Capecitabine plus temozolomide (CAP-TEM) in patients with advanced neuroendocrine neoplasms (NEN): An Italian multicenter retrospective analysis.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 281-281 ◽  
Author(s):  
Francesca Spada ◽  
Caterina Fumagalli ◽  
Lorenzo Antonuzzo ◽  
Luca Messerini ◽  
Davide Radice ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Methylation Status ◽  
Variable Number ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
Mgmt Methylation ◽  
Homogeneous Population ◽  
Mgmt Gene ◽  
Grade 3 ◽  
Different Origins

281 Background: A combination of capecitabine (CAP) and temozolomide (TEM) has been successfully used as first-line treatment in low-grade pancreatic neuroendocrine neoplasms (PNEN). We reviewed activity and toxicity of the same regimen in patients with advanced NEN with different primary and grading. Methods: Clinical data of patients who had received oral CAP 1500 mg/m2/day over 14 days bid plus oral TEM 150-200 mg/m2/day on days 10-14 of each 28-day cycle, were retrospectively reviewed. The methylenguanilmetiltransferase (MGMT) methylation-status (MGMT-gene >5% = responders) and TS-polymorphisms (2R/2R, 2R/3R = responders, 3R/3R = non-responders) in tumor-tissue/peripheral-blood were evaluated by pyrosequencing. Results: Since March 2012, 29 patients were selected. The primary tumor was: pancreas in 14 patients (48%), gastrointestinal (GI) in 5 (17%), unknown in 2 (7%), lung in 8 (28%). According to 2010 WHO classification, Ki67 was <2% (G1) in 3%, 3-20% (G2) in 45% patients, >20% (G3) in 21% with two "low G3" (Ki67 21-30%), and unknown in 3%. Among lung: 7% typical and 21% atypical (Travis’ classification). 72% patients (21/29) were progressive on different therapies: peptide-receptor-radiotherapy (38%), chemotherapy (38%), everolimus (14%). Partial-response (PR) occurred in 14% (4/29) of patients (95% CI: 4-32), stable-disease (SD) in 59% (17/29) (95% CI: 39-77) mainly PNET. The two "low G3" responded. Disease control rate (PR+SD): 72% (95% CI: 53-87). Median TTP: 9 months (95% CI: 5.6-N.E.). Thrombocytopenia was the most frequent grade 3 toxicity, always temporary. All 4 PR patients had genotype 2R/3R-2R/2R investigated for the 28 base-pair (bp) variable number of tandem repeats (VNTR) in the 5'UTR of the TS-gene, and MGMT-gene inactivation by epigenetic silencing. Conclusions: This analysis suggests that CAP-TEM chemotherapy could be active and well tolerated in pretreated patients with advanced NEN of different origins and grading. This warrants a prospective investigation in a more homogeneous population (G2 and “low-G3” GEP NEN or lung carcinoids), in order to validate the predictive value of MGMT methylation-status and TS-polymorphisms.

scholarly journals Evaluation of MGMT gene methylation in neuroendocrine neoplasms

2021 ◽  
Author(s):  
Rosa Della Monica ◽  
Mariella Cuomo ◽  
Roberta Visconti ◽  
Annabella di Mauro ◽  
Michela Buonaiuto ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Pcr ◽  
Well Differentiated

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O-6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high resolution next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs

WP1-18 Risk factors and patterns of recurrence of low grade glioma: a systematic review

2019 ◽  
Vol 90 (3) ◽  
pp. e6.3-e6
Author(s):  
V Narbad ◽  
JP Lavrador ◽  
A Elhag ◽  
S Acharya ◽  
J Hanrahan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Tp53 Mutation ◽  
Methylation Status ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Diffuse Glioma ◽  
Idh Mutation ◽  
Mgmt Methylation ◽  
Inclusion Criteria

ObjectivesTo review the risk factors and patterns of progression/recurrence of low grade glioma (LGG).DesignSystematic review of the published literature.SubjectsInclusion criteria were peer reviewed publications of cohort studies of recurrent/progressive LGG. Studies of wider populations were included if relevant LGG data could be analysed separately.MethodsMedline and Cochrane databases were searched using MeSH and non-MeSH terms, including ‘glioma’, ‘astrocytoma’, ‘oligoastrocytoma’, ‘diffuse glioma’, ‘oligodendroglioma’, ‘low grade’ and ‘disease recurrence’ by two independent reviewers.ResultsOverall, 917 studies were screened, of which 57 studies met the inclusion criteria. The most frequently described risk factor for recurrent LGG was suboptimal extent of resection (EOR) of the initial tumour (in 20 studies); recurrence was also associated with the patient’s age (2), tumour location (4), neurological status (3), tumour volume (6), bihemispherical tumour (3) and astrocytic histology (6). IDH mutation was associated with recurrence in 1 out of 3 studies, but TP53 mutation (2 of 4) and MGMT methylation status (4) were not. Malignant transformation was associated with TP53 mutations (3), IDH mutation (1) and EOR (1). Favourable progression free survival (PFS) and/or overall survival (OS) were associated with greater EOR (16), oligodendroglioma histology (2 of 4), initial KPS (3) and the use of adjuvant therapies (9 of 14). IDH mutation was associated with improved PFS and OS (3 of 4). TP53 mutation improved PFS in 1 of 3 studies. MGMT methylation and 1 p/19q codeletion may predict treatment response but their effects on survival are unclear.ConclusionsAstrocytoma histology, IDH and TP53 mutation statuses and surgical treatment (EOR) are essential in determining the time to recurrence or progression in LGG.

Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2000-2000 ◽  
Author(s):  
R. Stupp ◽  
R. Goldbrunner ◽  
B. Neyns ◽  
U. Schlegel ◽  
P. Clement ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Tumor Resection ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Liver Function Tests ◽  
Mri Imaging ◽  
Mgmt Gene ◽  
Grade 3

2000 Background: To evaluate safety, toxicity, and efficacy of the combination of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, in addition to standard temozolomide (TMZ) and radiotherapy (RT). Methods: 52 pts (PS 0–1: 92%, 2: 8%; median age 57 yrs) after tumor resection (n=43/83%) or biopsy (n= 9/17%) were treated with standard TMZ/RT (Stupp et al. NEJM 2005). In addition cilengitide (500 mg i.v., 2x/week) was started one week before TMZ/RT and given throughout for the duration of chemotherapy or until progression. The primary endpoint was progression free survival rate at 6 months (target: 65%). Pts were followed with MRI every 2 months. Histopathologic diagnosis and MRI imaging were independently reviewed, O6-Methylguanine- DNA methyltransferase (MGMT) promotor methylation status was assessed in 45 (86.5%) pts. Results: 46 pts (92%) completed RT, = 90% of concomitant TMZ was received by 42 pts and cilengitide by 45 pts. 20 pts (3 ongoing) completed 6 cycles of maintenance TMZ and cilengitide. Observed hematological grade 3 and 4 toxicities were: lymphopenia (28/52, 53.8%), thrombocytopenia (7/52 pt. 13.4%) and neutropenia (5/52, 9.6%). Treatment related non-hematologic grade 3/4 toxicities were reported for n=3/52 (5.7%) patients: constitutional symptoms (asthenia, fatigue, anorexia, n=3); elevated liver function tests (n=1), deep venous thrombosis and pulmonary embolism (n=1). One patient with a history of sigmoid diverticulosis experienced sigmoid perforation (grade 2). In total, 34/52 (65.4% [95% CI, 50.9–78.0%]) of the pts were progression free at 6 months. Pts with MGMT gene-promotor methylation in the tumor were more likely to reach 6 months PFS endpoint. Conclusions: The study reached its primary endpoint. The combination of the integrin inhibitor RGD peptide Cilengitide and TMZ/RT was well tolerated, PFS at 6 months is encouraging. MGMT gene promoter methylation correlates with outcome. At the time of ASCO, updated results and survival estimates after a minimum follow-up of at least 1 year will be available. [Table: see text]

scholarly journals Management of Gliomas: Individualized Treatment Options

2020 ◽  
Vol 18 (7.5) ◽  
pp. 985-988
Author(s):  
Louis Burt Nabors
Keyword(s):  
Performance Status ◽  
Treatment Options ◽  
Methylation Status ◽  
Low Grade ◽  
Prognostic Impact ◽  
Mgmt Methylation ◽  
Methyl Transferase ◽  
Low Performance ◽  
Hypofractionated Radiation

Optimizing treatment for patients with low-grade gliomas should focus on the role of radiation and chemotherapy, as well as the prognostic impact of molecular diagnostics (1p/19q and IDH status). For anaplastic oligodendroglioma, focus should be placed on molecular markers (particularly 1p/19q status) and combination treatment with chemotherapy (temozolomide or PCV [procarbazine, lomustine, and vincristine]) and radiation. For patients with malignant glioblastomas, the role of methylguanine methyl-transferase (MGMT) methylation status has become increasingly important to treatment decisions. MGMT methylation status should be considered in elderly patients and/or those with low performance status (methylated patients benefit from temozolomide) and a hypofractionated radiation schedule should be used.

