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Environmental and Molecular Mutagenesis Jul 2019Procarbazine hydrochloride (PCH) is a DNA-reactive hematopoietic carcinogen with potent and well-characterized clastogenic activity. However, there is a paucity of in...
Integrated In Vivo Genotoxicity Assessment of Procarbazine Hydrochloride Demonstrates Induction of Pig-a and LacZ Mutations, and Micronuclei, in MutaMouse Hematopoietic Cells.
Procarbazine hydrochloride (PCH) is a DNA-reactive hematopoietic carcinogen with potent and well-characterized clastogenic activity. However, there is a paucity of in vivo mutagenesis data for PCH, and in vitro assays often fail to detect the genotoxic effects of PCH due to the complexity of its metabolic activation. We comprehensively evaluated the in vivo genotoxicity of PCH on hematopoietic cells of male MutaMouse transgenic rodents using a study design that facilitated assessments of micronuclei and Pig-a mutation in circulating erythrocytes, and lacZ mutant frequencies in bone marrow. Mice were orally exposed to PCH (0, 6.25, 12.5, and 25 mg/kg/day) for 28 consecutive days. Blood samples collected 2 days after cessation of treatment exhibited significant dose-related induction of micronuclei in both immature and mature erythrocytes. Bone marrow and blood collected 3 and 70 days after cessation of treatment also showed significantly elevated mutant frequencies in both the lacZ and Pig-a assays even at the lowest dose tested. PCH-induced lacZ and Pig-a (immature and mature erythrocytes) mutant frequencies were highly correlated, with R values ≥0.956, with the exception of lacZ vs. Pig-a mutants in mature erythrocytes at the 70-day time point (R = 0.902). These results show that PCH is genotoxic in vivo and demonstrate that the complex metabolism and resulting genotoxicity of PCH is best evaluated in intact animal models. Our results further support the concept that multiple biomarkers of genotoxicity, especially hematopoietic cell genotoxicity, can be readily combined into one study provided that adequate attention is given to manifestation times. Environ. Mol. Mutagen. 60:505-512, 2019. © 2018 Her Majesty the Queen in Right of Canada.
Topics: Animals; Carcinogens; Cell Nucleus; DNA Damage; Erythrocytes; Hematopoietic Stem Cells; Lac Operon; Male; Mice; Micronucleus Tests; Mutagenesis; Mutagenicity Tests; Mutagens; Mutation; Procarbazine; Reticulocytes
PubMed: 30592561
DOI: 10.1002/em.22271 -
Cureus Oct 2020Background The role of Procarbazine Lomustine and Vincristine (PCV) chemotherapy is already established in terms of improving survival in low-grade glioma (LGG). This...
Background The role of Procarbazine Lomustine and Vincristine (PCV) chemotherapy is already established in terms of improving survival in low-grade glioma (LGG). This improved survival has led to the increasing administration of PCV to LGG patients over the past years. However, like other chemotherapies, serious hematological and non-hematological toxicities may occur. The purpose of this study was to evaluate the toxicity profile of PCV and its clinical relevance in our practice. Materials and Methods We reviewed 63 patients of LGG retrospectively who received chemotherapy PCV between January 2015 and January 2018 at Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore. Results Significant hematological toxicity as grade 3 anemia, thrombocytopenia, and neutropenia occurred in 19%, 27%, and 46% respectively with PCV. Other toxicities such as neurotoxicity, vomiting and derangement of liver enzymes occurred in 3.2%, 19%, and 19% respectively. Patients who were on concurrent anticonvulsants had no increase in PCV toxicity. Survival was not impacted by hematological toxicities up to grade 3. Conclusion PCV chemotherapy is associated with major hematological, hepatic, and clinical toxicities (vomiting, constipation, and neuropathy). Hematological toxicities influenced the course of treatment in terms of delays and interruptions.
PubMed: 33224664
DOI: 10.7759/cureus.11070 -
Journal of Gynecology Obstetrics and... May 2021Progress in oncology has improved patient survival. However, cancer chemotherapy can be gonadotoxic and affect their fertility. Recourse to fertility preservation before...
