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Environmental and Molecular Mutagenesis Jan 2019The utility and sensitivity of the newly developed flow cytometric Pig-a gene mutation assay have become a great concern recently. In this study, we have examined the...
Assessment of the Pig-a, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate.
The utility and sensitivity of the newly developed flow cytometric Pig-a gene mutation assay have become a great concern recently. In this study, we have examined the feasibility of integrating the Pig-a assay as well as micronucleus and Comet endpoints into acute and subchronic general toxicology studies. Male Sprague-Dawley rats were treated for 3 or 28 consecutive days by oral gavage with procarbazine hydrochloride (PCZ) or ethyl carbamate (EC) up to the maximum tolerated dose. The induction of CD59-negative reticulocytes and erythrocytes, micronucleated reticulocytes in peripheral blood, micronucleated polychromatic erythrocytes in bone marrow, and Comet responses in peripheral blood, liver, kidney, and lung were evaluated at one, two, or more timepoints. Both PCZ and EC produced positive responses at most analyzed timepoints in all tissue types, both with the 3-day and 28-day treatment regimens. Furthermore, comparison of the magnitude of the genotoxicity responses indicated that the micronucleus and Comet endpoints generally produced greater responses with the higher dose, short-term treatments in the 3-day study, while the Pig-a assay responded better to the cumulative effects of the lower dose, but repeated subchronic dosing in the 28-day study. Collectively, these results indicate that integration of several in vivo genotoxicity endpoints into a single routine toxicology study is feasible and that the Pig-a assay may be particularly suitable for integration into subchronic dose studies based on its ability to accumulate the mutations that result from repeated treatments. This characteristic may be especially important for assaying lower doses of relatively weak genotoxicants. Environ. Mol. Mutagen. 60:56-71, 2019. © 2018 Wiley Periodicals, Inc.
Topics: Animals; CD59 Antigens; Comet Assay; Erythrocytes; Glycosylphosphatidylinositols; Male; Micronucleus Tests; Mutagens; Procarbazine; Rats; Rats, Sprague-Dawley; Reticulocytes; Urethane
PubMed: 30240497
DOI: 10.1002/em.22227 -
Hematology. American Society of... Dec 2016Long-term survivors of Hodgkin lymphoma (HL) experience several late adverse effects of treatment, with second malignant neoplasms (SMNs) and cardiovascular diseases... (Review)
Review
Long-term survivors of Hodgkin lymphoma (HL) experience several late adverse effects of treatment, with second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) being the leading causes of death in these patients. Other late effects have also been identified, such as pulmonary dysfunction, endocrinopathies (thyroid dysfunction, infertility), neck muscle atrophy, and persistent fatigue. HL survivors have two- to fourfold increased risks to develop SMNs and CVD compared with the general population. With respect to SMNs, radiotherapy is associated with 1.5- to 15-fold increased risk of solid malignancies. The relative risk (RR) of solid tumors increases steadily with increasing follow-up time from 5 to 15 years since radiotherapy, and remains elevated for at least 40 years. The RR of solid SMNs increases strongly with younger age at first treatment. Risks of lung, breast, and gastrointestinal (GI) cancers increase with higher radiation dose. Alkylating agent chemotherapy, especially procarbazine, does not only increase risk of leukemia but also of solid malignancies, in particular, cancers of the lung and GI tract. In contrast, gonadotoxic chemotherapy decreases the risk of radiation-associated breast cancer, through induction of premature menopause. Smoking appears to multiply the radiation- and chemotherapy-associated risks of lung cancer. Both radiotherapy and chemotherapy for HL may cause cardiovascular toxicity. Radiotherapy increases the risk of coronary heart disease, valvular heart disease, congestive heart failure (HF), and pericarditis, whereas anthracycline-containing chemotherapy increases the risks of HF and valvular heart disease. Cardiovascular toxicity following radiotherapy is usually observed from 5 to at least 35 years after therapy, whereas anthracycline-related toxicity is already observed during treatment, up to at least 25 years. The joint effects of anthracyclines, radiotherapy, and conventional cardiovascular risk factors (eg, hypertension, smoking, and physical inactivity) appear to be additive rather than multiplicative. HL survivors need lifelong risk-based screening for selected SMNs and CVDs. Furthermore, preventive strategies should include lifestyle and drug-based interventions to minimize exposure to conventional risk factors for cancer and CVD.
