Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas

AbstractPrimary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.

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Treatment of high-grade spinal cord astrocytoma of childhood with “8-in-1” chemotherapy and radiotherapy: a pilot study of CCG-945

Neurosurgical FOCUS ◽

10.3171/foc.1997.3.5.5 ◽

1997 ◽

Vol 3 (5) ◽

pp. E4

Author(s):

Jeffrey C. Allen ◽

Shraga Aviner ◽

Allan J. Yates ◽

James M. Boyett ◽

Joel M. Cherlow ◽

...

Keyword(s):

Spinal Cord ◽

Survival Rates ◽

Extent Of Resection ◽

Leptomeningeal Metastases ◽

High Risk Population ◽

High Grade ◽

High Grade Astrocytoma ◽

Cancer Group ◽

Dismal Prognosis ◽

To Receive

The purpose of this study was to devise an improved method of treating high-grade gliomas of the spinal cord in children who have a dismal prognosis following conventional treatment. Eighteen children with newly diagnosed high-grade astrocytomas arising in the spinal cord were enrolled in the Children's Cancer Group (CCG) protocol 945. Following surgery, they were all assigned to receive two courses of “8-drugs-in-1-day” (8-in-1) chemotherapy prior to radiotherapy and eight additional courses thereafter. A centralized neuropathology review was used to confirm the diagnosis of high-grade astrocytoma in 13 of the 18 children: anaplastic astrocytoma, (eight patients), glioblastoma multiforme (four patients), and mixed malignant glioma (one patient). Diagnoses were discordant in five patients. There were eight boys and five girls in the group with confirmed diagnoses, with a median age of 7 years (range 1-15 years). The extent of resection was confirmed by computerized tomography or magnetic resonance (MR) evaluation in five of 13 patients. There were six gross-total or near-total resections (>90%), four partial or subtotal resections (10-90%), and three biopsies. Six patients showed evidence of leptomeningeal metastases at diagnosis based on staging MR examinations. Eight of the 13 patients completed at least eight of the prescribed 10 courses of chemotherapy; five received craniospinal radiotherapy and five spinal radiotherapy. The 5-year progression-free and total survival rates for the 13 children were 46 ± 14% and 54 ± 14%, respectively. Seven patients suffered a relapse at the primary site, four of whom also had leptomeningeal metastases. Seven of the 13 patients (54%) remain alive at the time of this report at a median of 76 months (range 51-93 months) from study entry. Six patients died between 8 and 38 months after diagnosis, all with active disease. Intensification of therapy may further improve outcome in this high-risk population.

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Treatment of high-grade spinal cord astrocytoma of childhood with “8-in-1” chemotherapy and radiotherapy: a pilot study of CCG-945

Journal of Neurosurgery ◽

10.3171/jns.1998.88.2.0215 ◽

1998 ◽

Vol 88 (2) ◽

pp. 215-220 ◽

Cited By ~ 98

Author(s):

Jeffrey C. Allen ◽

Shraga Aviner ◽

Allan J. Yates ◽

James M. Boyett ◽

Joel M. Cherlow ◽

...

Keyword(s):

