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The Oncologist Apr 2024The clinical efficacy of anti-CD20 radioimmunotherapy (RIT) is due to a combination of extracellular mechanisms involving immune-mediated cytotoxicity, and intracellular...
PURPOSE
The clinical efficacy of anti-CD20 radioimmunotherapy (RIT) is due to a combination of extracellular mechanisms involving immune-mediated cytotoxicity, and intracellular mechanisms related to inhibition of CD20 signaling and DNA damage from ionizing radiation. In 2002, the first RIT was approved by the U.S. Food and Drug Administration for the treatment of patients with indolent B-cell follicular non-Hodgkin lymphoma (NHL). The 2 approved agents, 90 Y-ibritumomab tiuxetan (90Y-IT, Zevalin, Acrotech Biopharma) and 131 I-tositumomab (131-IT, Bexxar, GlaxoSmithKline) both target CD20. The aim of this study was to review the clinical applications and supporting clinical trial data of anti-CD20 RIT for lymphoma.
METHODS
A review of published articles and abstracts on the clinical efficacy and safety of 90Y-IT and iodine I 131 tositumomab was performed.
RESULTS
The clinical efficacy and safety of anti-CD20 RIT have been demonstrated in numerous clinical trials and case series. Agents have produced significant responses in patients with follicular NHLs and in off-label applications. Importantly, RIT has demonstrated promising findings in high-risk lymphomas and heavily pretreated and refractory patient populations. Associated toxicity profiles are noted as tolerable, acceptable, and most often reversible.
CONCLUSIONS
In the 2 decades since its approval, anti-CD20 RIT continues to demonstrate efficacy, particularly with a proportion of patients maintaining long-term remissions. The combination of prolonged efficacy, tolerability, and treatment convenience makes RIT a reasonable alternative to other systemic therapies. It is recommended that further research on RIT should focus on biomarkers of long-term response, pretargeting, and sequencing of RIT in the treatment course.
Topics: Humans; Radioimmunotherapy; Yttrium Radioisotopes; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell
PubMed: 38207010
DOI: 10.1093/oncolo/oyad333 -
Ontario Health Technology Assessment... 2023Ovarian cancer affects the cells of the ovaries, and epithelial cancer is the most common type of malignant ovarian cancer. The homologous recombination repair pathway...
Homologous Recombination Deficiency Testing to Inform Patient Decisions About Niraparib Maintenance Therapy for High-Grade Serous or Endometrioid Epithelial Ovarian Cancer: A Health Technology Assessment.
BACKGROUND
Ovarian cancer affects the cells of the ovaries, and epithelial cancer is the most common type of malignant ovarian cancer. The homologous recombination repair pathway enables error-free repair of DNA double-strand breaks. Damage of key genes associated with this pathway leads to homologous recombination deficiency (HRD), which results in unrepaired DNA and can lead to cancer. Tumours with HRD are believed to be sensitive to treatment with poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as niraparib. We conducted a health technology assessment to evaluate the clinical utility and cost-effectiveness of HRD testing to inform patient decisions about the use of niraparib maintenance therapy for patients with high-grade serous or endometrioid epithelial ovarian cancer. We also evaluated the efficacy and safety of niraparib maintenance therapy in patients with HRD or homologous recombination proficiency (HRP), the cost-effectiveness of HRD testing, the budget impact of publicly funding HRD testing, and patient preferences and values.
METHODS
We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane risk-of-bias tool for randomized trials version 2, and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted a cost-utility analysis with a 5-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding HRD testing in people with ovarian cancer in Ontario. We performed a literature search for quantitative evidence of patient and provider preferences with respect to HRD testing and maintenance therapy with PARP inhibitors. To contextualize the potential value of HRD testing, we spoke with people with ovarian cancer.