BACKGROUND
Progress in oncology has improved patient survival. However, cancer chemotherapy can be gonadotoxic and affect their fertility. Recourse to fertility preservation before starting these treatments is therefore necessary in order to allow a better life quality after survival. The aim of this work was to study the impact of chemotherapy on ovarian reserve by AMH measurement.
METHODS
This is a descriptive and longitudinal study from 2015 to 2018 carried out at Aziza Othmana hospital ART center in Tunis on patient aged less than 41 years who were candidates for fertility preservation. Patients included had AMH measurement prior to cancer treatment. We called them back to follow up the AMH level after chemotherapy. The AMH assay was performed by electrochemilumiescence technique. At the end, only 66 patients met the inclusion criteria.
RESULTS
The most frequent pathologies were Hodgkin's lymphoma and breast cancer. The mean age of patients was 26.7 ± 6.8. The most used chemotherapy protocols were BEACOPP, ABVD or the combination of both in lymphoma and FEC + TXT for breast cancer treatment. A significant difference between AMH before and after chemotherapy was found for BEACOPP and FEC + TXT protocols (p < 10 3). The patient's age was correlated with the AMH decrease after chemotherapy (r = 0.577, p < 10 3).
CONCLUSION
Our results showed that the high risk gonadotoxicity protocols were BEACOPP for lymphoma treatment and FEC + TXT for breast cancer treatment. However, studies with a larger sample and more time extended monitoring are necessary for a better gonadotoxicity understanding of the cancer treatments available today.
Topics: Adolescent; Adult; Anti-Mullerian Hormone; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Breast Neoplasms; Cyclophosphamide; Dacarbazine; Docetaxel; Doxorubicin; Epirubicin; Etoposide; Female; Fertility Preservation; Fluorouracil; Hodgkin Disease; Humans; Longitudinal Studies; Luminescent Measurements; Ovarian Reserve; Prednisone; Procarbazine; Vinblastine; Vincristine; Young Adult
PubMed: 33307239
DOI: 10.1016/j.jogoh.2020.102035 -
Cancer Discovery Apr 2023We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5...
UNLABELLED
We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH gene specific to survivors of Hodgkin lymphoma, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, whereas therapy-related CH remains stable decades after treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.
SIGNIFICANCE
This first comprehensive CH analysis in long-term survivors of pediatric cancer presents the elevated prevalence and therapy exposures/diagnostic spectrum associated with CH. Due to the contrasting dynamics of clonal expansion for age-related versus therapy-related CH, longitudinal monitoring is recommended to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors. See related commentary by Collord and Behjati, p. 811. This article is highlighted in the In This Issue feature, p. 799.
Topics: Humans; Child; Clonal Hematopoiesis; Hematopoiesis; Mutation; Hodgkin Disease; Survivors
PubMed: 36751942
DOI: 10.1158/2159-8290.CD-22-0956 -
American Journal of Hematology Jun 2023There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We...
There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.
Topics: Humans; Aged; Middle Aged; Aged, 80 and over; Rituximab; Methotrexate; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Activities of Daily Living; Retrospective Studies; Temozolomide; Lymphoma; Central Nervous System; Central Nervous System Neoplasms
PubMed: 36965007
DOI: 10.1002/ajh.26919 -
Current Oncology Reports Jan 2021IDH-mutant low-grade gliomas (LGG) have emerged as a distinct clinical and molecular entity with unique treatment considerations. Here, we review updates in IDH-mutant... (Review)
Review
PURPOSE OF REVIEW
IDH-mutant low-grade gliomas (LGG) have emerged as a distinct clinical and molecular entity with unique treatment considerations. Here, we review updates in IDH-mutant LGG diagnosis and classification, imaging biomarkers, therapies, and neurocognitive and patient-reported outcomes.
