The Experts below are selected from a list of 24303 Experts worldwide ranked by ideXlab platform
Jan Sundquist - One of the best experts on this subject based on the ideXlab platform.
-
risk of somatic diseases in offspring of survivors with childhood or adolescent central Nervous System Tumor in sweden
International Journal of Cancer, 2021Co-Authors: Wuqing Huang, Kristina Sundquist, Jan SundquistAbstract:With the improvement of treatments, a growing number of survivors with childhood or adolescent central Nervous System (CNS) Tumor are parenting their own children. We aimed to explore the risk of somatic diseases among children of these survivors compared to population controls. Children of survivors with CNS Tumor below age of 20 were identified between 1973 and 2014 by combining the several Swedish registers. Five children without parental CNS Tumor were matched randomly to generate the population comparisons. Relative risk (RR) and absolute excess risk (AER) were calculated for overall somatic diseases, and hazard ratio (HR) was calculated for specific type of somatic diseases. A total of 2231 somatic disease diagnoses were identified in children of survivors with a cumulative incidence rate of 94.77 per 1000 person-years, whereas the rate was 92.79 in matched comparisons thus resulting in an overall RR of 1.02 (95% CI = 0.98-1.07) and AER of 1.98 (95% CI = -2.06, 6.13). Specifically, five of 1364 children of survivors had CNS Tumor with an incidence rate of 0.21 per 1000 person-year, whereas the rate was 0.04 in children of matched children, generating a HR of 4.91 (95% CI = 1.42-16.96). Children of male survivors were at a statistically increased risk of malignancy, as well as infectious and parasitic diseases. In conclusion, no significantly higher risk of overall somatic diseases was found in children of survivors with CNS Tumor before the age of 20, but children with a paternal diagnosis of CNS Tumor had significantly increased risk of malignancies and infectious and parasitic diseases.
-
psychiatric disorders in offspring of childhood or adolescent central Nervous System Tumor survivors a national cohort study
Cancer Medicine, 2020Co-Authors: Wuqing Huang, Kristina Sundquist, Jan SundquistAbstract:BACKGROUND: Children experience a higher risk of psychiatric problems when their parents are diagnosed with cancer. However, the psychological effect among offspring who are born after parental cancer diagnosed in childhood or adolescence is unknown. We aimed to investigate the risk of psychiatric disorders in children of survivors with childhood or adolescent central Nervous System (CNS) Tumors.METHODS: By combining several nationwide Swedish registers, we identified all children who had at least one parent previously diagnosed with CNS Tumor below the age of 20. Five children without parental CNS Tumor were randomly selected for the matching. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence interval (CI).RESULTS: The incidence rate of psychiatric disorders was 8.46 per 1000 person-years in children of CNS Tumor survivors, whereas the rate was 7.47 in the matched comparisons, yielding an adjusted HR of 1.10 (95% CI = 0.94, 1.28). Boys of survivors had a higher risk of psychiatric disorders (adjusted HR = 1.29, 95% CI = 1.04, 1.59). The risk of the specific types of psychiatric disorders in children of Tumor survivors was comparable with that in the matched comparisons, except for mental retardation. Children of survivors experienced 2.36 times higher risk of mental retardation (95% CI = 1.21, 4.58), mainly of mild mental retardation (adjusted HR = 2.99, 95% CI = 1.40, 6.38).CONCLUSION: Children of survivors with CNS Tumor in early life did not experience a significantly increased risk of overall psychiatric disorders, with the exception of an elevated risk of mental retardation that was mainly mild. (Less)
-
risk of being born preterm in offspring of survivors with childhood or adolescent central Nervous System Tumor in sweden
International Journal of Cancer, 2020Co-Authors: Wuqing Huang, Kristina Sundquist, Jan Sundquist, Casey CrumpAbstract:An increasing number of patients with central Nervous System (CNS) Tumor could survive to reproductive age. However, it is largely unknown whether the history of CNS Tumor might affect pregnancy outcome. We aimed to explore the risk of being born preterm among children of CNS Tumor survivors. By linking several nationwide registers in Sweden, we identified 1,369 children whose parents were childhood or adolescent CNS Tumor survivors. Children whose parents did not have CNS Tumor were matched randomly with a 5:1 ratio to generate the reference group. Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI). The prevalence of preterm birth (PTB) was 6.9% among children of survivors with CNS Tumor and 5.2% among the matched controls. Children of survivors had an increased risk of PTB (adjusted OR = 1.29, 95%CI 1.01-1.65) compared to the matched controls. This risk was increased specifically among offspring of those diagnosed in childhood (adjusted OR = 1.53, 95%CI 1.14-2.06) but not adolescence (adjusted OR = 0.89, 95%CI 0.56-1.41). For families with more than one child, the risk was slightly lower among the second child as compared to the first child. The risk was negatively associated with time interval between parental diagnosis and childbirth. Parental medulloblastoma and ependymoma were most strongly associated with a higher risk of PTB. Children of survivors with CNS Tumor experienced an elevated risk of PTB. However, the risk diminishes gradually after parental diagnosis of CNS Tumor. Offspring of childhood CNS Tumor survivors and medulloblastoma or ependymoma survivors may have the highest risk of PTB.