Combined IDH1 mutation and MGMT methylation status on long-term survival of patients with cerebral low-grade glioma

2015 ◽  
Vol 138 ◽  
pp. 37-44 ◽  
Author(s):  
Kazuhiro Tanaka ◽  
Takashi Sasayama ◽  
Katsu Mizukawa ◽  
Kumi Takata ◽  
Nor Shazrina Sulaiman ◽  
...  
Keyword(s):  
Methylation Status ◽  
Idh1 Mutation ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Mgmt Methylation ◽  
Term Survival ◽  
Long Term Survival

Quantitative evaluation of post-bone marrow transplant engraftment status using fluorescent-labeled variable number of tandem repeats

2000 ◽  
Vol 05 (2) ◽  
pp. 129-138
Author(s):  
Robert A. Luhm ◽  
Daniel B. Bellissimo ◽  
Arejas J. Uzgiris ◽  
William R. Drobyski ◽  
Martin J. Hessner
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplant ◽  
Quantitative Evaluation ◽  
Tandem Repeats ◽  
Marrow Transplant ◽  
Variable Number

Dopaminergic Genes Polymorphisms and Prefrontal Cortex Efficiency Among Obese People - Whether Gender is a Differentiating Factor?

2019 ◽  
Vol 19 (6) ◽  
pp. 405-418
Author(s):  
Maciej Bieliński ◽  
Natalia Lesiewska ◽  
Roman Junik ◽  
Anna Kamińska ◽  
Andrzej Tretyn ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Executive Functions ◽  
Tandem Repeats ◽  
Wisconsin Card Sorting Test ◽  
Variable Number ◽  
Card Sorting ◽  
Obese People ◽  
Perseverative Errors ◽  
Wisconsin Card Sorting ◽  
Sorting Test

Background:Obesity is a chronic condition associated with poorer cognitive functioning. Wisconsin Card Sorting Test (WCST) is a useful tool for evaluating executive functions. In this study, we assessed the association between dopaminergic gene polymorphisms: DAT1 (SLC6A3), COMTVal158Met, DRD4 (48-bp variable number of tandem repeats - VNTR) and WCST parameters to investigate the functions of the frontal lobes in obese individuals.Objective:To find the significant correlations between polymorphisms of DAT1, COMTVal158Met, DRD4 and executive functions in obese subjects.Methods:The analysis of the frequency of individual alleles was performed in 248 obese patients (179 women, 69 men). Evaluation of the prefrontal cortex function (operating memory and executive functions) was measured with the Wisconsin Card Sorting Test (WCST). Separate analyzes were performed in age subgroups to determine different activities and regulation of genes in younger and older participants.Results:Scores of WCST parameters were different in the subgroups of women and men and in the age subgroups. Regarding the COMT gene, patients with A/A and G/A polymorphisms showed significantly better WCST results in WCST_P, WCST_CC and WCST_1st. Regarding DAT1 men with L/L and L/S made less non-perseverative errors, which was statistically significant. In DRD4, significantly better WCST_1st results were found only in older women with S allele.Conclusion:Obtained results indicate the involvement of dopaminergic transmission in the regulation of prefrontal cortex function. Data analysis indicates that prefrontal cortex function may ensue, from different elements such as genetic factors, metabolic aspects of obesity, and hormonal activity (estrogen).

scholarly journals Molecular characteristics of Brucella melitensis isolates from humans in Qinghai Province, China

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhi-Jun Zhao ◽  
Ji-Quan Li ◽  
Li Ma ◽  
Hong-Mei Xue ◽  
Xu-Xin Yang ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Brucella Melitensis ◽  
Draft Genome ◽  
Geographic Origin ◽  
Variable Number ◽  
Human Brucellosis ◽  
Molecular Characteristics ◽  
Whole Genome ◽  
Qinghai Province ◽  
Variable Number Tandem Repeats

Abstract Background The prevalence of human brucellosis in Qinghai Province of China has been increasing rapidly, with confirmed cases distributed across 31 counties. However, the epidemiology of brucellosis transmission has not been fully elucidated. To characterize the infecting strains isolated from humans, multiple-locus variable-number tandem repeats analysis (MLVA) and whole-genome single-nucleotide polymorphism (SNP)-based approaches were employed. Methods Strains were isolated from two males blood cultures that were confirmed Brucella melitensis positive following biotyping and MLVA. Genomic DNA was extracted from these two strains, and whole-genome sequencing was performed. Next, SNP-based phylogenetic analysis was performed to compare the two strains to 94 B. melitensis strains (complete genome and draft genome) retrieved from online databases. Results The two Brucella isolates were identified as B. melitensis biovar 3 (QH2019001 and QH2019005) following conventional biotyping and were found to have differences in their variable number tandem repeats (VNTRs) using MLVA-16. Phylogenetic examination assigned the 96 strains to five genotype groups, with QH2019001 and QH2019005 assigned to the same group, but different subgroups. Moreover, the QH2019005 strain was assigned to a new subgenotype, IIj, within genotype II. These findings were then combined to determine the geographic origin of the two Brucella strains. Conclusions Utilizing a whole-genome SNP-based approach enabled differences between the two B. melitensis strains to be more clearly resolved, and facilitated the elucidation of their different evolutionary histories. This approach also revealed that QH2019005 is a member of a new subgenotype (IIj) with an ancient origin in the eastern Mediterranean Sea.

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