Frequent MGMT (06-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience

BackgroundGlioblastoma (GBM) is the most aggressive intracranial tumor which can be divided into two subtypes based on status of isocitrate dehydrogenase (IDH). A small fraction of patients after receiving standard treatment can be long-term survivors (LTS). This study was designed to disclose the predictors and clinical implications associated with LTS in IDH wildtype and mutant GBM.MethodsPatients who survived beyond five years after diagnosis of GBM were defined as LTS, while those with a survival less than one year were defined as short-term survivors (STS). A total of 211 patients with diagnosis of GBM in Beijing Tiantan Hospital from January 2007 to January 2015 were enrolled, including 44 (20.9%) LTS and 167 (79.1%) STS. The clinical, radiological and molecular features between groups were systematically compared.ResultsCompared with STS, LTS were a subgroup of patients with a younger age at diagnosis (P=0.006), a higher KPS score (P=0.011), higher rates of cystic change (P=0.037), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (P=0.007), and IDH mutation (P=0.049), and more likely to have undergone gross total resection (P<0.001). Survival analysis demonstrated that LTS with wildtype IDH conferred a longer progression-free survival (66.0 vs. 27.0 months, P=0.04), but a shorter post-progression survival (46.5 months vs. not reached, P=0.0001) than those of LTS with mutant IDH. LTS with mutant IDH showed a trend towards increased survival after receiving re-operation (P=0.155) and reirradiation (P=0.127), while this clinical benefit disappeared in the subset of LTS with wildtype IDH (P>0.05).ConclusionThe prognostic value and therapeutic implications associated with LTS in GBM population significantly differed on the basis of IDH status. Our findings provide a new approach for physicians to better understand the two subtypes of GBM, which may assist in making more tailored treatment decisions for patients.

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Temozolomide Induces the Acquisition of Invasive Phenotype by O6-Methylguanine-DNA Methyltransferase (MGMT)+ Glioblastoma Cells in a Snail-1/Cx43-Dependent Manner

International Journal of Molecular Sciences ◽

10.3390/ijms22084150 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4150

Author(s):

Paweł Kochanowski ◽

Jessica Catapano ◽

Maciej Pudełek ◽

Tomasz Wróbel ◽

Zbigniew Madeja ◽

...

Keyword(s):

Dna Methyltransferase ◽

Treatment Result ◽

Dependent Manner ◽

Down Regulation ◽

Cx43 Expression ◽

Cell Lineages ◽

Methylguanine Dna Methyltransferase ◽

U87 Cells ◽

Invasive Cell

Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMTlow (U87) and MGMThigh (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMThigh T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMTlow and MGMThigh cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMThigh T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation.

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Persistent psychological distress in long-term survivors of pediatric sarcoma: the experience at a single institution

Psycho-Oncology ◽

10.1002/pon.1024 ◽

2006 ◽

Vol 15 (10) ◽

pp. 898-910 ◽

Cited By ~ 45

Author(s):

Lori Wiener ◽

Haven Battles ◽

Donna Bernstein ◽

Lauren Long ◽

Joanne Derdak ◽

...

Keyword(s):

Psychological Distress ◽

Single Institution ◽

Pediatric Sarcoma ◽

Long Term Survivors

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Limiting numbers of G156A O6-methylguanine–DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection

Blood ◽

10.1182/blood.v95.10.3078 ◽

2000 ◽

Vol 95 (10) ◽

pp. 3078-3084 ◽

Cited By ~ 93

Author(s):

Brian M. Davis ◽

Omer N. Koç ◽

Stanton L. Gerson

Keyword(s):

