A Report of a Desmoplastic Ganglioglioma in a 12-year-old Girl with Review of the Literature

Summary Desmoplastic infantile ganglioglioma is a supratentorial tumor that typically occurs in infants below the age of 24 months. Rare tumors with the same radiological and histological characteristics have been described in older subjects. We report a case of desmoplastic ganglioglioma in a 12-year-old girl with a 13 years follow-up. The patient presented with an inaugural generalized seizure. CT scan demonstrated a large superficial parieto-occipital mass, attached to the dura with solid and cystic components. Surgical resection was macroscopically complete. No adjuvant treatment was given. Thirteen years after surgery, the patient is symptom free. Histological examination revealed a pleomorphic tumor involving the meningeal space and the cortex. Meningeal portion was made of neoplastic astrocytes enmeshed in a dense network of connective tissue. The cortical component showed abnormal neurons, tumoral astrocytes and small foci of poorly differentiated cells with rare mitoses. Our observation and the seven others found in the literature indicate that desmoplastic gangliogliomas can occur in children and even in young adults. Despite some worrisome radiological and histological features, these tumors should not be misdiagnosed as malignant glioma. Like infantile cases, non-infantile desmoplastic gangliogliomas seem to have a favorable prognosis without additional therapy, if a total surgical resection can be performed.     

Good Clinical Course in Infants with Desmoplastic Cerebral Neuroepithelial Tumor Treated by Surgery Alone

We investigated why surgery alone provides for a benign clinical course in patients with desmoplastic infantile ganglioglioma and astrocytoma (DIG/A). The clinical course of 4, less than six-month-old girls, surgically treated at our institutions, was evaluated retrospectively. All presented with the clinical symptom of increasing head circumference. CT and MRI scans revealed a solid tumor attached to the dura that was surrounded by large, multiple cysts, in fronto-temporo-parietal lobe. Gross total removal succeeded in all 4 cases because the solid components of the tumor were very firm in contrast to the soft adjacent brain tissue. Microscopically, the surgical specimens consisted almost entirely of dense fibrous connective tissue containing generally elongate cells with inconspicuous cytoplasm. Most of these cells were immunopositive for GFAP. There was no evidence of tumor cells in the cyst wall. In 3 cases, some small neurons were positive for neurofilament immunostain. A high proportion of undifferentiated small cells in a less demoplastic area far from the dura were immunopositive for MIB-1. All of the 4 patients have been free of recurrence for more than five years. In patients with DIG/A, there are 5 reasons for a good clinical course. [1] At surgery, the tumor margin is clearly discernible because of the difference between the solid tumor and the soft adjacent brain tissue. [2] The tumor is located in the superficial cerebral hemisphere. [3] Large, multiple cysts surround the tumor. [4] The growth point appears to be adjacent to the cysts. [5] The cyst walls are free of invading tumor cells.     

Reimagining pilocytic astrocytomas in the context of pediatric low-grade gliomas

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children and are associated with lifelong clinical morbidity. Relative to their high-grade adult counterparts or other malignant childhood brain tumors, there is a paucity of authenticated preclinical models for these pLGGs and an incomplete understanding of their molecular and cellular pathogenesis. While large-scale genomic profiling efforts have identified the majority of pathogenic driver mutations, which converge on the MAPK/ERK signaling pathway, it is now appreciated that these events may not be sufficient by themselves for gliomagenesis and clinical progression. In light of the recent World Health Organization reclassification of pLGGs, and pilocytic astrocytoma (PA), in particular, we review our current understanding of these pediatric brain tumors, provide a conceptual framework for future mechanistic studies, and outline the challenges and pressing needs for the pLGG clinical and research communities.     

Frequencies of BRAF mutations in clinical Pathology of cutaneous melanoma: a meta-analysis

Objective To explore the frequencies of BRAF mutations and the relationship between BRAF mutations and clinicopathological features of CM. Methods We search relevant literatures and the meta-analysis were conducted by Revman5.0 software. Results 9 studies were involved of BRAF mutations and 1134 patients are included. BRAF mutations are 47.3% of CM;As for patients over 50 years old, the OR of BRAF mutations is 2.30, 95% CI 1.36~3.91; the OR of BRAF mutations for SSM is 2.11, 95% CI 1.64~ 2.71; the OR of BRAF mutations for lesions in the trunk is 2.35, 95% CI 1.71~3.21; the OR of BRAF mutations for invasion depth less than 1mm is1.56, 95%CI 1.08~2.25. Conclusion mutations are more frequent in patients over 50 years old, in SSM and in patients whose lesions in the truck and invasion depth less than 1mm .They have no relationship with sex.     