Spinal Cord ◽

Survival Rates ◽

Extent Of Resection ◽

Leptomeningeal Metastases ◽

High Risk Population ◽

High Grade ◽

Content Type ◽

High Grade Astrocytoma ◽

Dismal Prognosis ◽

Fine Print

Object. The purpose of this study was to devise an improved method of treating high-grade gliomas of the spinal cord in children who have a dismal prognosis following conventional treatment. Methods. Eighteen children with newly diagnosed high-grade astrocytomas arising in the spinal cord were enrolled in the Children's Cancer Group (CCG) protocol 945. Following surgery, they were all assigned to receive two cycles of “8-drugs-in-1-day” (8-in-1) chemotherapy prior to radiotherapy and eight additional cycles thereafter. A centralized neuropathology review was used to confirm the diagnosis of high-grade astrocytoma in 13 of the 18 children: anaplastic astrocytoma (eight patients), glioblastoma multiforme (four patients), and mixed malignant glioma (one patient). Diagnoses were discordant in five patients. There were eight boys and five girls in the group with confirmed diagnoses, with a median age of 7 years (range 1–15 years). The extent of resection was confirmed by computerized tomography or magnetic resonance (MR) evaluation in five of 13 patients. There were six gross-total or near-total resections (> 90%), four partial or subtotal resections (10–90%), and three biopsies. Six patients showed evidence of leptomeningeal metastases at diagnosis based on staging MR examinations. Eight of the 13 patients completed at least eight of the prescribed 10 cycles of chemotherapy; five received craniospinal radiotherapy and five spinal radiotherapy. Conclusions. The 5-year progression-free and total survival rates for the 13 children were 46 ± 14% and 54 ± 14%, respectively. Seven patients suffered a relapse at the primary site, four of whom also had leptomeningeal metastases. Seven of the 13 patients (54%) remain alive at the time of this report at a median of 76 months (range 51–93 months) from study entry. Six patients died between 8 and 38 months after diagnosis, all with active disease. Intensification of therapy may further improve outcome in this high-risk population.

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Mutations of H3.3 and H3.1 in a large cohort of glioma tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13540 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13540-e13540

Author(s):

Ashley Love Sumrall ◽

Joanne Xiu ◽

Jennifer M Eschbacher ◽

Sandeep Mittal ◽

Zoran Gatalica ◽

...

Keyword(s):

Spinal Cord ◽

Brain Stem ◽

Treatment Strategies ◽

Large Cohort ◽

Molecular Entity ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Pediatric Tumors ◽

Heterogeneous Distribution ◽

Dismal Prognosis

e13540 Background: Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are notoriously difficult to treat, and the prevalence and molecular correlates of H3 mutations in a large glioma population have not been systematically reported. We aim to survey a large cohort of gliomas for H3-mutations. Methods: Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2018 were analyzed. NextGen sequencing was done on 592 genes (NextSEQ Illumina); MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing (ArcherDx FusionPlex). Results: Of the 1763 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. Overall, H3 mutations were more prevalent in pediatric tumors (8 of 26, 31%) than adult tumors (34 of 1737, 2%). All H3 mutations seen in pediatric tumors were from grade IV tumors. Among the 34 H3-mutated adult tumors, histology differed. There were 2 grade II tumors (diffuse astrocytoma), 1 low grade glioma from the spinal cord, 1 anaplastic ganglioglioma and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53 (69%. Vs. 37%), ATRX (46% vs. 24%), NF1 (23% vs. 12%) , PDGFRA (17% vs. 1%), FGFR1 (12% vs. 1%), FBXW7 (5% vs. 0), BLM (3% vs. 0) and TSC2 (2% vs.0) compared with H3-WT (p < 0.05). The H3-WT tumors were more enriched for MGMT-methylation (53% vs. 26%) and PTEN mutation (22% vs. 7%) (p < 0.05). In H3-mutated tumors that were MGMT-methylated (n = 10), most H3-mutations seen were G34R (n = 8) while K27M (n = 2) was largely exclusive. Conclusions: This survey of a large cohort of gliomas revealed a heterogeneous distribution of H3 mutations. The co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we are closer to developing more insight into novel treatment strategies for a class of tumors with historically dismal prognosis.

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Molecular profile of ampulla of vater carcinoma (AVC): A rare tumor type with meaningful molecular alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4119 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4119-4119

Author(s):

João Pinto ◽

Helena Verdaguer ◽

Maria Teresa Salcedo ◽

Anna Pedrola ◽

Jorge Hernando-Cubero ◽

...

Keyword(s):