Gene Therapy ◽

Dna Methyltransferase ◽

Drug Induced ◽

Methylguanine Dna Methyltransferase ◽

Patients With Cancer ◽

Colony Forming Units ◽

Dominant Selectable Marker ◽

Selection For

Abstract The limited efficacy of hematopoietic gene therapy can be improved by in vivo selection for transduced long-term repopulating cells (LTRC). We selected for G156A MGMT (▵MGMT) transduced LTRC present in 5 × 104 to 100 × 104 marrow cells infused into nonmyeloablated mice by the administration of O6-benzylguanine (BG) and BCNU every 3 to 4 weeks. To facilitate engraftment, mice were given a nonablative dose of BG and BCNU before infusion. Without selection, ▵MGMT was not detected in any hematopoietic colony-forming units (CFU) 24 to 30 weeks after infusion. After BG and BCNU, ▵MGMT+ CFU were frequently detected, and their proportions increased with each treatment cycle. After 2 to 3 cycles of BG and BCNU, many mice were stably reconstituted with 75% to 100% ▵MGMT+ CFU for at least 6 months, representing up to 940-fold enrichment. Thus, BG and BCNU stem cell toxicity allows ▵MGMT-transduced LTRC to repopulate the bone marrow. This degree of selection pressure in nonmyeloablated mice is far greater than that observed in previous drug-resistance gene transfer studies. These data support our approved clinical trial to select for drug-resistant, transduced hematopoietic cells, potentially decreasing cumulative drug-induced myelosuppression in patients with cancer. These data also suggest that ▵MGMT may be a potent, dominant, selectable marker for use in dual gene therapy.

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Temozolomide in the Treatment of Aggressive Pituitary Tumours - An Overview of Existing Knowledge and Future Perspectives

European Neurological Review ◽

10.17925/enr.2012.07.04.228 ◽

2012 ◽

Vol 7 (4) ◽

pp. 228

Author(s):

Ann McCormack ◽

Keyword(s):

Dna Methyltransferase ◽

Treatment Algorithm ◽

Pituitary Tumours ◽

Methylguanine Dna Methyltransferase ◽

Pituitary Tumorigenesis ◽

Significant Efficacy ◽

Primary Determinant ◽

Acth Secreting ◽

Term Data

The management of aggressive pituitary tumours remains a challenge, however, the recent identification of temozolomide as a chemotherapeutic agent with significant efficacy against these tumours has heralded a new therapeutic era. There has been an exponential growth in the international experience with temozolomide over the past five years, now totalling 50 published cases. Overall, 67 % of cases demonstrated a response to temozolomide. Prolactin- and adrenocorticotrophic hormone (ACTH)-secreting tumours respond more frequently than non-functioning tumours. Response is typically evident in the first three months of treatment. Adverse effects occur in almost half of patients, although the majority are mild. The expression of a DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), as determined by immunohistochemistry, appears to be the primary determinant of response to temozolomide in pituitary tumours. There is suggestion that MGMT may also play a role in pituitary tumorigenesis. Over the next few years we will see temozolomide used earlier in the treatment algorithm of aggressive pituitary tumours, making it imperative to collect global long-term data on its use.

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Incidence of non-breast cancer neoplasms (non-BCN) diagnosed prior and subsequent to breast cancer (BC): Single institution experience.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13689 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13689-e13689

Author(s):

Zorica Tomasevic ◽

Zoran Tomasevic ◽

Danica Grujicic ◽

Marina Nikitovic ◽

Zorka Milovanovic

Keyword(s):