BRAF基因突变与皮肤黑色素瘤临床病理特征关系的meta分析

目的 探讨BRAF突变频率以及该突变与皮肤黑色素瘤(CM)临床病理特征的关系.方法 使用Pubmed、Embase、维普、清华同方等数据库检索2013年4月以前相关文献,按纳入排除标准筛选文献,采用Revman5.0软件进行统计分析.结果 涉及BRAF突变有9项研究,共1134例患者.CM患者BRAF突变率为47.3％.50岁以上患者BRAF突变OR =2.30,95％ CI为1.36 ～3.91；浅表扩散性黑色素瘤(SSM)B RAF突变OR =2.11,95％CI为1.64～2.71;病灶在躯干时BRAF基因突变OR=2.35,95％ CI为1.71～3.21;浸润深度小于1mm时BRAF突变OR=1.56,95％ CI为1.08 ～2.25.结论 BRAF基因突变易发生于年龄50岁以上、SSM、病灶在躯干及浸润深度小于1mm的患者,而与性别无关.     

Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas

BRAF rearrangements and BRAF V600E point mutations are recurring events in pediatric low-grade gliomas. However, their clinical significance, including possible interactions between these markers and other glioma biomarkers, is unclear. In this study a retrospective cohort of 198 pediatric low-grade gliomas (including 40 treated with adjuvant therapy) was analyzed for BRAF rearrangements, BRAF V600E, p16/CDKN2A deletion, p53 expression, and MIB1 proliferation index. In tumors with BRAF rearrangement, homozygous p16 deletion correlated with shorter progression-free survival (P = .04). A high MIB1 proliferation index trended toward worse response to adjuvant radiotherapy compared to BRAF-rearranged, p16-intact tumors (P = .08). On multivariate analysis, the 2 most consistently powerful independent adverse prognostic markers were midline location (P = .0001) and p16 deletion (P = .03). Tumors with BRAF V600E had a strong trend toward an increased risk for progression (hazard ratio = 2.48, P = .07), whereas those with BRAF rearrangement had a milder trend toward reduced risk (hazard ratio = .54, P = .15). These data suggest that p16 deletion adversely impacts the outcomes of BRAF-driven gliomas, that high proliferation index may be a better marker of progression risk than BRAF, that BRAF rearrangement and BRAF V600E might not necessarily produce comparable outcomes, and that none of these markers is stronger than tumor location in determining prognosis in pediatric low-grade gliomas.     

Clinical significance of BRAF mutations in colorectal cancer

BRAF mutations, present in 5 to 10% of colorectal cancers, have a proved oncogenic effect which is linked to their implication in the RAS/MAPK intracellular signalling pathway and they occurred at early stage of colorectal carcinogenesis. Many studies have therefore assessed their clinical significance as diagnostic and prognostic marker in colorectal cancers. More recently, their location downstream to EGFR and KRAS in the RAS/MAPK pathway have led to their evaluation as predictive marker of resistance to anti-EGFR monoclonal antibodies. This article aims to review the role of BRAF mutations in the diagnostic strategy of Lynch syndrome, their prognostic value in colorectal cancers and their potential value as predictive marker of resistance to anti-EGFR antibodies.     

Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas

The recent discovery of activating mutations in the BRAF gene in many cutaneous melanomas led us to screen the genomic sequence of BRAF exons 11 and 15 in a series of 48 intraocular (uveal) melanomas, together with control samples from three cutaneous melanomas and the SK-Mel-28 cell line, which has a BRAF mutation. The same mutation was detected in two-thirds of our cutaneous melanoma samples, but was not present in any uveal melanomas. This finding further underlines the distinction between uveal and cutaneous melanomas, and suggests that BRAF inhibitors are unlikely to benefit patients with uveal melanoma.     

Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort

Background

Mutations of NRAS and BRAF have been described in Caucasian melanomas. However, the status and the clinical significance of BRAF and NRAS mutations in the Asian population have not been investigated on a large scale.

Methods

Melanoma samples (n = 432) were analysed for mutations in exons 11 and 15 of the BRAF gene, and exons 1 and 2 of the NRAS gene in genomic DNA by polymerase chain reaction (PCR) amplification and Sanger sequencing. Mutations of BRAF and NRAS genes were correlated to clinicopathologic features and prognosis of the patients.

Results

The incidence of somatic mutations within the BRAF and NRAS genes was 25.5% (110/432) and 7.2% (31/432), respectively. Among the 110 patients with BRAF mutations, 98 patients (89.1%) had V600E mutations. Melanomas without chronic sun-induced damage (Non-CSD) were more likely (P < 0.01) to show BRAF mutations while NRAS mutation frequency was unbiased between melanoma subtypes. Patients with genetic mutations in BRAF (P < 0.01) or NRAS (P = 0.04) gene are more likely to have ulceration as compared to patients without BRAF or NRAS mutations, respectively. Both BRAF (P = 0.003) and NRAS mutations (P = 0.031) are inversely correlated to overall survival.

Conclusions

BRAF mutation is frequent while mutations in NRAS gene are rare. The most prevalent BRAF mutation type is V600E. Patients with mutations in BRAF or NRAS gene are frequently present with ulceration, and mutation in BRAF or NRAS gene is indicator for poor prognosis. Our study may warrant a clinical trial of kinase inhibitors targeting BRAF V600E in Chinese and Asian melanoma patients.     

原发性肝癌中 KRAS 及 BRAF 基因突变及其临床意义

目的：检测原发性肝癌患者血浆中的 KRAS 与 BRAF 基因突变机率及特征,研究与疾病进展的相关性及对治疗的意义。方法：收集肝癌患者血液（51例）,观察组25例,为肝癌伴肝外转移患者;对照组26例,为病灶局限于肝脏的肝癌患者。所有的患者抽取外周血10ml,从血样中游离 DNA,采用人类 KRAS ／NRAS 基因突变联合检测试剂盒及人类 BRAF 基因 V600E 突变检测试剂盒分别对 KRAS 基因和 BRAF 基因突变进行检测,并分析基因突变机率及与其突变特征。结果：51例肝癌患者中,伴肝外转移患者 KRAS 基因突变率（24％,6／25）明显高于无肝外转移患者 KRAS 基因突变率（0％,0／26;P ＜0．05）;肝癌患者中 BRAF 基因突变率为0％（0／51）。结论：本研究表明肝癌患者 KRAS 基因会发生明显的突变,且肝癌伴肝外转移患者,KRAS基因突变频率明显增加。未检测出 BRAF 基因突变或 BRAF 基因突变率较低。     

Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen

Between March 9, 1984 and January 29, 1992, 42 children with newlydiagnosed symptomatic or previously diagnosed progressive low-gradegliomas received outpatient chemotherapy as their primary treatment.This study was a single arm, phase II trial designed to estimate the time to tumor progression and toxicity of this regimen. Procarbazine, 6-thioguanine, and dibromodulcitolwere given before lomustine (CCNU) and vincristine was given 1and 3 weeks after CCNU. Patients were treated for six treatmentcycles or until the tumor progressed, whichever came first. Twenty-three patients had juvenile pilocytic astrocytomas, 11had astrocytomas, one had oligodendroglioma, one had ganglioglioma, and six had radiographically diagnosed low-grade gliomas. The mean age of the patients was 5 years (median, 3 years). The median time to treatment failure was 132 weeks (95% confidence interval:106, 186 weeks). Only eight patients have died; the estimated 5-yearsurvival rate is 78% (95% confidenceinterval, 60% 87%). There were two episodes of grade 4 neutropenia, and three episodes of grade 4 thrombocytopenia. Thisregimen was safe, able to be delivered in the outpatient setting, andproduced prolonged periods of disease stabilization in children with low-grade gliomas.     

Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations

Background:

The detection of V600E BRAF mutations has fundamental clinical consequences as the treatment option with BRAF inhibitors such as vemurafenib or dabrafenib yields response rates of ∼48%. Heterogeneity with respect to BRAF mutation in different metastases has been described in single cases. As this has important implications for the determination of BRAF status and treatment of patients, it is essential to acquire more data.

Methods:

A total of 300 tumour samples from 187 melanoma patients were analysed for BRAF mutations by pyrosequencing. Equivocal results were confirmed by capillary sequencing. Clinical data with respect to melanoma type, tumour site and survival were summarised for 53 patients with multiple analysed tumour samples (2–13 per patient).

Results:

BRAF mutations were found in 84 patients (44.9%) and 144 tumour samples (48%) with BRAF mutations in 45.5% of primary tumours and 51.3% of metastases, respectively. In 10 out of 53 patients (18.9%) where multiple samples were analysed results were discordant with respect to mutation findings with wild-type and mutated tumours in the same patient. Mutations did not appear more frequently over the course of disease nor was its occurrence associated with a specific localisation of metastases.

Conclusion:

As heterogeneity with respect to BRAF mutation status is detected in melanoma patients, subsequent testing of initially wild-type patients can yield different results and thus make BRAF inhibitor therapy accessible. The role of heterogeneity in testing and for clinical response to therapy with a BRAF inhibitor needs to be further investigated.     

KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer

Background:

We evaluated KRAS (mKRAS (mutant KRAS)) and BRAF (mBRAF (mutant BRAF)) mutations to determine their prognostic potential in assessing patients with colorectal cancer (CRC) for lung metastasectomy.

Methods:

Data were reviewed from 180 patients with a diagnosis of CRC who underwent a lung metastasectomy between January 1998 and December 2011.

Results:

Molecular analysis revealed mKRAS in 93 patients (51.7%), mBRAF in 19 patients (10.6%). In univariate analyses, overall survival (OS) was influenced by thoracic nodal status (median OS: 98 months for pN−, 27 months for pN+, P<0.0001), multiple thoracic metastases (75 months vs 101 months, P=0.008) or a history of liver metastases (94 months vs 101 months, P=0.04). mBRAF had a significantly worse OS than mKRAS and wild type (WT) (P<0.0001). The 5-year OS was 0% for mBRAF, 44% for mKRAS and 100% for WT, with corresponding median OS of 15, 55 and 98 months, respectively (P<0.0001). In multivariate analysis, WT BRAF (HR: 0.005 (95% CI: 0.001–0.02), P<0.0001) and WT KRAS (HR: 0.04 (95% CI: 0.02–0.1), P<0.0001) had a significant impact on OS.

Conclusions:

mKRAS and mBRAF seem to be prognostic factors in patients with CRC who undergo lung metastasectomy. Further studies are necessary.     

Low frequency of BRAF and CDKN2A mutations in endometrial cancer

Several pathways have been implicated in the pathogenesis of endometrial carcinoma. Based on recent reports, BRAF mutations provide an alternative route for activation of the RAS signalling pathway. The CDKN2A (p16) tumour suppressor gene is also altered in several tumour types. We therefore wanted to assess the pattern and prognostic impact of BRAF mutations and p16 alterations in endometrial carcinomas. Only 1 of 48 tumours (2%) was found to have a BRAF mutation in exon 15, whereas 8 of 45 tumours (18%) had a K-ras mutation. Homozygous deletion, amplification, promoter region methylation or mutation of the p16 gene was seen in 6 cases (13%), and 18 cases (38%) carried polymorphisms in the p16 gene. All tumours with presence of p16 methylation, non-sense mutation, deletion or amplification exhibited loss of p16 expression as evaluated by immunohistochemistry. Presence of a p16 hit was significantly correlated with high FIGO stage (p = 0.04), high histologic grade (p = 0.02), estrogen receptor negativity (p = 0.05), pathologic expression of p53 (p = 0.02), pathologic expression of p16 (p = 0.05) and poor survival (p = 0.02). There was also a significant correlation between loss of p16 expression and K-ras mutations, pathologic p53 expression and serous papillary/clear cell histologic types (p = 0.05/p = 0.001/p = 0.002). In conclusion, BRAF mutation is an infrequent finding in endometrial carcinomas. Loss of p16 expression is seen in all cases with alterations of the p16 gene. The presence of a p16 hit might be important in a subset of endometrial carcinomas with aggressive clinical behaviour. However, the mechanism of p16 inactivation remains unclear for the majority of cases exhibiting loss of expression, but the interactions with K-ras and p53 should be further studied.     