Clinical Trials ◽

Stage Iv ◽

Molecular Profile ◽

Tumor Type ◽

Phase I Clinical Trials ◽

Histological Subtypes ◽

Rare Type ◽

Molecular Alterations ◽

Dismal Prognosis ◽

Stage Iv Disease

4119 Background: AVC is a rare type of cancer with dismal prognosis and limited therapeutic options due to the lack of specific clinical trials. Two histologic subtypes predominate, namely pancreatobiliary and intestinal. A variety of molecular alterations have been described in AVC, but their clinical and therapeutic implications have not been studied in detail. Methods: Retrospective cohort study of patients (pts) diagnosed with AVC treated in our institution from 2010 to 2018. We routinely performed Next Generation Sequencing in all AVC tumors. Our main objectives were to describe the molecular profile of AVC and correlate with clinical outcomes. Results: Out of 26 pts with AVC, 13 pts were male (50%), median age 65 (range 43-83), 7 pts (27%) had stage IV disease at diagnosis. Histologic type was pancreatobiliary in 18 pts (69%), intestinal in 7 pts (27%) and mixed in one case (4%). We identified KRAS mutations (mut) in 10 pts (7 pancreatobiliary, 2 intestinal, 1 mixed), TP53 mut in 6 pts (4/1/1), PIK3CA mut in 3 pts (3/0/0), ERBB2 mut in 3 pts (2/1/0), CTNNB1 mut in 3 pts (2/1/0). In pancreatobiliary we found single cases with RNF43, BRCA1 and CHEK2 mut; while in intestinal we found single cases with NRAS and BRAF mut. One tumor of intestinal subtype had microsatellite instability (MSI). Three pts were included in phase I clinical trials, 2 of them with trials based on tumor profile (ERBB2 mut with pan-HER inhibitor and MSI with immunotherapy). Median overall survival (OS) was 21 months for pts with stage I, II and III disease (95% CI 12.37-not reached) and 13.2 months for stage IV disease at diagnosis (95% CI 5.73-not reached). In cox models, median OS was not dependent on KRAS or TP53 mutation status, or histological subtypes. Conclusions: AVC is a rare type of cancer with two differentiated histological subtypes harboring unique molecular alterations that can be matched to investigational therapies. A broader knowledge of the biology of these tumors is needed to improve patient outcomes.

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Molecular Markers with Predictive and Prognostic Relevance in Lung Cancer

Lung Cancer International ◽

10.1155/2012/729532 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Alphy Rose-James ◽

Sreelekha TT

Keyword(s):

Lung Cancer ◽

Molecular Markers ◽

Prognostic Markers ◽

Small Cell Lung Carcinoma ◽

Prognostic Significance ◽

Great Promise ◽

Small Cell Lung ◽

Kras Mutations ◽

Cell Lung Carcinoma ◽

Molecular Alterations

Lung cancer accounts for the majority of cancer-related deaths worldwide of which non-small-cell lung carcinoma alone takes a toll of around 85%. Platinum-based therapy is the stronghold for lung cancer at present. The discovery of various molecular alterations that underlie lung cancer has contributed to the development of specifically targeted therapies employing specific mutation inhibitors. Targeted chemotherapy based on molecular profiling has shown great promise in lung cancer treatment. Various molecular markers with predictive and prognostic significance in lung cancer have evolved as a result of advanced research. Testing of EGFR and Kras mutations is now a common practice among community oncologists, and more recently, ALK rearrangements have been added to this group. This paper discusses various predictive and prognostic markers that are being investigated and have shown significant relevance which can be exploited for targeted treatment in lung cancer.

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S4-KL-1 UPDATE OF WHO2016 CLASSIFICATION OF ADULT DIFFUSE GLIOMAS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.014 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii3-ii4

Author(s):

Takashi Komori

Keyword(s):