Breast Cancer ◽

Medical Records ◽

Genetic Factors ◽

Subsequent Development ◽

Limited Data ◽

Single Institution ◽

Long Term Survivors ◽

Similar Incidence

e13689 Background: The risk for developing subsequent non-BCN in BC patients is recognized as growing problem hence more patients are long term survivors. Limited data are available for non-BCN developed prior to BC. Better defining of types and frequency of non-BCN might be important for recognition of cancer predisposing factors. We aim to evaluate incidence, type, and time of development for all non-BCN in BC patients at the Institute for Oncology and Radiology of Serbia (IORS). Methods: During 2019, 2384 BC patients were seen at the IORS for treatment or follow up, all medical records have been evaluated for potential non-BCN diagnosis. Results: 230 (9.7%) patients also had variety of histologically confirmed non-BCN: in 78 (34%) as prior to BC, median 5 years (1-42); as synchronous with BC in 12 (5%) median 4 months (0 < 12 months) and in 140 (61%) as subsequent to BC, median 8 years (≥1-33). Six most frequent non-BCNs are presented in table. Conclusions: Amongst 230 BC patients 34 different non-BCN were identified. All non-BCNs were more frequently developed subsequently to BC, representing 61% of all non-BCN cases, with expected exception of HL hence 12/13 (92%) occurred prior to BC. EC,TC, OC, CRC and LC, represents 54 % of all non-BCN and were diagnosed more frequently as subsequent to BC while TC had similar incidence as prior and subsequent to BC. Subsequent development might be related solely to genetic factors, but at least in some cases, influence of BC treatment (tamoxifen, cyclophosphamide, radiotherapy) cannot be excluded.[Table: see text]

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Reduced therapy for Wilms' tumor: analysis of treatment results from a single institution.

Journal of Clinical Oncology ◽

10.1200/jco.1988.6.10.1630 ◽

1988 ◽

Vol 6 (10) ◽

pp. 1630-1635 ◽

Cited By ~ 15

Author(s):

J A Wilimas ◽

E C Douglass ◽

S Lewis ◽

D Fairclough ◽

G Fullen ◽

...

Keyword(s):

Wilms Tumor ◽

Survival Rates ◽

Stage Iv ◽

Single Institution ◽

Relapse Free Survival ◽

Free Survival ◽

Favorable Histology ◽

Long Term Survivors ◽

Extent Of Disease

From 1968 to 1986, 192 patients from 0 to 17 years of age were enrolled in three consecutive protocol-controlled studies of Wilms' tumor at St Jude Children's Research Hospital. Tumors were completely excised at the time of diagnosis whenever possible, and patients were subsequently treated with chemotherapy and radiotherapy according to the initial extent of disease. All patients received dactinomycin and vincristine, with doxorubicin added to the regimens in studies 2 and 3. Chemotherapy was extended to 18 months in study 2 (n = 53), but was limited to 12 months for most patients in study 3 (n = 107). In the third study, radiation was eliminated altogether for patients with stage I or II tumors and was reduced to 12 Gy for those with more advanced disease. Intensification of chemotherapy in study 2 improved the 5-year relapse-free survival rate over that in study 1 (82% v 52%), but the accompanying increase in toxicity was considered unacceptable. Comparison of 2-year relapse-free survival rates in studies 2 and 3 indicated that the reduction of therapy in the latter trial did not jeopardize disease control: 88% v 86% for patients with stage II or III disease, favorable histology; 75% v 57% for the same stages, unfavorable histology; and 57% v 61% for stage IV patients. At least 80% of all patients enrolled in study 3 will be long-term survivors. We conclude that rescheduling of effective antitumor drugs and eliminating or reducing radiotherapy are feasible alternatives in the treatment of Wilms' tumor with favorable histologic features.

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Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide

Journal of Clinical Oncology ◽

10.1200/jco.2008.19.2195 ◽

2009 ◽

Vol 27 (8) ◽

pp. 1257-1261 ◽

Cited By ~ 86

Author(s):

Martin Glas ◽

Caroline Happold ◽

Johannes Rieger ◽

Dorothee Wiewrodt ◽

Oliver Bähr ◽

...

Keyword(s):

Survival Data ◽

Dna Methyltransferase ◽

Standard Dose ◽

Standard Group ◽

Newly Diagnosed ◽

Who Grade ◽

Term Survival ◽

Long Term Survival ◽

Methylguanine Dna Methyltransferase

Purpose To evaluate long-term survival in a prospective series of patients newly diagnosed with glioblastoma and treated with a combination of lomustine (CCNU), temozolomide (TMZ), and radiotherapy. Patients and Methods Thirty-nine patients received radiotherapy of the tumor site only (60 Gy) and CCNU/TMZ chemotherapy (n = 31 received standard-dose CCNU, 100 mg/m2 on day 1 and TMZ 100 mg/m2/d on days 2 to 6; n = 8 received intensified-dose CCNU 110 mg/m2 on day 1 and TMZ 150 mg/m2 on days 2 to 6) for up to six courses. Results In the whole cohort, the median overall survival (mOS) was 23.1 months; 47.4% survived for 2 years, and 18.5% survived for 4 years. After a median follow-up of 41.5 months, mOS had not been reached in the intensified group and was significantly higher than in the standard group (22.6 months; P = .024). In the intensified group, four of eight patients survived for at least 56 months, two of them without recurrence. O6-methylguanine–DNA methyltransferase (MGMT) gene promotor methylation in the tumor tissue was associated with significantly longer mOS (methylated, 34.3 months v nonmethylated, 12.5 months). A multivariate Cox proportional hazard model revealed MGMT status (methylated v nonmethylated; relative risk [RR] of death, 0.43; P = .003) and chemotherapy dose (intensified v standard; RR, 0.37; P = .012) as independent prognostic factors. WHO grade 4 hematoxicity was observed more frequently in the intensified group (57% v 16%). Conclusion The combination of radiotherapy, CCNU, and TMZ yielded promising long-term survival data in patients with newly diagnosed glioblastoma. Intensification of CCNU/TMZ chemotherapy may add an additional survival benefit, albeit with greater acute toxicity.

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Temozolomide in the Treatment of Aggressive Pituitary Tumours – An Overview of Existing Knowledge and Future Perspectives

European Endocrinology ◽

10.17925/ee.2012.08.02.116 ◽

2010 ◽

Vol 8 (2) ◽

pp. 116

Author(s):

Ann McCormack ◽

Keyword(s):

Dna Methyltransferase ◽

Treatment Algorithm ◽

Pituitary Tumours ◽

Methylguanine Dna Methyltransferase ◽

Pituitary Tumorigenesis ◽

Significant Efficacy ◽

Primary Determinant ◽

Acth Secreting ◽

Term Data

The management of aggressive pituitary tumours remains a challenge, however, the recent identification of temozolomide as a chemotherapeutic agent with significant efficacy against these tumours has heralded a new therapeutic era. There has been an exponential growth in the international experience with temozolomide over the past five years, now totalling 50 published cases. Overall, 67 % of cases demonstrated a response to temozolomide. Prolactin- and adrenocorticotrophic hormone (ACTH)-secreting tumours respond more frequently than non-functioning tumours. Response is typically evident in the first three months of treatment. Adverse effects occur in almost half of patients, although the majority are mild. The expression of a DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), as determined by immunohistochemistry, appears to be the primary determinant of response to temozolomide in pituitary tumours. There is suggestion that MGMT may also play a role in pituitary tumorigenesis. Over the next few years we will see temozolomide used earlier in the treatment algorithm of aggressive pituitary tumours, making it imperative to collect global long-term data on its use.

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Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina

International Journal of Endocrinology ◽

10.1155/2015/587893 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 20

Author(s):

Oscar D. Bruno ◽

Lea Juárez-Allen ◽

Silvia B. Christiansen ◽

Marcos Manavela ◽

Karina Danilowicz ◽

...

Keyword(s):

Pituitary Adenoma ◽

Dna Methyltransferase ◽

Pituitary Tumors ◽

Cooperative Work ◽

Minimum Time ◽

Cushing's Disease ◽

Nonfunctioning Pituitary Adenoma ◽

Methylguanine Dna Methyltransferase ◽

Small Series

We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34–78 years, presenting aggressive pituitary tumors. In all the patients tested O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140–320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelson’s syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing’s disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on—until now—incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration.

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