Topics: Age Factors; Cardiovascular Diseases; Hodgkin Disease; Humans; Neoplasms, Second Primary; Risk Factors; Survivors; Time Factors
PubMed: 27913498
DOI: 10.1182/asheducation-2016.1.323 -
Klinicka Onkologie : Casopis Ceske a... 2021Advanced stages of classical Hodgkin lymphoma can be cured by the first-line treatment in 80% of patients. Conventional treatment options include ABVD chemotherapy... (Review)
Review
BACKGROUND
Advanced stages of classical Hodgkin lymphoma can be cured by the first-line treatment in 80% of patients. Conventional treatment options include ABVD chemotherapy (doxorubicin bleomycin, vinblastine, dacarbazine) or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) are commonly used in advanced stages. The result of interim positron emission tomography allows adjustment of the treatment intensity during chemotherapy and this approach can affect the treatment results and toxicity.
PURPOSE
This review summarizes current options of conventional chemotherapy and implementation of brentuximab vedotin and PD-1 inhibitors in combination with chemotherapy into the first-line treatment.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Hodgkin Disease; Humans; Immune Checkpoint Inhibitors; Nivolumab; Positron-Emission Tomography
PubMed: 34911330
DOI: 10.48095/ccko2021450 -
Acta Clinica Croatica Feb 2022Treatment of glioblastoma is challenging due to its aggressive and highly invasive nature, and no significant advances in survival have been achieved recently. The aim...
Treatment of glioblastoma is challenging due to its aggressive and highly invasive nature, and no significant advances in survival have been achieved recently. The aim of our retrospective study was identification of predictive factors and consequent survival outcome in patients who underwent surgical and oncologic treatment of glioblastoma. The study was conducted at the Department of Neurosurgery, Osijek University Hospital Centre. The authors designed a retrospective cohort study in 63 patients who underwent surgical and oncologic treatment between January 1, 2012 and December 31, 2017. Data were collected by reviewing medical records of the patients with histologically proven glioblastoma. Statistical analysis of study results revealed a significant impact of postoperative radiotherapy (p=0.002) and chemotherapy (p=0.016) on progression-free survival and overall survival (p=0.001 and p=0.009, respectively). Postoperative Karnofsky performance scale (p=0.027) was found to be significant in progression-free survival, and so was the interval between surgery and commencement of oncologic therapy (p=0.049). In conclusion, overall survival and prognosis in the treatment of glioblastoma remain poor, although prompt approach in postoperative adjuvant treatments improved progression-free survival.
Topics: Brain Neoplasms; Glioblastoma; Humans; Neurosurgical Procedures; Prognosis; Retrospective Studies
PubMed: 35282478
DOI: 10.20471/acc.2021.60.03.06 -
DNA Repair Jun 2019Alkylating agents have been used since the 60ties in brain cancer chemotherapy. Their target is the DNA and, although the DNA of normal and cancer cells is damaged... (Review)
Review
Alkylating agents have been used since the 60ties in brain cancer chemotherapy. Their target is the DNA and, although the DNA of normal and cancer cells is damaged unselectively, they exert tumor-specific killing effects because of downregulation of some DNA repair activities in cancer cells. Agents exhibiting methylating properties (temozolomide, procarbazine, dacarbazine, streptozotocine) induce at least 12 different DNA lesions. These are repaired by damage reversal mechanisms involving the alkyltransferase MGMT and the alkB homologous protein ALKBH2, and through base excision repair (BER). There is a strong correlation between the MGMT expression level and therapeutic response in high-grade malignant glioma, supporting the notion that O-methylguanine and, for nitrosoureas, O-chloroethylguanine are the most relevant toxic damages at therapeutically relevant doses. Since MGMT has a significant impact on the outcome of anti-cancer therapy, it is a predictive marker of the effectiveness of methylating anticancer drugs, and clinical trials are underway aimed at assessing the influence of MGMT inhibition on the therapeutic success. Other DNA repair factors involved in methylating drug resistance are mismatch repair, DNA double-strand break (DSB) repair by homologous recombination (HR) and DSB signaling. Base excision repair and ALKBH2 might also contribute to alkylating drug resistance and their downregulation may have an impact on drug sensitivity notably in cells expressing a high amount of MGMT and at high doses of temozolomide, but the importance in a therapeutic setting remains to be shown. MGMT is frequently downregulated in cancer cells (up to 40% in glioblastomas), which is due to CpG promoter methylation. Astrocytoma (grade III) are frequently mutated in isocitrate dehydrogenase (IDH1). These tumors show a surprisingly good therapeutic response. IDH1 mutation has an impact on ALKBH2 activity thus influencing DNA repair. A master switch between survival and death is p53, which often retains transactivation activity (wildtype) in malignant glioma. The role of p53 in regulating survival via DNA repair and the routes of death are discussed and conclusions as to cancer therapeutic options were drawn.