RESULTS
The clinical evidence review included two studies in high-grade epithelial ovarian cancer (one in patients with newly diagnosed advanced cases and one in patients with recurrent cancer). The studies evaluated niraparib maintenance therapy compared with no maintenance therapy and used HRD testing to group patients according to HRD status. Compared to placebo, niraparib maintenance therapy improved progression-free survival in patients with newly diagnosed and recurrent ovarian cancer, and in tumours with HRD or HRP (GRADE: High), but the studies did not compare the results between the HRD and HRP groups. The frequency of adverse events was higher in the niraparib group. We identified no studies that evaluated the clinical utility of HRD testing.We conducted a primary economic evaluation to evaluate the cost-effectiveness of HRD testing for people with newly diagnosed ovarian cancer in an Ontario setting. Our analysis used a 5-year time horizon. HRD testing (for all eligible people or only for people with wild type) resulted in a lower proportion of patients receiving niraparib maintenance therapy, leading to lower costs and fewer quality-adjusted life-years (QALYs). The average total cost per patient was $131,375 for no HRD testing, $126,867 for HRD testing only in people with wild type, and $127,746 for HRD testing in all eligible people. The average total QALYs per patient were 2.087 for no HRD testing, 1.971 for HRD testing only in people with wild type, and 1.971 for HRD testing in all eligible people. Our budget impact analysis suggested that assuming a high uptake rate, publicly funding HRD testing for people with newly diagnosed ovarian cancer would lead to a total saving of $9.00 million (if HRD testing were funded for all) to $12.67 million (if HRD testing were funded for people with wild type) over the next 5 years. Publicly funding HRD testing for people with recurrent cancer would lead to a total saving of $16.31 million (if HRD testing were funded for all) to $21.67 million (if HRD testing were funded for people with wild type) over the next 5 years.We identified no studies that evaluated quantitative preferences for HRD testing. Based on two studies that evaluated patients and oncologists' preferences for maintenance therapy with a PARP inhibitor in the recurrent setting, a decrease in moderate to severe adverse events was more important for patients than an improvement in progression-free survival; however, improvement in progression-free survival was more important for oncologists. Both patients and oncologists accepted some trade-offs between efficacy and safety. The people with ovarian cancer we spoke with demonstrated a shared value for access to information, prevention of cancer recurrence, and overall survival with minimal adverse effects. This was consistent with findings from another survey in patients with ovarian cancer and at least one episode of recurrence, which suggest that patients prioritize treatment benefit over some treatment adverse events in the context of niraparib maintenance therapy. Interviewees also emphasized the importance of the patient-doctor partnership, access to local health care services, and patient education.
CONCLUSIONS
In patients with newly diagnosed (advanced) or recurrent high-grade serous or endometrioid ovarian cancer, niraparib maintenance therapy improved progression-free survival compared with no maintenance therapy in tumours with HRD or HRP (GRADE: High). Because we identified no studies on the clinical utility of HRD testing, we cannot comment on how it would affect patient decisions and clinical outcomes.Over a 5-year time horizon, HRD testing for people with wild type could save $4,509 per person and lead to a loss of 0.116 QALY. The findings of our economic analyses are dependent on assumptions about the use of niraparib following HRD testing. We estimate that publicly funding HRD testing would lead to a total saving of $9 million to $12.67 million for newly diagnosed cancer, and a total saving of $16.31 million to $21.67 million for recurrent cancer over 5 years, assuming the use of niraparib maintenance therapy would be reduced following HRD testing.Patients prioritized decreasing the risk of moderate to severe adverse events of maintenance therapy with PARP inhibitors over improving progression-free survival, and oncologists prioritized improving progression-free survival over decreasing the risk of moderate to severe adverse events. However, both patients and oncologists were open to accepting certain trade-offs between treatment efficacy and toxicity. The people we interviewed, who had lived experience with ovarian cancer and genetic testing, valued the potential clinical benefits of HRD testing for themselves and their family members. They emphasized patient education as an important consideration for public funding in Ontario.
Topics: Humans; Female; Carcinoma, Ovarian Epithelial; Technology Assessment, Biomedical; Poly(ADP-ribose) Polymerase Inhibitors; Carcinoma, Endometrioid; Ovarian Neoplasms
PubMed: 37637244
DOI: No ID Found -
Journal of Applied Toxicology : JAT Jun 2024Steroids stand for a class of hormones (natural and synthetic) known to be helpful for a number of disorders. Despite the aforementioned beneficial effects of using... (Review)
Review
Steroids stand for a class of hormones (natural and synthetic) known to be helpful for a number of disorders. Despite the aforementioned beneficial effects of using these hormones, anabolic-androgenic steroids (AAS) are also widely abused in a non-therapeutic manner for muscle-building and strength-increasing properties that may lead to genotoxicity in different tissues. The present study aims to understand whether genotoxicity may be a suitable biomarker for AAS exposure in vivo in both experimental animal and human studies. All studies published in PubMed/Medline, Scopus, and Web of Science electronic databases that presented data on DNA damage caused by AAS were analyzed. A total of 15 articles were included in this study, and after thoroughly reviewing the studies, a total of 8 articles were classified as Strong, 6 were classified as Moderate, and only 1 was classified as Weak, totaling 14 studies being considered either Strong or Moderate. This classification makes it possible to consider the present findings as reliable. The meta-analysis data revealed a statistically significant difference in Wistar rat testis cells with AAS compared to control for tail length and % tail DNA (p < 0.001), so that the selected articles were considered homogeneous and the I of 0% indicated low heterogeneity. In summary, genotoxicity can be considered a suitable biomarker for monitoring AAS exposure as a result of DNA breakage and oxidative DNA damage.