Kristina Sundquist - One of the best experts on this subject based on the ideXlab platform.
-
risk of somatic diseases in offspring of survivors with childhood or adolescent central Nervous System Tumor in sweden
International Journal of Cancer, 2021Co-Authors: Wuqing Huang, Kristina Sundquist, Jan SundquistAbstract:With the improvement of treatments, a growing number of survivors with childhood or adolescent central Nervous System (CNS) Tumor are parenting their own children. We aimed to explore the risk of somatic diseases among children of these survivors compared to population controls. Children of survivors with CNS Tumor below age of 20 were identified between 1973 and 2014 by combining the several Swedish registers. Five children without parental CNS Tumor were matched randomly to generate the population comparisons. Relative risk (RR) and absolute excess risk (AER) were calculated for overall somatic diseases, and hazard ratio (HR) was calculated for specific type of somatic diseases. A total of 2231 somatic disease diagnoses were identified in children of survivors with a cumulative incidence rate of 94.77 per 1000 person-years, whereas the rate was 92.79 in matched comparisons thus resulting in an overall RR of 1.02 (95% CI = 0.98-1.07) and AER of 1.98 (95% CI = -2.06, 6.13). Specifically, five of 1364 children of survivors had CNS Tumor with an incidence rate of 0.21 per 1000 person-year, whereas the rate was 0.04 in children of matched children, generating a HR of 4.91 (95% CI = 1.42-16.96). Children of male survivors were at a statistically increased risk of malignancy, as well as infectious and parasitic diseases. In conclusion, no significantly higher risk of overall somatic diseases was found in children of survivors with CNS Tumor before the age of 20, but children with a paternal diagnosis of CNS Tumor had significantly increased risk of malignancies and infectious and parasitic diseases.
-
psychiatric disorders in offspring of childhood or adolescent central Nervous System Tumor survivors a national cohort study
Cancer Medicine, 2020Co-Authors: Wuqing Huang, Kristina Sundquist, Jan SundquistAbstract:BACKGROUND: Children experience a higher risk of psychiatric problems when their parents are diagnosed with cancer. However, the psychological effect among offspring who are born after parental cancer diagnosed in childhood or adolescence is unknown. We aimed to investigate the risk of psychiatric disorders in children of survivors with childhood or adolescent central Nervous System (CNS) Tumors.METHODS: By combining several nationwide Swedish registers, we identified all children who had at least one parent previously diagnosed with CNS Tumor below the age of 20. Five children without parental CNS Tumor were randomly selected for the matching. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence interval (CI).RESULTS: The incidence rate of psychiatric disorders was 8.46 per 1000 person-years in children of CNS Tumor survivors, whereas the rate was 7.47 in the matched comparisons, yielding an adjusted HR of 1.10 (95% CI = 0.94, 1.28). Boys of survivors had a higher risk of psychiatric disorders (adjusted HR = 1.29, 95% CI = 1.04, 1.59). The risk of the specific types of psychiatric disorders in children of Tumor survivors was comparable with that in the matched comparisons, except for mental retardation. Children of survivors experienced 2.36 times higher risk of mental retardation (95% CI = 1.21, 4.58), mainly of mild mental retardation (adjusted HR = 2.99, 95% CI = 1.40, 6.38).CONCLUSION: Children of survivors with CNS Tumor in early life did not experience a significantly increased risk of overall psychiatric disorders, with the exception of an elevated risk of mental retardation that was mainly mild. (Less)
-
risk of being born preterm in offspring of survivors with childhood or adolescent central Nervous System Tumor in sweden