Prognostic Significance ◽

Primary Source ◽

Homozygous Deletion ◽

World Health ◽

Diffuse Astrocytoma ◽

High Grade ◽

Cns Tumor ◽

Molecular Alterations ◽

Microvascular Proliferation ◽

Diffuse Gliomas

Abstract The World Health Organization (WHO) central nervous system (CNS) tumor classification has represented the primary source of diagnosis and grading criteria of brain tumors. Nonetheless, recent advances of studies on their molecular alterations require more rapid update of recommendations for clinical practice. To accomplish this, cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established in 2016 and has published four updates. For adult gliomas, update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed a new term NEC (Not Elsewhere Classified); update 2 revised clarifications regarding diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant; update 3 proposed molecular criteria for an IDH-wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma, which would behave similarly to a grade IV glioblastoma. Nonetheless, no consensus on pathologic or molecular markers that could be incorporated into a more clinically relevant grading scheme for IDH-mutant gliomas has been reached. The molecular alterations previously studied using relatively large cohorts include CDKN2A/B homozygous deletion, CDK4 amplification, RB1 mutation/homozygous deletion, PIK3CA or PIK3R1 mutations, PDGFRA amplification, NMYC amplification, global hypomethylation, genomic instability and chromosome 14 loss. The proliferative activity, based on the mitotic count or Ki67 indices, and other morphologic features typical of a high grade that might stratify the risk better than the current criteria have also been evaluated. Despite the discordance among the results of previous studies, CDKN2A/2B homozygous deletions have been shown prognostic significance in high-grade IDH-mutant astrocytomas and microvascular proliferation stratifies IDH-mutant gliomas lacking a CDKN2A homozygous deletion, suggesting that the integration of molecular information and traditional histological findings is still essential for achieving maximum risk stratification of adult cases of IDH-mutant diffuse gliomas. The grading scheme for adult IDH-mutant as well as wild-type gliomas should therefore be revised in the next WHO update.

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French patterns of psychotropic drug use

Psychiatry and Psychobiology ◽

10.1017/s0767399x00003801 ◽

1990 ◽

Vol 5 (5) ◽

pp. 301-308

Author(s):

V Kovess ◽

M Ortun

Keyword(s):

Drug Use ◽

General Practitioners ◽

Psychotropic Drug ◽

Psychotropic Drugs ◽

Elderly Population ◽

The Elderly ◽

Population Surveys ◽

Minor Tranquilizers ◽

French People ◽

Few Data

SummaryFrench publications on psychotropics are curiously few. Data are available and French consumption of psychotropics, at least minor tranquilizers has been consistently reported as being higher than that found in other countries. The authors attempt to answer three questions: is French consuption of psychotropics really higher than other countries? Who is consuming those drugs? In which context? After having reviewed comparative data on sales, data from population surveys are analysed together with samples of prescriptions by different categories of physicians. It seems likely that French people consume more anxiolytics but this does not apply to other psychotropic drugs. Given the fact that drugs are almost free of charge in France, it is always difficult to discriminate between what has been prescribed and what has been taken. Overconsumption of anxiolytics is due to the overconsumption of the elderly population (over 60). Minor tranquilizers are mainly prescribed by general practitioners for psychological reasons.

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PATH-10. RELATIONSHIP BETWEEN CYTOGENETIC COMPLEXITY AND PERITUMORAL EDEMA IN HIGH-GRADE ASTROCYTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.606 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi145-vi145

Author(s):

Kyoung Su Sung ◽

Young-Jin Song ◽

Jin-Yeong Han ◽

Ki-Uk Kim

Keyword(s):

Prognostic Significance ◽

Growth Factor Receptor ◽

Chromosome 7 ◽

High Grade ◽

Peritumoral Edema ◽

Complex Karyotype ◽

Egfr Amplification ◽

High Grade Astrocytoma ◽

Average Survival ◽

Endothelial Growth Factor

Abstract The purpose of the study is to reveal the association of cytogenetic complexity and peritumoral edema volume (PTEV) and its prognostic significance in high-grade astrocytoma patients by culturing patient tumor cells. Twenty-seven high-grade astrocytoma patients were divided into three groups according to karyotype complexity: normal, non-complex karyotype (NCK), and complex karyotype (CK). Endothelial growth factor receptor (EGFR) amplification was detected by FISH, and its association with chromosome 7 abnormalities was analyzed. Mean PTEV of each group was compared by ANOVA to evaluate the relationship between PTEV and cytogenetic complexity. The PTEV of patients in normal (n=6), NCK (n=8), and CK (n=13) groups were 24.52±17.73, 34.26±35.04, and 86.31±48.7 cm3, respectively (P=0.005). Ten out of 11 patients with EGFR amplification showed abnormalities in chromosome 7. The mean PTEV of EGFR-amplified and non-amplified groups were 80.4±53.7 and 41.3±37.9 cm3, respectively (P=0.035). The average survival of patients with PTEV less than 90 cm3 was 30.52±26.11 months, while in patients with PTEVs over or equal to 90 cm3, it was 10.83±5.53 months (P=0.007). The results show an association of complex karyotype with the PTEV of high-grade astrocytoma. EGFR amplification plays a significant role in the formation of peritumoral edema, causing PTEV to increase, which is related with survival. This implies that cytogenetic karyotype can be applied as a prognostic factor.

