scholarly journals The genetic basis of intradural spinal tumors and its impact on clinical treatment

2015 ◽  
Vol 39 (2) ◽  
pp. E3 ◽  
Author(s):  
Michael Karsy ◽  
Jian Guan ◽  
Walavan Sivakumar ◽  
Jayson A. Neil ◽  
Meic H. Schmidt ◽  
...  
Keyword(s):  
Treatment Options ◽  
Cancer Recurrence ◽  
Genetic Alterations ◽  
Spinal Tumors ◽  
Therapeutic Effects ◽  
Low Grade ◽  
Primary Therapy ◽  
Targeted Interventions ◽  
Molecular Alterations ◽  
The Impact

Genetic alterations in the cells of intradural spinal tumors can have a significant impact on the treatment options, counseling, and prognosis for patients. Although surgery is the primary therapy for most intradural tumors, radiochemothera-peutic modalities and targeted interventions play an ever-evolving role in treating aggressive cancers and in addressing cancer recurrence in long-term survivors. Recent studies have helped delineate specific genetic and molecular differences between intradural spinal tumors and their intracranial counterparts and have also identified significant variation in therapeutic effects on these tumors. This review discusses the genetic and molecular alterations in the most common intradural spinal tumors in both adult and pediatrie patients, including nerve sheath tumors (that is, neurofibroma and schwannoma), meningioma, ependymoma, astrocytoma (that is, low-grade glioma, anaplastic astrocytoma, and glioblastoma), hemangioblastoma, and medulloblastoma. It also examines the genetics of metastatic tumors to the spinal cord, arising either from the CNS or from systemic sources. Importantly, the impact of this knowledge on therapeutic options and its application to clinical practice are discussed.

scholarly journals Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322983
Author(s):  
Benjamin Goeppert ◽  
Damian Stichel ◽  
Reka Toth ◽  
Sarah Fritzsche ◽  
Moritz Anton Loeffler ◽  
...  
Keyword(s):  
Treatment Options ◽  
Genetic Alterations ◽  
Integrative Analysis ◽  
Intermediate Form ◽  
Precursor Lesions ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Cells Of Origin ◽  
Sample Set ◽  
Methylation Profiling

ObjectiveA detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options.DesignWe analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling.ResultsPatients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin.ConclusionIntegrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.

scholarly journals IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3754
Author(s):  
Fabiana Crispo ◽  
Michele Pietrafesa ◽  
Valentina Condelli ◽  
Francesca Maddalena ◽  
Giuseppina Bruno ◽  
...  
Keyword(s):  
Treatment Options ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Idh1 Mutation ◽  
Primary Malignancy ◽  
Pharmacological Agents ◽  
Molecular Alterations ◽  
Starting Point ◽  
Metabolic Remodeling ◽  
Mutant Idh1

Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the IDH1 mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some IDH1 point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of IDH1 mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant IDH1 in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.

scholarly journals Immunity and inflammation: the neglected key players in congenital heart disease?

2021 ◽  
Author(s):  
Laura M. Wienecke ◽  
Sarah Cohen ◽  
Johann Bauersachs ◽  
Alexandre Mebazaa ◽  
Benjamin G. Chousterman
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Chronic Inflammation ◽  
Congenital Heart ◽  
Heart Surgery ◽  
Treatment Options ◽  
Open Heart Surgery ◽  
Genetic Alterations ◽  
Immune Alterations ◽  
The Impact

AbstractAlthough more than 90% of children born with congenital heart disease (CHD) survive into adulthood, patients face significantly higher and premature morbidity and mortality. Heart failure as well as non-cardiac comorbidities represent a striking and life-limiting problem with need for new treatment options. Systemic chronic inflammation and immune activation have been identified as crucial drivers of disease causes and progression in various cardiovascular disorders and are promising therapeutic targets. Accumulating evidence indicates an inflammatory state and immune alterations in children and adults with CHD. In this review, we highlight the implications of chronic inflammation, immunity, and immune senescence in CHD. In this context, we summarize the impact of infant open-heart surgery with subsequent thymectomy on the immune system later in life and discuss the potential role of comorbidities and underlying genetic alterations. How an altered immunity and chronic inflammation in CHD influence patient outcomes facing SARS-CoV-2 infection is unclear, but requires special attention, as CHD could represent a population particularly at risk during the COVID-19 pandemic. Concluding remarks address possible clinical implications of immune changes in CHD and consider future immunomodulatory therapies.