International Journal of Cancer, 2020Co-Authors: Wuqing Huang, Kristina Sundquist, Jan Sundquist, Casey CrumpAbstract:An increasing number of patients with central Nervous System (CNS) Tumor could survive to reproductive age. However, it is largely unknown whether the history of CNS Tumor might affect pregnancy outcome. We aimed to explore the risk of being born preterm among children of CNS Tumor survivors. By linking several nationwide registers in Sweden, we identified 1,369 children whose parents were childhood or adolescent CNS Tumor survivors. Children whose parents did not have CNS Tumor were matched randomly with a 5:1 ratio to generate the reference group. Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI). The prevalence of preterm birth (PTB) was 6.9% among children of survivors with CNS Tumor and 5.2% among the matched controls. Children of survivors had an increased risk of PTB (adjusted OR = 1.29, 95%CI 1.01-1.65) compared to the matched controls. This risk was increased specifically among offspring of those diagnosed in childhood (adjusted OR = 1.53, 95%CI 1.14-2.06) but not adolescence (adjusted OR = 0.89, 95%CI 0.56-1.41). For families with more than one child, the risk was slightly lower among the second child as compared to the first child. The risk was negatively associated with time interval between parental diagnosis and childbirth. Parental medulloblastoma and ependymoma were most strongly associated with a higher risk of PTB. Children of survivors with CNS Tumor experienced an elevated risk of PTB. However, the risk diminishes gradually after parental diagnosis of CNS Tumor. Offspring of childhood CNS Tumor survivors and medulloblastoma or ependymoma survivors may have the highest risk of PTB.
Daniel J Brat - One of the best experts on this subject based on the ideXlab platform.
-
relative survival after diagnosis with a primary brain or other central Nervous System Tumor in the national program of cancer registries 2004 to 2014
Neuro-Oncology Practice, 2020Co-Authors: Quinn T Ostrom, Daniel J Brat, Haley Gittleman, Gabrielle Truitt, Carol Kruchko, Reda J Wilson, Jill S BarnholtzsloanAbstract:Background The majority of reported cancer survival statistics in the United States are generated using the National Cancer Institute's publicly available Surveillance, Epidemiology, and End Results (SEER) data, which prior to 2019 represented 28% of the US population (now 37%). In the case of rare cancers or special subpopulations, data sets based on a larger portion of the US population may contribute new insights into these low-incidence cancers. The purpose of this study is to characterize the histology-specific survival patterns for all primary malignant and nonmalignant primary brain Tumors in the United States using the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR). Methods Survival data were obtained from the NPCR (includes data from 39 state cancer registries, representing 81% of the US population). Relative survival rates (RS) with 95% CI were generated using SEER*Stat 8.3.5 from 2004 to 2014 by behavior, histology, sex, race/ethnicity, and age at diagnosis. Results Overall, there were 488 314 cases from 2004 to 2014. Overall 5-year RS was 69.8% (95% CI = 69.6%-69.9%). Five-year RS was 35.9% (95% CI = 35.6%-36.1%) for malignant and 90.2% (95% CI = 90.1%-90.4%) for nonmalignant Tumors. Pilocytic astrocytoma had the longest 5-year RS (94.2%, 95% CI = 93.6%-94.6%) of all glioma subtypes, whereas glioblastoma had the shortest 5-year RS (6.1%, 95% CI = 6.0%-6.3%). Nonmalignant nerve sheath Tumors had the longest 5-year RS (99.3%, 95% CI = 99.1%-99.4%). Younger age and female sex were associated with increased survival for many histologies. Conclusions Survival after diagnosis with primary brain Tumor varies by behavior, histology, and age. Using such a database that includes more than 80% of the US population may represent national survival patterns.
-
what every neuropathologist needs to know update on cimpact now
Journal of Neuropathology and Experimental Neurology, 2019Co-Authors: Gabrielle Yeaney, Daniel J BratAbstract:: World Health Organization (WHO) central Nervous System Tumor classification represents the primary source of updates on diagnostic classes, grades, and criteria. However, recent and ongoing advances in molecular pathogenesis warrant more rapid integration into clinical practice between WHO updates. To accomplish this, the consortium to inform molecular and practical approaches to CNS Tumor taxonomy-not official WHO (cIMPACT-NOW) was established in 2016. Since then, cIMPACT-NOW has convened 3 separate working committees to address classification and grading questions and challenges. This review covers the progress that these working committees have made on their specific topics.
