Absence Of BRAF V600E Mutation Research Articles

Hairy Cell Leukemia with Severe Leukocytosis

Introduction Hairy cell leukemia (HCL) is a rare indolent mature B-cells neoplasm that typically manifests with pancytopenia and splenomegaly. Nevertheless, significant splenomegaly, high hairy cells count in the blood, elevated β 2 microglobulin, and increased LDH can predict resistance to purine analogs. The absence of BRAF V600E mutation in HCL is rare and is associated with poorer outcomes. Case Presentation A 68-year-old female patient presented with symptomatic massive splenomegaly, leukocytosis (89,000 /microliter), monocytopenia, and thrombocytopenia. β 2microgobulin level was 4.4 mcg/L. Lactate dehydrogenase was 521 U/L. Peripheral blood and bone marrow examinations revealed typical hairy cells morphology, and the cells were positive for CD19, CD20, CD103, CD25, CD11c, CD200 (dim), and surface-Kappa. CD38 was negative. BRAF V600E result was wild-type. IGHV was mutated (IGHV3-49). She received first-line therapy with a 5-day course of Cladribine (0.15 mg/kg/day) with initial resolution of leukocytosis, normalization of platelets, and a 50% reduction in spleen size. This was followed by consolidation with an 8-weekly course of Rituximab (375 mg/m 2). Soon after the 2 nd dose of Rituximab, leukocytosis recurred, and she was initiated on second-line therapy with Bendamustine (90 mg/m 2 on days 1 and 2) along with Rituximab (BR). She has not achieved any durable response following two cycles of BR. Unfortunately, she suffered a septic shock requiring admission to our intensive care unit. Upon routine mental status evaluation, brain MRI revealed innumerable supratentorial and infratentorial bilateral acute/subacute and old microhemorrhages (Figure 1). This prompted further evaluation of unexplained recurrent episodes of pulmonary hemorrhages while on mechanical ventilation that were found to be secondary to pulmonary end-arterial cavitating lesions suggestive of hairy cells infiltration (Figure 2 arrowheads). As she was clinically unstable, we attempted to control leukocytosis with corticosteroids, leukapheresis aggressively and started the patient on Ibrutinib, but she succumbed to her disease. Discussion Recently, the 5 th edition of the World Health Organization classification of hematolymphoid tumors highlighted the splenic B-cell lymphoma and leukemia family that encompasses hairy cell leukemia (HCL), splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN), formerly known as hairy-cell leukemia variant, splenic diffuse red pulp small B-cell lymphoma (SDRPL) and splenic marginal zone lymphoma (SMZL). HCL is typically an indolent mature B-cell neoplasm with characteristic pathologic features that preferentially insinuate the bone marrow and the spleen causing impaired hematopoiesis and splenomegaly. Unlike other disorders within this group, HCL commonly harbors BRAF V600E somatic mutation in almost all cases. Rarely, patients with HCL can have extramedullary involvement by the malignant cells. Leukocytosis in HCL appears to increase the risk of developing extramedullary lesions that can present unique clinical challenges necessitating early and effective therapy. According to the literature, brain lesions in HCL were described in three other cases, and leukocytosis was a common denominator. Our patient with significant leukocytosis had brainand pulmonary lesions, and the latter was the cause of her demise due tounusually aggressive and refractory disease. Therefore, we hypothesize that leukocytosis in HCL can be “the tip of the iceberg”. The higher the leukocytosis, the higher the burden of extramedullary disease, as in our case, who had simultaneous lesions in the brain and lungs. Patients with HCL and leukocytosis may warrant initial diagnostic evaluation to ensure the absence of potentially sinister lesions, which can inform subsequent monitoring and management plans. Additionally, more novel therapies could be considered sooner in the treatment course to control the disease and these lesions. Finally, our patient did not harbor BRAF V600E mutation, which likely resulted in further worse outcomes and limited the usage of targeted therapies like BRAF inhibitors.

Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: A retrospective observational cohort study.

e21524 Background: The association of objective imaging response with first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in a real-world context. We compared likelihood of objective response between patients receiving first line anti-programmed cell death protein 1 (anti-PD1) monotherapies (pembrolizumab or nivolumab), or combination nivolumab with the cytotoxic T-cell lymphocyte-antigen 4 inhibitor ipilimumab and outlined the association between objective response and baseline characteristics and survival outcomes. Methods: We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from 2013-2020 in Alberta, Canada. Best imaging response was assessed by Response Evaluation Criteria in Solid Tumors, Version 1.1. The primary outcome was likelihood of objective imaging response (complete or partial response) between patients receiving anti-PD1 monotherapy and those receiving combination nivolumab-ipilimumab. Secondary outcomes were the identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT) endpoints. Results: Of the 255 patients included, 49/255 (19.2%) had complete response 112/255 (43.9%) had partial response, 28/255 (11.0%) had stable disease, and 66/255 (25.9%) had progressive disease. Median OS was not evaluable (NE) (95% CI NE-NE) for complete responders, NE (95% CI 52.93 months-NE) for partial responders, 21.30 months (95% CI 15.20 months-NE) for stable disease, and 7.72 months (95% CI 5.77-10.6 months) for progressive disease (log rank p < 0.0001). A robust delineation of TTNT by imaging response was also seen. Likelihood of objective response was similar between patients treated with nivolumab-ipilimumab compared to those receiving anti-PD1 monotherapy (OR 1.87 95% CI 0.85-4.20, p = 0.124). Normal LDH level (OR 2.13; 95% CI 1.01-4.35, p = 0.047), non-mucosal primary site (OR 9.09; 95% CI 2.44-33.33, p < 0.001), and absence of BRAF V600E mutation (OR 3.23; 95% CI 1.39-7.69, p = 0.007) were independently associated with likelihood of objective imaging response in multivariable analysis. Conclusions: In this real-world analysis, we demonstrate no significant difference in likelihood of objective response between patients treated with anti-PD1 monotherapy and combination nivolumab-ipilimumab, and demonstrate that a normal LDH level, non-mucosal primary site, and absence of BRAF V600E mutation are associated with response. Imaging response was also strongly associated with both OS and TTNT irrespective of therapy received. These results may help inform treatment selection, and aid in counseling of advanced melanoma patients treated with first line ICI therapy in a routine clinical practice setting.

A Novel and Effective Model to Predict Skip Metastasis in Papillary Thyroid Carcinoma Based on a Support Vector Machine

IntroductionSkip metastasis, referred to as lymph node metastases to the lateral neck compartment without involvement of the central compartment, is generally unpredictable in papillary thyroid carcinoma (PTC). This study aims to establish an effective predictive model for skip metastasis in PTC.Meterials and MethodsRetrospective analysis was performed of clinical samples from 18192 patients diagnosed with thyroid cancer between 2016 to 2020. The First Affiliated Hospital of Wenzhou Medical University. The lateral lymph node metastasis was occureed in the training set (630 PTC patients) and validation set (189 PTC patients). The univariate and multivariate analyses were performed to detect the predictors of skip metastasis and the support vector machine (SVM) was used to establish a model to predict skip metastasis.ResultsThe rate of skip metastasis was 13.3% (84/631). Tumor size (≤10 mm), upper location, Hashimoto’s thyroiditis, extrathyroidal extension, absence of BRAFV600E mutation, and less number of central lymph node dissection were considered as independent predictors of skip metastasis in PTC. For the training set, these predictors performed with 91.7% accuracy, 86.4% sensitivity, 92.2% specificity, 45.2% positive predictive value (PPV), and 98.9% negative predictive value (NPV) in the model. Meanwhile, these predictors showed 91.5% accuracy,71.4% sensitivity, 93.1% specificity, 45.5% PPV, and 97.6% NPV in validation set.ConclusionThis study screened the predictors of the skip lateral lymph node metastasis and to establish an effective and economic predictive model for skip metastasis in PTC. The model can accurately distinguish the skip metastasis in PTC using a simple and affordable method, which may have potential for daily clinical application in the future.