RECENT FINDINGS
CDKN2A/B homozygous deletion in IDH-mutant astrocytoma is associated with shorter survival, similar to WHO grade 4. The T2-FLAIR mismatch, a highly specific but insensitive sign, is diagnostic of IDH-mutant astrocytoma. Maximal safe resection is currently indicated in all LGG cases. Radiotherapy with subsequent PCV (procarbazine, lomustine, vincristine) provides longer overall survival compared to radiotherapy alone. Temozolomide in place of PCV is reasonable, but high-level evidence is still lacking. LGG adjuvant treatment has important quality of life and neurocognitive side effects that should be considered. Although incurable, IDH-mutant LGG have a favorable survival compared to IDH-WT glioma. Recent advances in molecular-based classification, imaging, and targeted therapies will hopefully improve survival and quality of life.
Topics: Brain Neoplasms; Chromosomes, Human, Pair 1; DNA Mutational Analysis; Glioma; Humans; Isocitrate Dehydrogenase; Neoplasm Grading
PubMed: 33492489
DOI: 10.1007/s11912-020-01006-6 -
Cancer Epidemiology, Biomarkers &... Dec 2022Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated...
BACKGROUND
Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups.
METHODS
The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 μg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG).
RESULTS
Overall, the optimal surveillance strategy was annual FIT (47 μg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 μg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 μg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG).
CONCLUSIONS
Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy.
IMPACT
Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.
Topics: Humans; Middle Aged; Aged; Adult; Cost-Benefit Analysis; Hodgkin Disease; Procarbazine; Early Detection of Cancer; Colorectal Neoplasms; Occult Blood; Colonoscopy; Survivors
PubMed: 36166472
DOI: 10.1158/1055-9965.EPI-22-0019 -
Journal of Cancer Research and... 2020Hodgkin's lymphoma (HL) can be treated with combined modality treatment (CMT) to limit long-term toxicities in the early favorable stage. Early unfavorable and advanced...
BACKGROUND
Hodgkin's lymphoma (HL) can be treated with combined modality treatment (CMT) to limit long-term toxicities in the early favorable stage. Early unfavorable and advanced stage HL is mainly treated with chemotherapy followed by radiation to the bulky site. This study examines the impact of CMT in early as well as advanced stage HL.
MATERIALS AND METHODS
From 2001 to 2011, 125 patients with Stage I to IV HL were analyzed. Median age of the patients was 25 years (range 12-68 years). CMT, chemotherapy, and radiation alone were given to 51, 64, and 10 patients, respectively. Chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was given to 100 patients, 6 patients received ABVD-like regimen, and 9 patients received cyclophosphamide, vincristine, procarbazine, and prednisone regimen. Radiotherapy (RT) was given to 61 (49%) patients, involved field RT to 55 (90%), and extended-field RT to 6 (10%) patients, respectively. Median radiation dose was 30 Gy (18-40 Gy).
RESULTS
All 25 patients with early-stage achieved complete response (CR) with CMT. At a median follow-up of 70 months (range 12-230 months), relapse was seen in two patients (1 local and 1 distant). Of 26 patients with advanced stage, 25 achieved a CR and 1 had stable disease with CMT. Relapse occurred in one patient (distant). In patients with early-stage treated with chemotherapy only ( n = 30, 24%), 9 patients had relapse (4 local and 5 distant) while in those with RT only ( n = 10, 8%), 4 developed distant relapse. In patients with advanced stage treated with chemotherapy only ( n = 34, 27%), 8 relapsed (5 local and distant, 3 distant only). Patients with relapse were salvaged with CMT ( n = 6), chemotherapy ( n = 15), or RT ( n = 3). Two patients have died. Five years' disease-free survival (DFS) in patients with early favorable stage, early unfavorable stage, and advanced stage was 91%, 82%, and 73%, respectively ( P = 0.026). DFS was significantly better with CMT than chemotherapy or radiation alone. Five years' overall survival (OS) was 93%, 92%, and 84%, respectively ( P = 0.139). Second malignancy occurred in 3 (2.4%) patients; carcinoma of the tongue, pseudomyxoma peritonei, and non-HL each, respectively. None of these patients had received prior radiation.