-
cimpact now the consortium to inform molecular and practical approaches to cns Tumor taxonomy a new initiative in advancing Nervous System Tumor classification
Brain Pathology, 2017Co-Authors: David N Louis, Daniel J Brat, David W Ellison, David Capper, Werner Paulus, Kenneth D Aldape, Guido Reifenberger, Arie Perry, Cynthia Hawkins, Dominique FigarellabrangerAbstract:The 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) is a major shift in the way neuropathologists analyze and diagnose brain Tumors as it incorporates molecular and histological information together to define many entities (1). While the 2016 CNS WHO thereby facilitates more precise diagnosis of well-understood entities and clearer designation of less-understood entities, it also presents a number of practical challenges for neuropathologists, requiring substantial shifts in their day-to-day practices (2). Nonetheless, neuropathologiste will learn the System readily over time, and will adapt as needed to the new requirements.
-
international society of neuropathology haarlem consensus guidelines for Nervous System Tumor classification and grading
Brain Pathology, 2014Co-Authors: David N Louis, Daniel J Brat, David W Ellison, Kenneth D Aldape, Guido Reifenberger, Arie Perry, Peter V Collins, Peter C Burger, Andreas Von Deimling, Charles G EberhartAbstract:Major discoveries in the biology of Nervous System Tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central Nervous System Tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each Tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding Tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central Nervous System Tumors.
Gareth D Evans - One of the best experts on this subject based on the ideXlab platform.
-
cancer and central Nervous System Tumor surveillance in pediatric neurofibromatosis 2 and related disorders
Clinical Cancer Research, 2017Co-Authors: Vivian Y. Chang, Gareth D Evans, Hector Salvador, Ayelet Erez, Stephan D Voss, Harriet Druker, Hamish S Scott, Uri TaboriAbstract:The neurofibromatoses consist of at least three autosomal-dominant inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. For over 80 years, these conditions were inextricably tied together under generalized neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis. The last 26 years have seen a great improvement in understanding of the clinical and molecular features of these conditions as well as insights into management. Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multiTumor disease course. Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central Nervous System (CNS) Tumors necessitating MRI surveillance to optimize management. At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic. Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of Tumor involvement. The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath Tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition. Clin Cancer Res; 23(12); e54-e61. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
-
cancer and central Nervous System Tumor surveillance in pediatric neurofibromatosis 1
Clinical Cancer Research, 2017Co-Authors: Vivian Y. Chang, Gareth D Evans, Hector Salvador, Ayelet Erez, Stephan D Voss, Hamish S Scott, Kami Wolfe Schneider, Sharon E Plon, Uri TaboriAbstract:Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multiSystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath Tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks ( See all articles in the online-only CCR Pediatric Oncology Series.
-
cancer and central Nervous System Tumor surveillance in pediatric neurofibromatosis 1
Clinical Cancer Research, 2017Co-Authors: Vivian Y. Chang, Gareth D Evans, Hector Salvador, Ayelet Erez, Stephan D Voss, Hamish S Scott, Kami Wolfe Schneider, Sharon E Plon, Uri TaboriAbstract:Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multiSystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath Tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46-e53. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
-
second primary Tumors in neurofibromatosis 1 patients treated for optic glioma substantial risks after radiotherapy
Journal of Clinical Oncology, 2006Co-Authors: Saba Sharif, Rosalie E Ferner, Jillian M Birch, James E Gillespie, Rao H Gattamaneni, Michael E Baser, Gareth D EvansAbstract:Purpose Optic pathway gliomas (OPGs) are the most common CNS Tumor in neurofibromatosis 1 (NF1) patients. We evaluated the long-term risk of second Tumors in NF1-related OPGs after radiotherapy. Patients and Methods We reviewed 80 NF1 OPG patients from two NF1 clinics to evaluate the long-term risk of developing subsequent Nervous System Tumors, with or without radiotherapy. Results Fifty-eight patients were assessable for second Tumors. Nine (50%) of 18 patients who received radiotherapy after their OPGs developed 12 second Tumors in 308 person-years of follow-up after radiotherapy. Eight (20%) of 40 patients who were not treated with radiotherapy developed nine Tumors in 721 person-years of follow-up after diagnosis of their OPGs. The relative risk of second Nervous System Tumor after radiotherapy was 3.04 (95% CI, 1.29 to 7.15). Conclusion There is a significantly increased risk of second Nervous System Tumors in those NF1 patients who received radiotherapy for their OPGs, especially when treated in ch...
Henry S Friedman - One of the best experts on this subject based on the ideXlab platform.
