary, uterus, and pelvic cavity appeared normal. Upon sectioning during the surgery, the cross-sectional surface of the left ovary revealed a dark brown solid tumor. Following an intra-operative frozen-section diagnosis as metastatic melanoma, total hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph dissection was performed. Histological examination confirmed the diagnosis as malignant melanoma metastasis to the left ovary and the obturator lymph node: the same laterality (left) as the primary site. The tumor was entirely composed of malignant melanoma cells with no evidence of teratoma. Combined chemotherapy with dabrafenib mesylate and trametinib was planned based on the positive BRAF mutations. This case highlights the importance that physicians should have high index of suspicion for the occurrence of ovarian melanoma metastasis after melanoma surgery. We also made extensive literature review on this issue, of which description may contribute to better understanding of this condition.

Two Atypical Cases of Classical Hairy Cell Leukaemia and Hairy Cell Leukaemia Variant: A Case Study

Introduction: Classical Hairy Cell Leukaemia (cHCL) and Hairy Cell Leukaemia variant (HCL-v) are both rare and slow-growing mature B cell neoplasms. According to flowcytometry data, they fall into the group classified as CD5- CD10- B cell lymphoproliferative disorders. Methods: Two cases with features atypical to two neoplasms at the time of diagnosis were studied. Results: Case 1 was a 15 year old male with right cervical lymph nodes (1x1 cm) in the posterior triangle, a few ecchymotic patches on the arm and a massive splenomegaly. C-reactive protein (CRP) level was 53 mg/dL. Erythrocyte Sedimentation Rate (ESR) was 98 mm/1 st hour. Full Blood Count (FBC) revealed typical features of pancytopenia with monocytopenia. The liver and renal profiles were normal. Morphology of bone marrow was suggestive of cHCL. Flowcytometry and BRAF V600E mutation was positive confirming the diagnosis of cHCL. Case 2 was a 55 year old male presenting with moderate splenomegaly and absolute lymphocytosis. The FBC revealed leukocytosis which is commonly seen with monocytopenia. Blood pictures revealed many hairy cells with moderately basophilic cytoplasm and visible nucleoli suggesting HCL-v. Flowcytometry findings and negative BRAF V600E mutation confirmed HCL-v. Conclusions: Clinical findings, blood images, morphology of bone marrow, flowcytometric findings and positive BRAF V600E mutation confirmed the diagnosis of cHCL in case 1 (15 year old boy) making it as a very rare case. The morphological findings on blood, the presence of characteristic CD markers on flowcytometry and negativity of BRAF V600E confirmed the case 2 as HCL-v, despite having CD10 positivity and monocytopenia.Keywords: Flowcytometric immunophenotyping, Hairy cell leukaemia, Hairy cell leukaemia variant

Focus on the dabrafenib, vemurafenib, and trametinib in clinical outcome of melanoma: a systematic review and meta-analysis

Background: Melanoma is the most serious lethal skin cancer, affects the melanin producer cells (melanocytes). Surgery is the most common treatment, whereas for the advance stage the development of a treatment is recommended. BRAF (Dabrafenib and Vemurafenib) inhibitor or MEK inhibitor (Trametinib) is used as the most frequently targeted therapy of melanoma due to more than 80% patient with positive BRAF mutation. In this review, those treatments will be investigated systematically to identify their clinical outcome.Method: This systematic literature review (SLR) was performed from Cochrane, Science Direct, Google Scholar, and Pubmed. Cochrane Risk-of-Bias Tool RoB2 is used to assess RCT studies and New-castle Ottawa Scale Assessment to assess cohort studies by 3 different assessors. Data analysis was carried out by using Review Manager (RevMan 5.4). Heterogenicity test was assessed by I2 Â and Chi2 statisticResult: There are 20 studies used in this article (13 RCT and 7 cohorts). The overall survival (OS) and progression-free survival (PFS) of study that using targeted therapy (vemurafenib, trametinib, or dabrafenib) compare other therapies (chemotherapy, immunotherapy,etc) showed risk ratio (RR) was 1.12 (95%CI 1.07,1.17;Â I2=100%; p&lt;0,00001). The OS and PFS with monotherapy compare of vemurafenib, trametinib, or dabrafenib with combination therapy showed RR was 1.09 (95%CI.06,1.13;I2=99%; p&lt;0,00001). Conclusion: BRAF and MEK targeted therapy has a good prognosis for a patient with a positive BRAF gene mutation and could be combined with other therapy for a better clinical outcome rather than monotherapy.Keyword: melanoma, dabrafenib, vemurafenib, and trametinib