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Molecular Diagnostics of Thyroid Tumors

Archives of Pathology & Laboratory Medicine ◽

10.5858/2010-0664-rair.1 ◽

2011 ◽

Vol 135 (5) ◽

pp. 569-577 ◽

Cited By ~ 2

Author(s):

Yuri E. Nikiforov

Keyword(s):

Thyroid Cancer ◽

Molecular Markers ◽

Fine Needle Aspiration ◽

Thyroid Nodules ◽

Needle Aspiration ◽

Genetic Alterations ◽

Braf V600e ◽

Fine Needle ◽

Molecular Alterations ◽

Diagnostic Use

Abstract Context.—Thyroid cancer is the most common type of endocrine malignancy and its incidence is steadily increasing. Papillary carcinoma and follicular carcinoma are the most common types of thyroid cancer and represent those tumor types for which use of molecular markers for diagnosis and prognostication is of high clinical significance. Objective.—To review the most common molecular alterations in thyroid cancer and their diagnostic and prognostic utility. Data Sources.—PubMed (US National Library of Medicine)–available review articles, peer-reviewed original articles, and experience of the author. Conclusions.—The most common molecular alterations in thyroid cancer include BRAF and RAS point mutations and RET/PTC and PAX8/PPARγ rearrangements. These nonoverlapping genetic alterations are found in more than 70% of papillary and follicular thyroid carcinomas. These molecular alterations can be detected in surgically resected samples and fine-needle aspiration samples from thyroid nodules and can be of significant diagnostic use. The diagnostic role of BRAF mutations has been studied most extensively, and recent studies also demonstrated a significant diagnostic utility of RAS, RET/PTC, and PAX8/PPARγ mutations, particularly in thyroid fine-needle aspiration samples with indeterminate cytology. In addition to the diagnostic use, BRAF V600E mutation can also be used for tumor prognostication, as this mutation is associated with higher rate of tumor recurrence and tumor-related mortality. The use of these and other emerging molecular markers is expected to improve significantly the accuracy of cancer diagnosis in thyroid nodules and allow more individualized surgical and postsurgical management of patients with thyroid cancer.

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Neural induction and regionalisation in the chick embryo

Development ◽

10.1242/dev.114.3.729 ◽

1992 ◽

Vol 114 (3) ◽

pp. 729-741 ◽

Cited By ~ 41

Author(s):

K.G. Storey ◽

J.M. Crossley ◽

E.M. De Robertis ◽

W.E. Norris ◽

C.D. Stern

Keyword(s):

Spinal Cord ◽

Nervous System ◽

Molecular Markers ◽

Chick Embryo ◽

Normal Development ◽

Neural Induction ◽

Stage 4 ◽

Embryo Chick ◽

Host Embryo ◽

Embryonic Region

Induction and regionalisation of the chick nervous system were investigated by transplanting Hensen's node into the extra-embryonic region (area opaca margin) of a host embryo. Chick/quail chimaeras were used to determine the contributions of host and donor tissue to the supernumerary axis, and three molecular markers, Engrailed, neurofilaments (antibody 3A10) and XlHbox1/Hox3.3 were used to aid the identification of particular regions of the ectopic axis. We find that the age of the node determines the regions of the nervous system that form: young nodes (stages 2–4) induced both anterior and posterior nervous system, while older nodes (stages 5–6) have reduced inducing ability and generate only posterior nervous system. By varying the age of the host embryo, we show that the competence of the epiblast to respond to neural induction declines after stage 4. We conclude that during normal development, the initial steps of neural induction take place before stage 4 and that anteroposterior regionalisation of the nervous system may be a later process, perhaps associated with the differentiating notochord. We also speculate that the mechanisms responsible for induction of head CNS differ from those that generate the spinal cord: the trunk CNS could arise by homeogenetic induction by anterior CNS or by elongation of neural primordia that are induced very early.

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