The use of BRAF V600E mutation‐specific immunohistochemistry in pediatric Langerhans cell histiocytosis

BRAF p.V600E mutations are detected in greater than 50% of pediatric Langerhans cell histiocytosis (LCH) lesions. However, the use of mutation‐specific BRAF V600E immunohistochemistry (IHC) as a surrogate for molecular testing in pediatric LCH is unknown. We tested the mutation‐specific BRAF V600E monoclonal antibody (clone VE1) in formalin‐fixed, paraffin‐embedded LCH samples from 26 pediatric patients (14 males and 12 females, ages 7 mo–17 y) using allele‐specific real‐time polymerase chain reaction (PCR) with a limit of detection of 0.5% as the comparative gold standard. BRAF VE1 staining was scored for both intensity (0‐3+) and percentage of immunoreactive tumor cells (0%‐100%). BRAF VE1 immunoreactivity was determined using both lenient (≥1+, ≥1%) and stringent (≥2+, ≥10%) scoring criteria. Using lenient‐scoring criteria, we found that the sensitivity and specificity of IHC compared with allele‐specific real‐time PCR were 100.0% and 18.2%, respectively. The poor specificity of lenient IHC analysis was attributable to weak, 1+ staining in both BRAF‐mutated and wild‐type LCH. Using stringent‐scoring criteria, we found that specificity improved to 100.0% at the expense of sensitivity that decreased to 80.0%. Stringent scoring generated 3 false‐negative results, but in all cases, neoplastic tissue comprised less than 5% of the stained section and/or the specimen was decalcified. In conclusion, highly sensitive molecular assays remain the gold standard for BRAF mutation analysis in LCH paraffin‐embedded lesions. To avoid false‐positive results, unequivocal VE1 staining of 2+ intensity in greater than or equal to 10% neoplastic histiocytes is required. However, negative VE1 results require additional studies to exclude false‐negatives, and stringent‐scoring criteria may not be optimal for scant or decalcified specimens.     

Efficacy of first-line systemic treatment in correlation with BRAF V600E and different KRAS mutations in metastatic colorectal cancer - a single institution retrospective analysis

Background

KRAS mutation status in codons 12 and 13 is recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Despite having a wild type KRAS (wt-KRAS), not all patients with wt-KRAS respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway. Consequently, other molecular markers in colorectal cancer are needed to be evaluated to predict the response to therapy.

Patients and methods

In this retrospective study, objective responses (OR), time to progression (TTP), overall survival (OS) were analyzed in 176 metastatic colorectal cancer (mCRC) patients treated with first-line chemotherapy in combination with monoclonal antibodies in respect of KRAS status in codons 12 and 13 and BRAF mutational status.

Results

The KRAS mutations were found in 63 patients (35.8 %), the KRAS mutation in codon 12 in 53 patients (30.1%) and the KRAS mutation in codon 13 in 10 patients (5.7%). The BRAF V600E mutation was detected in 13 of 176 patients (7.4%). In the subgroup of mCRC patients having wt-KRAS and wild type BRAF (wt-BRAF), the objective response rates were higher (OR 54.0% ,CR 14.7%, PR 39.3%) than in the patients with wt-KRAS and mt-BRAF (OR 38.5%,CR 15.4%, PR 23.1%), the difference was not statistically significant (p= 0.378). Median OS in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 107.4 months and 45 months, respectively. The difference was statistically significant (p= 0.042). TTP in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 16 months and 12 months, respectively. The difference was not statistically significant (p= 0.558).

Conclusions

Patients with BRAF V600E mutation have statistically significantly worse prognosis than the patients with wt-BRAF and progress earlier during treatment. The definitive role of the BRAF V600E mutation as a prognostic and predictive factor for the response to anti-EGFR monoclonal antibodies needs to be analyzed in large prospective clinical studies.