Focus on the dabrafenib, vemurafenib, and trametinib in the clinical outcome of melanoma: A systematic review and meta-analysis

Background: Melanoma is the most severe lethal skin cancer, affecting melanin producer cells (melanocytes). Surgery is the most common treatment, whereas, for the advanced stage, the development of treatment is recommended. BRAF (Dabrafenib and Vemurafenib) inhibitor or MEK inhibitor (Trametinib) is the most frequently targeted melanoma therapy due to more than 80% of patients with positive BRAF mutation. In this review, those treatments will be investigated systematically to identify their clinical outcome.&#x0D; Method: This systematic literature review (SLR) was performed from Cochrane, Science Direct, Google Scholar, and Pubmed. Cochrane Risk-of-Bias Tool RoB2 is used to assess RCT studies and New-castle Ottawa Scale Assessment to assess cohort studies by three different assessors. Data analysis was carried out by using Review Manager (RevMan 5.4). Heterogenicity test was assessed by I2 and Chi2 statistic&#x0D; Result: There are 20 studies used in this article (13 RCT and seven cohorts). The overall survival (OS) and progression-free survival (PFS) of the survey that using targeted therapy (vemurafenib, trametinib, or dabrafenib) compare other treatments (chemotherapy, immunotherapy, etc.) showed risk ratio (RR) was 1.12 (95%CI 1.07,1.17; I2=100%; p&lt;0,00001). The OS and PFS with monotherapy compare of vemurafenib, trametinib, or dabrafenib with combination therapy showed RR was 1.09 (95%CI.06,1.13; I2=99%; p&lt;0,00001). &#x0D; Conclusion: BRAF and MEK targeted therapy has a good prognosis for a patient with a positive BRAF gene mutation and could be combined with other treatments for better clinical outcomes rather than monotherapy.

A RARE CASE OF PULMONARY NON-LANGERHANS CELL HISTIOCYTOSIS

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Histiocytic neoplasms are a rare group of heterogeneous disorders which may involve the lung. The most common, Langerhans cell histiocytosis (LCH), is often associated with smoking. Less common are the Non-Langerhans cell histiocytosis, Erdheim-Chester disease (ECD) and Rosai-Dorman disease (RDD). Diagnosis and treatment are often delayed due to lack of proper interpretation of clinical, radiological and histological findings. The following case poses as a diagnostic challenge as the patient is elderly, with no smoking history, and thus falls into an unsuspecting population vulnerable to prolonged invasive workup and missed diagnoses. CASE PRESENTATION: A 75-year-old male, non-smoker, was admitted for evaluation of persistent dyspnea and cough for several weeks despite outpatient treatment with antibiotics. Presented afebrile, and hypoxic requiring 4L/min via nasal cannula. History revealed recurrent pneumonias for several months and persistent infiltrates on CXR. Chest CT showed emphysematous changes with intralobular septae thickening, and bilateral pleural effusions. Thoracentesis was attempted but was unsuccessful due to the thick nature of the aspirate. Following an unyielding bronchoscopy, a subsequent right upper lobe wedge biopsy showed histological features diagnostic of pulmonary histiocytosis. Pleomorphic inflammatory infiltrates were seen with variably abundant pale staining cytoplasm and focal emperipolesis. There was fibrosis distributed in a lymphangitic pattern with diffuse involvement, and focal necrosis without granuloma formation. Immunohistochemical stains of the histiocytes were positive for CD163 and Factor XIIIa with focal staining of S100 and negative for cytokeratins (AE1/AEE3 and CAM5.2), calretinin, WT-1 and BRAF V600E. As a result, patient was not a candidate for targeted therapy; yet, improved with a course of tapered steroids. Planned for further genetic workup involving the MAPK signaling pathway in the future. DISCUSSION: This case illustrates the significant histological similarities seen in ECD and RDD including lymphangitic distribution, S100-positive histiocytes and emperipolesis. A positive BRAF V600E mutation can be seen in about 50% of ECD cases but not in RDD, giving both diagnostic and therapeutic value. Unfortunately for this patient, the mutation was negative and a definitive subclassification could not be made. However, given the patient’s lack of multisystem involvement including the classic long bone osteosclerosis, a diagnosis of RDD could be favored. CONCLUSIONS: Histiocytic lung disorders vary in clinical manifestations, making it difficult to establish a timely diagnosis. A disparity in identification and targeted treatment still exists, as illustrated in this case. It is prudent to raise awareness of these disorders and highlight the key clinical and histopathologic features which discern them for accurate diagnosis and medical therapy. Reference #1: Haroche J, Abla O; Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease. Hematology Am Soc Hematol Educ Program 2015; 2015 (1): 571–578. doi: https://doi.org/10.1182/asheducation.V2015.1.571.3916289 Reference #2: DeMartino E et al. Langerhans Cell Histiocytosis and Other Histiocytic Diseases of the Lung. Clinics in Chest Medicine, Volume 37, Issue 3, 421 - 430 Reference #3: Goyal G, Young JR, Koster MJ, et al. The Mayo Clinic Histiocytosis Working Group Consensus Statement for the Diagnosis and Evaluation of Adult Patients With Histiocytic Neoplasms: Erdheim-Chester Disease, Langerhans Cell Histiocytosis, and Rosai-Dorfman Disease. Mayo Clin Proc. 2019;94(10):2054-2071. doi:10.1016/j.mayocp.2019.02.023 DISCLOSURES: No relevant relationships by Victoria Gonzalez, source=Web Response No relevant relationships by Kristen Hughes, source=Web Response No relevant relationships by Bernadette Schmidt, source=Web Response No relevant relationships by Emad Shehada, source=Web Response

Immunohistochemistry or Molecular Analysis: Which Method Is Better for Subtyping Craniopharyngioma?

Craniopharyngioma (CP) is mainly classified into two pathological subtypes: adamantinomatous (ACP) and papillary (PCP). CTNNB1 (β-catenin) mutations are detected in ACPs, and the BRAF V600E mutation is detected in PCPs. However, genetic analysis is not always possible in general medical practice. In this study, we investigated whether immunohistochemistry could replace genetic analysis as an aid in subtype diagnosis. Here, 38 CP patients who had undergone their first tumor resection were included. Among the 38 cases, 22 were morphologically diagnosed as ACP, 10 cases were diagnosed as PCP, and six cases were diagnosed as undetermined CP that were morphologically difficult to classify as either ACP or PCP. Results of immunohistochemistry and genetic analysis and clinical features were compared. Based on the immunohistochemistry, 26 (22 ACPs and four undetermined CPs) showed nuclear β-catenin expression, 11 (nine PCPs and two undetermined CPs) exhibited positive BRAF V600E immunostaining, and one PCP showed membranous β-catenin expression and negative BRAF V600E immunostaining. Among the 26 nuclear β-catenin expression cases, 11 had CTNNB1 mutations; however, 15 cases had mutations of neither CTNNB1 nor BRAF V600E. All 11 BRAF V600E immunopositive cases had BRAF V600E mutations. When comparing clinical features, pediatric patients and those with tumor calcification and less solid components on MRI more commonly had nuclear β-catenin expression tumors than BRAF V600E immunopositive tumors, reflecting the differences in clinical features between ACP and PCP. Accordingly, immunohistochemistry can replace genetic analysis as an aid to determine the subtype diagnosis of CP in general medical practice.

BRAF-V600 E AND AMELOBLASTOMA: IMMUNOHISTOCHEMICAL STUDY AND CLINICAL-PATHOLOGIC CORRELATION

Some studies have shown that ameloblastoma may show mutation in the BRAF-V600 E gene. Objective: The objective of this study was to evaluate the expression of the mutated BRAF-V600 E protein in cases of unicystic ameloblastoma (UA; n = 22) and multicystic ameloblastoma (MA; n = 18). Study Design: Clinical-pathologic parameters such as age, sex, and tumor location were correlated with positive and negative BRAF expression. Results: All cases of UA were identified in the mandible and only 1 case of MA was located in the maxilla. From the 40 cases, 33 (82.5%) were positive for the anti–BRAF-V600 E antibody, 18 of AU (82%), and 15 of AM (83%). The correlation between the BRAF expression and the variables did not show statistical significance (P> .05). Conclusion: The BRAF-V600 E mutation was frequent in the studied ameloblastomas and it occurs independently of age, sex, and subtype (UA and MA).