Molecular alterations to predict survival and response to chemotherapy of pediatric low-grade glioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10503-10503
Author(s):  
Michal Zapotocky ◽  
Scott Ryall ◽  
Anthony Arnoldo ◽  
Matthew Mistry ◽  
Alvaro Lassaletta ◽  
...  
Keyword(s):  
Large Population ◽  
Objective Response ◽  
Low Grade Glioma ◽  
Response To Therapy ◽  
Braf V600e ◽  
Low Grade ◽  
Long Term Outcome ◽  
Molecular Alterations ◽  
Response To Chemotherapy ◽  
The Impact

10503 Background: RAS/MAPK pathway mutations have been identified as the major drivers of pediatric low-grade glioma (pLGG). The impact of these alterations on outcome and response to therapy is still unknown. Methods: We performed a large population based study of all pLGG diagnosed from 1985-2015. Detailed treatment and very long term outcome data was collected on all patients. Known pLGG-related alterations were detected using NanoString and QX200™Droplet Digital™PCR. Molecular data was correlated with outcome and response to chemotherapy. Results: In our cohort of 614 patients, BRAF was found to be altered in 57% and wild-type (WT) in 43% of patients without neurofibromatosis 1 (NF1). Among BRAF-WT we identified H3.3K27M, FGFR1-TACC1, MYBL1 and other alterations. Molecular alterations stratified pLGG into several risk groups. Ten-year progression free survival (PFS) was 72.3% for NF1, 69.5% for KIAA1549-BRAF, 53.5% for BRAF-WT, 30.3% for BRAF-V600E and 0% for H3.3K27M mutations (p < 0.0001). Similarly, overall survival (OS) at 10 years delineated difference between excellent survival of KIAA1549-BRAF and NF1 compared to BRAF-V600E and BRAF-WT (p = 0.0005). Interestingly, all patients with FGFR1-TACC1 and MYBL1 were alive despite observed progressions. Strikingly, response to chemotherapy determined by changes in tumor size at 6 months of therapy correlated with pLGG alteration. Objective response to first line chemotherapy was observed in 46% of patients with KIAA1549-BRAF and 35% of NF1. In contrast, only 15% BRAF-V600E and 18% BRAF-WT responded and 41% tumors grew after six months of chemotherapy. Moreover, 5-year PFS after chemotherapy was strikingly low for BRAF-V600E and BRAF-WT (25% and 31.9% respectively) compared to KIAA1549-BRAF (50%) and NF1 (76.7%) (p = 0.001). This translated to decreased OS for BRAFV600E and BRAF-WT patients (p = 0.042). Conclusions: Our study provides evidence that molecular alterations dictate the outcome of pLGG. KIAA1549-BRAF harbors excellent prognosis and choice of therapy should be made in favor of less toxic agents to minimize deleterious late effects. In contrast, poor prognosis is associated with lack of response to chemotherapy in BRAF-V600E and BRAF-WT tumors.

scholarly journals Is Host Metabolism the Missing Link to Improving Cancer Outcomes?

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2338
Author(s):  
Christopher M. Wright ◽  
Anuradha A. Shastri ◽  
Emily Bongiorno ◽  
Ajay Palagani ◽  
Ulrich Rodeck ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Tumor Cells ◽  
Treatment Options ◽  
Detailed Knowledge ◽  
Pharmacological Agents ◽  
Molecular Alterations ◽  
Number Of Patients ◽  
Disease Site ◽  
New Treatment ◽  
The Impact

For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that—to optimize the impact of old and new treatment options—we need to take account of an epidemic that occurs independently of—but has major impact on—the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its’ attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population.