-
schedule dependent activity of temozolomide plus cpt 11 against a human central Nervous System Tumor derived xenograft
Clinical Cancer Research, 2000Co-Authors: Vikas J Patel, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Anthony E Pegg, Stewart P Johnson, Eileen M Dolan, Darell D Bigner, Henry S FriedmanAbstract:Temozolomide, an imidazole tetrazinone, and CPT-11, a camptothecin derivative, have previously been shown to have anti-central Nervous System Tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of temozolomide plus CPT-11 displays a schedule-dependent enhancement of antiTumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.
-
enhancement of irinotecan cpt 11 activity against central Nervous System Tumor xenografts by alkylating agents
Cancer Chemotherapy and Pharmacology, 1998Co-Authors: C A Coggins, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Darell D Bigner, C B Hare, O M Colvin, Henry S FriedmanAbstract:Two major obstacles in the treatment of patients with central Nervous System malignancies are drug resistance and host toxicity. The goal of combination chemotherapy is to achieve therapeutic effects that are more favorable than using a single drug alone, but without an increase in normal organ toxicity. The study reported here examined the combination of a topoisomerase I inhibitor, irinotecan (CPT-11), with three different alkylating agents: 1,3-bis(2-chloroethyl)-1-nitrosourea, busulfan, and cyclophosphamide. We evaluated the antiTumor effects of these three combinations against a panel of human Tumor xenografts derived from central Nervous System malignancies, including adult high-grade gliomas (D-54 MG, D-245 MG) and a childhood ependymoma (D-612 EP). In replicate experiments, the alkylating agents were given on day 1 in doses varying from 10% to 75% of the dose lethal to 10% of the animals, and CPT-11 was given on days 1-5 and 8-12 in doses varying from 10% to 100% of the dose lethal to 10% of the animals. The antiTumor effects of the various combinations ranged from less than additive (7.61 days below additive with 0.5 CPT-11 + 0.75 cyclophosphamide in D-54 MG) to statistically significant (P < 0.001) supraadditive effects (18.80 days above additive with 0.5 CPT-11 + 0.5 1,3-bis(2-chloroethyl)-1-nitrosourea in D-54 MG). These studies show that the combination of the topoisomerase inhibitor CPT-11 and alkylating agents may increase the antiTumor effect in some cases well above additive with no increase in host toxicity (0/10 deaths in both experiments cited above) and should be considered for combination chemotherapy of central Nervous System malignancies.
-
therapeutic efficacy of the topoisomerase i inhibitor 7 ethyl 10 4 1 piperidino 1 piperidino carbonyloxy camptothecin against pediatric and adult central Nervous System Tumor xenografts
Cancer Chemotherapy and Pharmacology, 1996Co-Authors: Bradley C Hare, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Darell D Bigner, Susan Marcelli, Janet A Houghton, Henry S FriedmanAbstract:Therapy of patients with malignant central Nervous System Tumors is frequently unsuccessful, reflecting limitations of current surgical, radiotherapeutic, and pharmacotherapeutic treatments. The camptothecin derivative irinotecan (CPT-11) has been shown to possess antiTumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, colon, or rectum and for patients with non-Hodgkin’s lymphoma. The current study was designed to test the efficacy of the drug against a panel of human Tumor xenografts derived from adult and pediatric central Nervous System malignancies. Tumors included childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP, D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), growing subcutaneously and intracranially in athymic nude mice. In replicate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose via intraperitoneal injection in 10% dimethylsulfoxide on days 1–5 and 8–12, which is the dosage lethal to 10% of treated animals. CPT-11 produced statistically significant (P<0.001) growth delays in all subcutaneous xenografts tested, including those resistant to busulfan, cyclophosphamide, procarbazine, and melphalan, with growth delays ranging from 21.3 days in D487 Med to 90+ days in several Tumor lines. Further, Tumor regression was evident in every treated animal bearing a subcutaneous Tumor, with some xenografts yielding complete Tumor regression. Statistically significant (P<0.001) increases in survival were demonstrated in the two intracranial xenografts – D341 EP (73.0% increase) and D-456 MG (114.2% increase) – treated with CPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-11 is the most active against central Nervous System xenografts and should be advanced to clinical trial as soon as possible.
-
activity of temozolomide in the treatment of central Nervous System Tumor xenografts
Cancer Research, 1995Co-Authors: Henry S Friedman, Stephen T Keir, Anthony E Pegg, Eileen M Dolan, Darell D Bigner, Susan Marcelli, Joseph J Catino, Clifford S ScholdAbstract:Abstract The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial Tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 1,3-bis(2-chloroethyl)-1-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8–7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from -3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central Nervous System cancers, including Mer+ Tumors resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea.