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Archives of Toxicology Aug 2023Mutagenicity testing is an essential component of health safety assessment. Duplex Sequencing (DS), an emerging high-accuracy DNA sequencing technology, may provide...
Mutagenicity testing is an essential component of health safety assessment. Duplex Sequencing (DS), an emerging high-accuracy DNA sequencing technology, may provide substantial advantages over conventional mutagenicity assays. DS could be used to eliminate reliance on standalone reporter assays and provide mechanistic information alongside mutation frequency (MF) data. However, the performance of DS must be thoroughly assessed before it can be routinely implemented for standard testing. We used DS to study spontaneous and procarbazine (PRC)-induced mutations in the bone marrow (BM) of MutaMouse males across a panel of 20 diverse genomic targets. Mice were exposed to 0, 6.25, 12.5, or 25 mg/kg-bw/day for 28 days by oral gavage and BM sampled 42 days post-exposure. Results were compared with those obtained using the conventional lacZ viral plaque assay on the same samples. DS detected significant increases in mutation frequencies and changes to mutation spectra at all PRC doses. Low intra-group variability within DS samples allowed for detection of increases at lower doses than the lacZ assay. While the lacZ assay initially yielded a higher fold-change in mutant frequency than DS, inclusion of clonal mutations in DS mutation frequencies reduced this discrepancy. Power analyses suggested that three animals per dose group and 500 million duplex base pairs per sample is sufficient to detect a 1.5-fold increase in mutations with > 80% power. Overall, we demonstrate several advantages of DS over classical mutagenicity assays and provide data to support efforts to identify optimal study designs for the application of DS as a regulatory test.
Topics: Male; Mice; Animals; Procarbazine; Mutation Rate; Bone Marrow; Mutagens; Mutation; Mutagenicity Tests; Mice, Transgenic; Lac Operon
PubMed: 37341741
DOI: 10.1007/s00204-023-03527-y -
Scientific Reports Jan 2021With the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma... (Meta-Analysis)
Meta-Analysis Review
With the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.
Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Dose-Response Relationship, Drug; Humans; Lymphoma, Non-Hodgkin; Methotrexate; Remission Induction; Treatment Outcome
PubMed: 33483528
DOI: 10.1038/s41598-020-80724-0 -
Veterinary and Comparative Oncology Mar 2024The most commonly utilized protocols to treat lymphoma in cats employ vincristine, cyclophosphamide and prednisone; with additional drugs sometimes used including...
Treatment of feline intermediate to high-grade alimentary lymphoma: A retrospective evaluation of 55 cats treated with the VAPC combination chemotherapy protocol (2017-2021).
The most commonly utilized protocols to treat lymphoma in cats employ vincristine, cyclophosphamide and prednisone; with additional drugs sometimes used including L-asparaginase and doxorubicin. Medical records were reviewed for 55 cats with alimentary lymphoma treated with a novel multiagent protocol using prednisolone, L-asparaginase, doxorubicin, vinblastine instead of vincristine, a higher dosage of cyclophosphamide and oral procarbazine (VAPC protocol). Outcomes evaluated were response to therapy, toxicity and progression-free survival (PFS). Grade 3 or 4 neutropenia was the most common treatment-related reason for chemotherapy dosage adjustment, occurring in 8 of 52 cats receiving vinblastine, 7 of 55 cats receiving cyclophosphamide and 1 of 40 cats receiving doxorubicin, but febrile neutropenia was identified in only two cats. Of 38 cats receiving chemotherapy for measurable disease, 26 (68.4%) achieved complete response (CR). Three cats achieved a partial response and 9 cats failed to achieve a remission. There were no identified factors influencing whether a cat was likely to achieve CR. For all 55 cats (including those receiving chemotherapy and surgery), median PFS was 184 days with 1, 2 and 3-year survival rates of 35.4%, 26.5% and 26.5%, respectively. On multivariate analysis, 40 cats that achieved CR had a median survival time of 341 days (78 days for PR, 45 days for NR); PFS times were also significantly affected by lymphocyte:monocyte L:M ratio (>3.4 = 700 days vs. ≤3.4 = 126 days) and B-cell versus T-cell phenotype (220 days vs. 42 days, respectively).
Topics: Cats; Animals; Vincristine; Asparaginase; Retrospective Studies; Vinblastine; Lymphoma, Non-Hodgkin; Lymphoma; Prednisone; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Cat Diseases
PubMed: 38152842
DOI: 10.1111/vco.12958 -
Frontiers in Immunology 2021DNA methylation patterns are essential in understanding carcinogenesis. However, the relationship between DNA methylation and the immune process has not been clearly...
DNA methylation patterns are essential in understanding carcinogenesis. However, the relationship between DNA methylation and the immune process has not been clearly established-this study aimed at elucidating the interaction between glioma and DNA methylation, consolidating glioma classification and prognosis. A total of 2,483 immune-related genes and 24,556 corresponding immune-related methylation probes were identified. From the Cancer Genome Atlas (TCGA) glioma cohort, a total of 683 methylation samples were stratified into two different clusters using unsupervised clustering, and eight types of other cancer samples from the TCGA database were shown to exhibit excellent distributions. A total of 3,562 differentially methylated probes (DMPs) were selected and used for machine learning. A five-probe signature was established to evaluate the prognosis of glioma as well as the potential benefits of radiotherapy and Procarbazine, CCNU, Vincristine (PCV) treatment. Other prognostic clinical models, such as nomogram and decision tree, were also evaluated. Our findings confirmed the interactions between immune-related methylation patterns and glioma. This novel approach for cancer molecular characterization and prognosis should be validated in further studies.
Topics: Aged; Brain Neoplasms; Clinical Decision-Making; DNA Methylation; Databases, Genetic; Decision Trees; Epigenome; Epigenomics; Female; Glioma; Humans; Machine Learning; Male; Middle Aged; Nomograms; Precision Medicine; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; Tumor Microenvironment
PubMed: 34804019
DOI: 10.3389/fimmu.2021.737650 -
Journal of Neurosurgery. Case Lessons Oct 2023High-grade gliomas are aggressive primary brain tumors, the most common of which is glioblastoma multiforme. Despite advances in treatment, the prognosis for these...
BACKGROUND
High-grade gliomas are aggressive primary brain tumors, the most common of which is glioblastoma multiforme. Despite advances in treatment, the prognosis for these patients remains poor. The most common chemotherapeutic agents used in the treatment of this pathology include temozolomide (TMZ), procarbazine, lomustine, and vincristine. It is unclear whether chemotherapy should be held during resection for high-grade gliomas, because the perioperative risk profile is not clearly defined.
OBSERVATIONS
The authors report a case series of 18 surgeries to investigate the effects of concurrent TMZ and lomustine chemotherapy on surgical complications in patients undergoing repeat resection for recurrent high-grade gliomas. The authors found no postoperative infections, self-limiting postoperative complications, or excessive intraoperative blood loss and found one intraoperative complication.
LESSONS
There may not be a need to pause TMZ and lomustine chemotherapy during recurrent resections for high-grade gliomas, and continuing these medications throughout the perioperative period may be appropriate. This case series suggests that patients receiving TMZ and lomustine chemotherapy who need a repeat resection for recurrent high-grade gliomas should consider remaining on their chemotherapy regimen because it has been shown in the literature to improve recurrence-free survival time.
PubMed: 37870760
DOI: 10.3171/CASE23341 -
Mutational signatures in T-lymphocytes of rats treated with N-propyl-N-nitrosourea and procarbazine.Environmental and Molecular Mutagenesis Jul 2021We have used whole genome sequencing (WGS) to determine mutational signatures induced in the T-cells of rats treated in vivo with N-propyl-N-nitrosourea (PNU) or...
We have used whole genome sequencing (WGS) to determine mutational signatures induced in the T-cells of rats treated in vivo with N-propyl-N-nitrosourea (PNU) or procarbazine (PCZ). The signatures from the treated rats were different from the signature of background mutations. The main component of the spontaneous T-cell mutational signature was C➔T transition with all other single base substitutions evenly distributed. The PNU-induced mutational signature showed relatively equal contributions from C➔T and T➔C transitions, and T➔A transversions. The PCZ-induced signature was characterized by T➔C transitions, T➔A and, to a smaller extent, T➔G transversions. C➔G transversions were infrequent in either the PNU or PCZ signatures. WGS not only allowed mutational signature detection, but also measured quantitative responses to mutagen treatment: 10-40× increases in the number of mutations per clone were detected in T-cell clones from treated rats. The overall strand specificity of induced mutations for annotated rat genes was comparable to the strand specificity of mutations determined previously for the endogenous X-linked Pig-a gene. Our results provide valuable reference data for future applications of WGS in safety research and risk assessment.
Topics: Animals; Antineoplastic Agents; Gene Expression Regulation; Male; Mutagens; Mutation; Nitrosourea Compounds; Procarbazine; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; T-Lymphocytes; Whole Genome Sequencing
PubMed: 34117657
DOI: 10.1002/em.22448 -
Human Reproduction Update Jun 2024Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating...
BACKGROUND
Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy.
OBJECTIVE AND RATIONALE
This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy.
SEARCH METHODS
A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine).
OUTCOMES
The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors.
WIDER IMPLICATIONS
Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field.
REGISTRATION NUMBER
Not applicable.
PubMed: 38942605
DOI: 10.1093/humupd/dmae020 -
Acta Medica Indonesiana Jan 2023Primary CNS Lymphoma (PCNSL) is a rare form aggressive extra nodal non-Hodgkin Lymphoma (NHL) that comprising 1-2% of the primary brain tumors that develops in...
Primary CNS Lymphoma (PCNSL) is a rare form aggressive extra nodal non-Hodgkin Lymphoma (NHL) that comprising 1-2% of the primary brain tumors that develops in the brain, spinal cord, eye or leptomeningeal area without evidence of systemic involvement. The overall incidence of PCNSL with immunocompetent patients is only 0,47/100.000 year in PCNSL. Approximately 10-20% of patients have ocular involvement and around one third have multifocal neurological disease. Overall long-term survival rate only 20-40%, this is because the management of PCNSL is limited to ability of the drug due to cross the blood brain barrier (BBB). We present a B-cell central nervous system lymphoma in an immunocompetent patient who treat responses with chemotherapy. A 35-year-old man presented to our hospital with suddenly unconscious 4 hours before admission. He was experiencing headache and blurred of vision withing 3 months and have episode seizure. On Examination, GCS E2 M3 Aphasia, Hemiparesis dextra, papil edema, VOD/VOS: NLP. The other physical exam was normal. Laboratory tests Hb 10,7 g/dl, LDH 446 U/L, and D-dimer 3,21ug/ml. Rubella IgG 76,9, CMV Ig G 245,6 and, HSV IgG and IgM negative, HIV test non-reactive, Toxoplasma IgG and Toxoplasma IgM negative, HbsAg and HCV test negative. Brain MRI and MRI Spectroscopy: Lobulated mass size 7,08 cm x 4,75 cm at caudates nucleus sinistra-periventricular lateralis sinistra, Cholin/NAA ratio: 5-9, Cholin/Creatin ration 6-11 suspect malignancy dd/Lymphoma. MRI whole spine: Bulging discus intervertebral C4-C5. Chest and Abdomen CT-Scan are normal. Bone Survey normal, EEG: Epileproform left temporal. Cerebrospinal Fluid: Gliosis reaction sup malignancy.The patient underwent craniotomy and biopsy Pathology Anatomy and IHC Basal Ganglia revealed a Diffuse Large B Cell Lymphoma (NHL) Non-Germinal Center, CD 20 +, Ki 67 95% (High Grade), CD 45 +, CD 3 -, BCL6 +, Mum 1+. The patient we give induction therapy with RMP Regimens (Rituximab 375 mg/m2, day 1, 15 and 29, High Dose Methotrexate (HDMTX) 3000mg/m2 day 2, 16 and 30, and Procarbazine 60mg/m2 day 3-12) because Procarbazine in not available in Palembang we change to Dacarbazine 375mg/m2 days 3,17 and 31), Dexamethasone 5mg/6 hours, and has finished Low Dose Whole Brain Radiotherapy for consolation therapy. PCNSL is rare form aggressive extra nodal NHL, especially in Immunocompetent patient. In this particular case of patients High Dose Methotrexate Chemotherapy has achieved high respond especially for this patient that showed GCS E4M5V6 and recovery neurological deficit after 2 cycle chemotherapy.
Topics: Male; Humans; Young Adult; Adult; Methotrexate; Central Nervous System Neoplasms; Procarbazine; Antineoplastic Combined Chemotherapy Protocols; Lymphoma, Non-Hodgkin; Lymphoma; Brain; Immunoglobulin G; Immunoglobulin M
PubMed: 36999259
DOI: No ID Found -
Clinical & Translational Oncology :... Jun 2021Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive...
PURPOSE
Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males.
METHODS
The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels.
RESULTS
Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis.
CONCLUSIONS
ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP's effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dacarbazine; Doxorubicin; Etoposide; Fertility; Hodgkin Disease; Humans; Infertility, Male; Male; Prednisone; Procarbazine; Vinblastine; Vincristine
PubMed: 32944834
DOI: 10.1007/s12094-020-02483-8 -
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