Topics: Brain Neoplasms; Cell Death; DNA Repair; Humans; Nitrosourea Compounds; Precision Medicine; Temozolomide
PubMed: 31039537
DOI: 10.1016/j.dnarep.2019.04.007 -
Journal of Clinical Oncology : Official... Apr 2022The AHL2011 study (ClinicalTrials.gov identifier: NCT01358747) demonstrated that a positron emission tomography (PET)-driven de-escalation strategy after two cycles of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The AHL2011 study (ClinicalTrials.gov identifier: NCT01358747) demonstrated that a positron emission tomography (PET)-driven de-escalation strategy after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) provides similar progression-free survival (PFS) and overall survival (OS) and reduces early toxicity compared with a nonmonitored standard treatment. Here, we report, with a prolonged follow-up, the final study results.
METHODS
Patients with advanced Hodgkin lymphoma (stage III, IV, or IIB with mediastinum/thorax ratio > 0.33 or extranodal involvement) age 16-60 years were prospectively randomly assigned between 6 × BEACOPP and a PET-driven arm after 2 × BEACOPP delivering 4 × ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in PET2- and 4 × BEACOPP in PET2+ patients. PET performed after four cycles of chemotherapy had to be negative to complete the planned treatment.
RESULTS
In total, 823 patients were enrolled including 413 in the standard arm and 410 in the PET-driven arm. With a 67.2-month median follow-up, 5-year PFS (87.5% 86.7%; hazard ratio [HR] = 1.07; 95% CI, 0.74 to 1.57; = .67) and OS (97.7% in both arms; HR = 1.012; 95% CI, 0.50 to 2.10; = .53) were similar in both randomization arms. In the whole cohort, full interim PET assessment predicted patients' 5-year PFS (92.3% in PET2-/PET4-, 75.4% [HR = 3.26; 95% CI, 18.3 to 5.77] in PET2+/PET4- and 46.5% [HR = 12.4; 95% CI, 7.31 to 19.51] in PET4+ patients, respectively; < .0001) independent of international prognosis score. Five-year OS was also affected by interim PET results, and PET2+/PET4- patients (93.5%; HR = 3.3; 95% CI, 1.07 to 10.1; = .036) and PET4+ patients (91.9%; HR = 3.756; 95% CI, 1.07 to 13.18; = .038) had a significant lower OS than PET2-/PET4- patients (98.2%). Twenty-two patients (2.7%) developed a second primary malignancy, 13 (3.2%) and 9 (2.2%) in the standard and experimental arms, respectively.
CONCLUSION
The extended follow-up confirms the continued efficacy and favorable safety of AHL2011 PET-driven strategy, which is noninferior to standard six cycles of BEACOPP. PET4 provides additional prognostic information to PET2 and allows identifying patients with particularly poor prognosis.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dacarbazine; Doxorubicin; Etoposide; Follow-Up Studies; Hodgkin Disease; Humans; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Positron-Emission Tomography; Prednisone; Procarbazine; Vinblastine; Vincristine; Young Adult
PubMed: 34990281
DOI: 10.1200/JCO.21.01777 -
Turkish Neurosurgery 2017Malignant glioma is the most common primary brain tumor in adults and the survival rate has remained very low. Thus, determining the optimal treatment for patients can... (Meta-Analysis)
Meta-Analysis Review
AIM
Malignant glioma is the most common primary brain tumor in adults and the survival rate has remained very low. Thus, determining the optimal treatment for patients can be challenging. To compare the efficacy of common therapies, we performed network meta-analysis to estimate the efficacy and safety among procarbazine, lomustine, vincristine, temozolomide, bevacizumab plus temozolomide, and placebo for patients with malignant glioma.
MATERIAL AND METHODS
Relevant studies (as of March, 2014) were identified by searching PubMed, Embase, and Central databases. The primary endpoint of the analysis was the overall survival (OS) and progression-free survival (PFS) of glioma patients.
RESULTS
Nine trials with a total of 3472 patients were included in our network meta-analyses. Compared with placebo, bevacizumab plus temozolomide was associated with the highest estimates of OS and PFS for 12 and 24 months (12 month OS odds ratio [OR]: 2.44; 95% credibility interval [CrIs]: 0.76-9.69; 24 month OS OR: 2.56; 95% CrIs: 1.12?5.24; 12 month PFS OR: 6.76; 95% CrIs: 2.80?17.34; 24 month PFS OR: 3.69; 95% CrIs: 0.62?28.63). However, bevacizumab plus temozolomide did not significantly improve OS or PFS compared to temozolomide alone.