Impact of Rituximab On the Treatment of Waldenström's Macroglobulinemia (WM).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2734-2734
Author(s):  
Sheeba K. Thomas ◽  
Kay B Delasalle ◽  
Jatin J. Shah ◽  
Luhua Wang ◽  
Robert Z. Orlowski ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Single Agent ◽  
Nucleoside Analogs ◽  
Low Grade ◽  
Primary Therapy ◽  
Treatment Groups ◽  
Before And After ◽  
The Impact

Abstract Abstract 2734 Background: Rituximab was first approved by the FDA for use in relapsed and/or refractory low grade or follicular B cell non-Hodgkin's lymphoma in 11/1997. Since that time it has been widely used in WM, and is the backbone of drug combinations developed for treatment of this disease. Methods: To evaluate the impact of rituximab on overall survival (OS), we retrospectively evaluated patients (pts) treated at our center who received primary therapy for symptomatic WM with combinations of either alkylating agents (AA), nucleoside analogs (NA) +/− AA, or bortezomib (B), each with or without rituximab (R). The effect of primary therapy on OS was compared between patients receiving primary therapy before and after rituximab use for WM began at our center (11/11/1998). OS was calculated from the date of initial treatment until date of death or last follow-up. Due to small patient numbers, those who received vincristine-doxorubicin-dexamethasone (2 pts), single agent rituximab (3 pts), or rituximab-alkylating agent combinations (11 pts) as primary therapy, were excluded from the analysis. Results: Among 315 patients with previously untreated symptomatic WM treated since 3/1966, 118 received AA alone; 137 received NA +/− AA alone (85 pts) or with R (52 pts), and 44 received B + R. Median age, hemoglobin, platelet count and β2 microglobulin were comparable between all treatment groups (AA alone, NA +/− AA alone, NA +/− AA + R, B + R). Only median albumin differed significantly, with levels of 3.7 g/dL (AA alone), 4.1 g/dL (NA+/− AA alone), 4.3 g/dL (NA+/− AA + R) and 4.4 g/dL (B + R), respectively (p < 0.01). The median OS of pts treated with AA was 4.5 years, and 6.5 years with NA +/− AA, while the median OS of pts treated with NA+/− AA + R (median follow-up: 8 years) and B + R (median follow-up: 2.6 years) has not been reached. Comparing all patients treated with vs. without R, median OS is >13 years vs. 5.6 years (p<0.01). Conclusions: While pts with WM have most certainly benefitted from improvements in supportive care and the greater availability of salvage therapy options in the modern era, the addition of rituximab to available therapies appears to have significantly improved the OS of patients with WM compared with AA or NA +/− AA alone. Our data supports the role of rituximab as an indispensable component of modern therapy for this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas

2020 ◽  
Vol 22 (10) ◽  
pp. 1474-1483 ◽  
Author(s):  
Kohei Fukuoka ◽  
Yasin Mamatjan ◽  
Ruth Tatevossian ◽  
Michal Zapotocky ◽  
Scott Ryall ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Progression Free Survival ◽  
Lymphocytic Infiltration ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Pleomorphic Xanthoastrocytoma ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Additional Information ◽  
Molecular Alterations

Abstract Background Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear. Methods We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers. Results Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma–like tumors could stratify these tumors into low and high risk (P = 0.0014). Conclusion The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.

scholarly journals Contrasting multidisciplinary clinic follow up for patients with high and low grade glioma.

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv16-iv16
Author(s):  
Giles Critchley ◽  
Sorin Bucur ◽  
Gill Walsh ◽  
Ruth Smith ◽  
Antonia Creak ◽  
...  
Keyword(s):  
Treatment Options ◽  
High Grade Glioma ◽  
Clinical Nurse Specialist ◽  
Low Grade Glioma ◽  
Nurse Specialist ◽  
Low Grade ◽  
Clinical Nurse ◽  
Mri Scans ◽  
Room Model ◽  
The Impact