CONCLUSION
CMT improved DFS in patients with HL. OS was similar in all patients irrespective of treatment combinations. The incidence of second malignancy was 2.4%.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Child; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prednisone; Procarbazine; Radiotherapy; Survival Rate; Treatment Outcome; Vinblastine; Vincristine; Young Adult
PubMed: 32362601
DOI: 10.4103/jcrt.JCRT_465_17 -
Journal of B.U.ON. : Official Journal... 2021To assess the efficacy and tolerance of proton re-irradiation in patients with unresectable recurrence of previously irradiated brain gliomas.
PURPOSE
To assess the efficacy and tolerance of proton re-irradiation in patients with unresectable recurrence of previously irradiated brain gliomas.
METHODS
Between February 2016 and December 2019, 44 patients with in-field recurrence after prior irradiation of brain gliomas were irradiated with intensity-modulated proton therapy. Seven patients (15.9%) originally had low-grade (WHO grade I-II) gliomas, nine patients (20.4%) had anaplastic astrocytoma (WHO grade III), and 28 patients (63.7%) had glioblastoma (WHO grade IV). All tumors were unresectable due to their localization. After a median time from the prior irradiation of 28.0 months [range, 12 to 173], patients received PT with 2.0 and 3.0 GyRBE per fraction, with median proton EQD2 (/=10) to a tumor of 55.0 GyRBE [range, 46.0 to 61.75]. Adjuvant chemotherapy (Temozolomide, or Procarbazine, Lomustine and vincristine, or Bevacizumab with Irinotecan) received 86.9% of the patients (n=40). Treatment-related toxicity was reported following CTCAE.
RESULTS
The median survival time was 12 months, with 1-year and 2-years overall survival (OS) amounting to 49.6% and 35.1%, respectively. The median progression-free survival (PFS) was 9 months, with 1- and 2-years PFS of 30.5% and 10.2%, respectively. Twenty-six patients died by the time of analysis; among them were 5 non-cancer deaths (19.2%), and 4 patients (15.4%) died of chemotherapy-associated severe toxicity. The incidence rate of radiation-induced necrosis was 6.8% (3 events).
CONCLUSIONS
Based on our results, we suggest re-irradiation of recurrent brain gliomas with proton therapy is able to achieve reasonable tumor control. Low adverse events rate and promising outcomes make it a safe treatment option with curative intent, even in unresectable cases.
Topics: Adult; Aged; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Progression-Free Survival; Proton Therapy; Re-Irradiation; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 34268961
DOI: No ID Found -
Biology Aug 2021Treatment of blood malignancies and other cancer diseases has been mostly unfeasible, so far. Therefore, novel treatment regimens should be developed and the currently... (Review)
Review
Treatment of blood malignancies and other cancer diseases has been mostly unfeasible, so far. Therefore, novel treatment regimens should be developed and the currently used ones should be further elaborated. A stable component in various cancer treatment regimens consists of vincristine, an antimitotic compound of natural origin. Despite its strong anticancer activity, mostly, it cannot be administered as monotherapy due to its unspecific action and severe side effects. However, vincristine is suitable for combination therapy. Multidrug treatment regimens including vincristine are standardly applied in the therapy of non-Hodgkin lymphoma and other malignancies, in which it is combined with drugs of different mechanisms of action, mainly with DNA-interacting compounds (for example cyclophosphamide), or drugs interfering with DNA synthesis (for example methotrexate). Besides, co-administration of vincristine with monoclonal antibodies has also emerged, the typical example of which is the anti-CD20 antibody rituximab. Although in some combination anticancer therapies, vincristine has been replaced with other drugs exhibiting lesser side effects, though, in most cases, it is still irreplaceable. This is strongly evidenced by the number of active clinical trials evaluating vincristine in combination cancer therapy. Therefore, in this article, we have reviewed the most common cancer treatment regimens employing vincristine and bring an overview of current trends in the clinical development of this compound.
PubMed: 34571726
DOI: 10.3390/biology10090849