CONCLUSION
Bevacizumab plus temozolomide combination therapy is not significantly more effective than temozolomide alone in improving survival of glioma patients. Moreover, bevacizumab was associated with higher hematologic toxicities. Bevacizumab should be used with caution in glioma patients. Additional randomized controlled trials are required to confirm this finding.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Disease-Free Survival; Glioma; Humans; Network Meta-Analysis
PubMed: 27337236
DOI: 10.5137/1019-5149.JTN.15462-15.0 -
Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV.Cancer Medicine Jan 2020The majority of patients with high-risk lower grade gliomas (LGG) are treated with single-agent temozolomide (TMZ) and radiotherapy despite three randomized trials... (Review)
Review
PURPOSE
The majority of patients with high-risk lower grade gliomas (LGG) are treated with single-agent temozolomide (TMZ) and radiotherapy despite three randomized trials showing a striking overall survival benefit with adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy and radiotherapy. This article aims to evaluate the evidence and rationale for the widespread use of TMZ instead of PCV for high-risk LGG.
METHODS AND MATERIALS
We conducted a literature search utilizing PubMed for articles investigating the combination of radiotherapy and chemotherapy for high-risk LGG and analyzed the results of these studies.
RESULTS
For patients with IDH mutant 1p/19q codeleted LGG tumors, there is limited evidence to support the use of TMZ. In medically fit patients with codeleted disease, existing data demonstrate a large survival benefit for PCV as compared to adjuvant radiation therapy alone. For patients with non-1p/19q codeleted LGG, early data from the CATNON study supports inclusion of adjuvant TMZ for 12 months. Subset analyses of the RTOG 9402 and EORTC 26951 do not demonstrate a survival benefit for adjuvant PCV for non-1p/19q codeleted gliomas, however secondary analyses of RTOG 9802 and RTOG 9402 demonstrated survival benefit in any IDH mutant lower grade gliomas, regardless of 1p/19q codeletion status.
CONCLUSIONS
At present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high-risk LGG, and we instead recommend tailoring chemotherapy recommendation based on IDH status, favoring adjuvant PCV for patients with any IDH mutant tumors, both those that harbor 1p/19q codeletion and those non-1p/19q codeleted. Given the critical role radiation plays in the treatment of LGG, radiation oncologists should be actively involved in discussions regarding chemotherapy choice in order to optimize treatment for their patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Chemoradiotherapy, Adjuvant; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Glioma; Humans; Isocitrate Dehydrogenase; Lomustine; Mutation; Neoplasm Grading; Procarbazine; Progression-Free Survival; Randomized Controlled Trials as Topic; Temozolomide; Vincristine
PubMed: 31701682
DOI: 10.1002/cam4.2686 -
Acta Neuropathologica Communications Mar 2017Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors....
Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.
Topics: Adult; Aged; Biomarkers, Tumor; Brain Neoplasms; Cohort Studies; DNA Methylation; Epigenesis, Genetic; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Recurrence, Local; Oligodendroglioma; Young Adult
PubMed: 28270234
DOI: 10.1186/s40478-017-0422-z -
Advances in Pharmacology (San Diego,... 2015The purpose of this chapter is to provide insight into which human cytochromes P450 (CYPs) may be involved in metabolism of chemical carcinogens and anticancer drugs. A... (Review)
Review
The purpose of this chapter is to provide insight into which human cytochromes P450 (CYPs) may be involved in metabolism of chemical carcinogens and anticancer drugs. A historical overview of this field and the development of literature using relevant animal models and expressed human CYPs have provided information about which specific CYPs may be involved in carcinogen metabolism. Definition of the biochemical properties of CYP activity came from several groups who studied the reaction stoichiometry of butter yellow and benzo[α]pyrene, including their role in induction of these enzyme systems. This chapter will list as much as is known about the human CYPs involved in carcinogen and anticancer drug metabolism, as well as summarize studies with rodent CYPs. A review of three major classes of anticancer drugs and their metabolism in humans is covered for cyclophosphamide, procarbazine, and anthracycline antibiotics, cancer chemotherapeutic compounds extensively metabolized by CYPs. The emerging information about human CYP gene polymorphisms as well as other enzymes involved in foreign compound metabolism provides considerable information about how these genetic variants affect carcinogen and anticancer drug metabolism. With information available from individual's genomic sequences, consideration of populations who may be at risk due to environmental exposure to carcinogens or how to optimize their cancer therapy regimens to enhance efficacy of the anticancer drugs appears to be an important field of study to benefit individuals in the future.
Topics: Animals; Antineoplastic Agents; Carcinogens; Cytochrome P-450 Enzyme System; Humans; Polymorphism, Genetic
PubMed: 26233902
DOI: 10.1016/bs.apha.2015.04.004