Clinicopathological parameters for predicting non-invasive follicular thyroid neoplasm with papillary features (NIFTP).

Background:Criteria for the preoperative diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) have not yet been confirmed. This study aimed to analyze differences in clinicopathological characteristics between follicular variant of papillary thyroid carcinoma (FVPTC) subtypes to determine which parameters are relevant in differentiating NIFTP from other variants.Methods:We retrospectively analyzed the records of 199 patients with a preoperative diagnosis of FVPTC who underwent thyroid surgery at Seoul St. Mary’s Hospital (Seoul, Korea) from 2011 to 2015. Clinicopathological features were analyzed retrospectively via a complete review of medical charts and pathology reports of patients.Results:The NIFTP and invasive encapsulated FVPTC (EFVPTC) groups showed relatively benign features, with a majority of the patients categorized as Bethesda category III (25.8% and 25.6%, respectively) or IV (34.8% and 30.2%, respectively), while the infiltrative FVPTC group showed more malignant features, with more patients categorized as category V (28.6%) or VI (47.6%) (p < 0.001). BRAFV600E mutations were significantly less prevalent in the NIFTP group (0%) and invasive EFVPTC group (4.7%) compared with the infiltrative FVPTC group (34.9%) (p < 0.001). Multivariate analysis showed that absence of BRAFV600E mutation (OR 20.311, p = 0.004) and lymph node metastasis (odds ratio 10.237, p = 0.004) were significantly associated with NIFTP.Conclusion:Although Bethesda category was a statistically significant factor in distinguishing FVPTC subtypes, it was not effective in conclusively distinguishing NIFTP and invasive EFVPTC. Absence of BRAFV600E mutation and lymph node metastasis are important features in distinguishing NIFTP from other subtypes.

Leucémie à tricholeucocytes

Hairy cell leukemia (HCL) is a well-defined entity. Proliferation with hair cells, morphological aspects of hairy cells are easy to identify. Hairy cells express markers CD11c, CD25, CD103 and CD123. In 80% of cases, a BRAFV600E mutation is highlighted. In the absence of a BRAFV600E mutation, the differential diagnosis with other hair cell proliferations can be difficult, especially with the variant form of hairy leukemia, diffuse lymphoma of the red pulp of the spleen or splenic lymphoma of the marginal zone. Purine analogues (PNA) with or without anti-CD20 antibodies remain the first-line reference treatment. In case of relapse or resistance to PNA, BRAF inhibitors, with or without MEK inhibitors, are proposed in patients with the mutation. In the absence of BRAFV600E mutation, moxetumomab-pasudotox represents an interesting alternative. A multidisciplinary discussion is always necessary. In complex cases, expert advice is desirable.

Epidemiological, clinical and molecular characterization of Lynch-like syndrome: A population-based study.

Colorectal carcinomas that are mismatch repair (MMR)-deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch-like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000-2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer-relevant genes. Among 107 MMR-deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E-negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP-positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population-based study design. Significantly more frequent CIMP-positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1-methylated colorectal carcinomas with CIMP-positive phenotype.

Mutação BRAF em pacientes idosos submetidos à tireoidectomia

To evaluate the frequency of the BRAF V600E mutation in patients over 65 years of age undergoing thyroidectomy, correlating its presence or absence with the different histologic lesions, their variants and with prognostic factors of papillary carcinoma. We evaluated 85 patients over 65 years of age who underwent thyroidectomy, analyzing the BRAF V600E mutation by RT-PCR performed after DNA extraction from the paraffin blocks. The study detected the presence or absence of BRAF V600E mutation in 47 patients (55.3%). Among the 17 papillary carcinomas studied, seven had the mutation (41.2%). There was a statistical association between the presence of this mutation and the classic variant of papillary carcinoma, and a trend of association with thyroid extravasation. BRAF mutation in the elderly is also exclusive of papillary carcinoma and is often significant. Furthermore, it is related to the classic variant and possibly to thyroid extravasation.