Abstract Patients with high grade glioma (HGG) and low grade glioma (LGG) may enter a period of stability in their disease when surveillance is required; during this time they often require different forms of support. We describe two different multidisciplinary clinics approaches to patients with gliomas, both of which are linked to the relevant multidisciplinary meetings (MDMs). Since 1987 the ‘joint glioma clinic’ (HGG clinic) has been run with a neurosurgeon, neurooncologist and clinical nurse specialist seeing patients and their carers in one room. Patients under surveillance undergo MRI scans and if there is evidence of recurrence then an immediate discussion can be held with the patient regarding options for further management. Since 2011 the Low grade glioma clinic (LGG clinic) has run with a multi room model. There are two neurosurgeons, a neurooncologist, a neuroradiologist, a neuropsychologist, a neurologist and a clinical nurse specialist present who discuss patients in a MDM. Subsequently a patient may then see one or more of the team in sequence in different rooms as needed. This allows issues such as epilepsy, neuropsychology, treatment options and surveillance intervals to be discussed with patients at one visit. There is a cohort of 106 patients under surveillance in the HGG joint glioma clinic and 270 patients in the LGG clinic. We believe a single visit can minimize the impact of the disease and provide different forms of support a needed. Both models allow rapid decision making when the period of surveillance ends due to transformation or recurrence.

Exploring Signaling Pathways and Pancreatic Cancer Treatment Approaches Using Genetic Models

2019 ◽  
Vol 19 (14) ◽  
pp. 1112-1125
Author(s):  
Shorooq Khader ◽  
Anita Thyagarajan ◽  
Ravi P. Sahu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathways ◽  
Treatment Options ◽  
Survival Rates ◽  
Genetic Alterations ◽  
Chemotherapeutic Agents ◽  
Genetic Models ◽  
Treatment Approaches ◽  
Regulatory Pathways ◽  
The Impact

Despite available treatment options, the overall survival rates of pancreatic cancer patients remain dismal. Multiple counter-regulatory pathways have been identified and shown to be involved in interfering with the efficacy of therapeutic agents. In addition, various known genetic alterations in the cellular signaling pathways have been implicated in affecting the growth and progression of pancreatic cancer. Nevertheless, the significance of other unknown pathways is yet to be explored, which provides the rationale for the intervention of new approaches. Several experimental genetic models have been explored to define the impact of key signaling cascades, and their mechanisms in the pathophysiology as well as treatment approaches of pancreatic cancer. The current review highlights the recent updates, and significance of such genetic models in the therapeutic efficacy of anti-tumor agents including the standard chemotherapeutic agents, natural products, cell signaling inhibitors, immunebased therapies and the combination of these approaches in pancreatic cancer.

scholarly journals Clinical and Molecular Features of Disseminated Pediatric Low Grade Glioma - A Systematic Review of Literature

2021 ◽  
Author(s):  
Joseline Haizel-Cobbina ◽  
Rut Thakkar ◽  
Kelsey Richard ◽  
Adrian Levine ◽  
Julie Bennett ◽  
...  
Keyword(s):  
Systematic Review ◽  
Disease Surveillance ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Risk Of Bias ◽  
Low Grade ◽  
Molecular Alterations ◽  
Molecular Features ◽  
1P Deletion ◽  
Csf Diversion

Abstract INTRODUCTIONGliomas account for approximately 46% of all pediatric CNS tumors. There is growing awareness of pediatric low-grade gliomas (PLGG) that disseminate to distant parenchymal or leptomeningeal locations either at the time of initial diagnosis or upon disease surveillance. Disseminated PLGGs (dPLGGs) are associated with a poorer prognosis than non-disseminated PLGGs. To date there is no comprehensive report characterizing the genome profile of dPLGGs and their associated management. This systematic review aims to identify the pattern of genetic alterations and treatment outcomes described for dPLGG.METHODSA systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively.RESULTSFifty-two studies published from 1994 to 2020 were included in this review with 368 cases reported. There was sporadic reporting of genetic alterations. The most common genetic alteration observed among study subjects was 1p deletion (76%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of cases demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted primarily of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone to surgical resection and CSF diversion, and depended largely upon tumor location and timing of dissemination. Overall, 73% of cases were alive at last follow-up (median, 40.2 months). All studies reviewed either ranked low or moderate for both quality and risk of bias assessments. CONCLUSIONWhile 1p deletion and BRAF-KIAA1549 fusion are the most commonly described molecular alterations in dPLGG, these tumors appear to express heterogeneous molecular and biological characteristics distinct from non-disseminated PLGGs. Additional studies on the molecular and biological features of these tumors are needed to better understand the pathogenesis of dPLGG and to inform the development of additional targeted regimens.

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