PubMed: 38840431
DOI: 10.1002/jat.4656 -
Blood Advances Feb 2024Venetoclax is a small molecule inhibitor of BCL-2 used in the treatment of acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL). Recent postmarketing... (Meta-Analysis)
Meta-Analysis
Venetoclax is a small molecule inhibitor of BCL-2 used in the treatment of acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL). Recent postmarketing studies of ibrutinib, another small molecule inhibitor, suggested that these agents may predispose to opportunistic infections. We sought to systematically review the randomized controlled trial (RCT) evidence of venetoclax to assess whether it predisposes patients to infectious adverse events (IAEs) and neutropenia. We systematically reviewed RCTs comparing venetoclax therapy with active or placebo controls for patients with hematologic malignancies. Data on IAEs and neutropenia were pooled by Bayesian meta-analysis, and we computed the probability of any increased risk (P[risk ratio (RR) > 1]) of IAEs or neutropenic complications. Seven RCTs were included, comprising 2067 patients. In CLL (n = 1032), there was a low probability of increased risk of high-grade (P[RR > 1] = 71.2%) and fatal IAEs (P[RR > 1] = 64.5%) and high-grade neutropenia (P[RR > 1] = 63.4%). There were insufficient data to perform a meta-analysis of IAEs in AML; however, 1 trial suggested an increased risk of IAEs with venetoclax. Furthermore, in AML (n = 642), venetoclax was associated with a high probability of increased risk of high-grade neutropenia (P[RR > 1] = 94.6%) and febrile neutropenia (P[RR > 1] = 90.6%). Our results suggest that venetoclax has a low probability of increased risk of IAEs or neutropenia in CLL. By contrast, there is likely increased risk of high-grade neutropenia and febrile neutropenia in AML. Importantly, our analyses did not identify any specific IAEs that would benefit from routine antimicrobial prophylaxis or pre-emptive testing.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Hematologic Neoplasms; Leukemia, Myeloid, Acute; Communicable Diseases; Febrile Neutropenia; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38154071
DOI: 10.1182/bloodadvances.2023011964 -
Toxicology Mechanisms and Methods Mar 2024In a world with a rising use of pesticides, these chemicals, although designed to effectively control pests, pose potential threats to the environment and non-target... (Review)
Review
In a world with a rising use of pesticides, these chemicals, although designed to effectively control pests, pose potential threats to the environment and non-target organisms, including humans. Thus, this systematic review aims to investigate a possible association between genetic polymorphisms and susceptibility and genotoxicity in individuals occupationally exposed to pesticides. This review was conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. A total of 14 carefully selected studies were thoroughly analyzed by two reviewers, who assigned scores based on previously set evaluation criteria. This study classified over half of the chosen studies as having moderate or strong quality, observing a correlation between certain genetic polymorphisms involved in xenobiotic metabolism and genotoxicity in workers exposed to pesticides. Results suggest that the genes associated with xenobiotic metabolism play a substantial role in determining individuals' susceptibility to genomic damage due to pesticide exposure, affecting both their peripheral blood and oral mucosa. This implies that individuals with specific genotypes may experience increased or decreased levels of DNA damage when exposed to these chemicals.
Topics: Humans; Pesticides; Occupational Exposure; Xenobiotics; Polymorphism, Genetic; DNA Damage
PubMed: 37982319
DOI: 10.1080/15376516.2023.2280806 -
Archives of Toxicology Jul 2024Benzene is used worldwide as a major raw material in a number of industrial processes and also a potent airborne pollutant emitted from traffic exhaust fume. The present... (Review)
Review
Benzene is used worldwide as a major raw material in a number of industrial processes and also a potent airborne pollutant emitted from traffic exhaust fume. The present systematic review aimed to identify potential associations between genetic polymorphisms and occupational benzene-induced genotoxicity. For this purpose, a total of 22 selected studies were carefully analysed. Our results revealed a positive relation between gene polymorphism and genotoxicity in individuals exposed to benzene, since 17 studies (out of 22) observed positive relations between genotoxicity and polymorphisms in xenobiotics metabolizing genes influencing, therefore, individuals' susceptibility to genomic damage induced by benzene. In other words, individuals with some genotypes may show increase or decrease DNA damage and/or higher or lower DNA-repair potential. As for the quality assessment, 17 studies (out of 22) were categorized as Strong or Moderate and, therefore, we consider our findings to be trustworthy. Taken together, such findings are consistent with the notion that benzene induces genotoxicity in mammalian cells being strongly dependent on the genetic polymorphism. Certainly, such findings are important for clarifying the role of biomarkers related to genotoxicity in human biomonitoring studies.
Topics: Humans; Benzene; Occupational Exposure; Polymorphism, Genetic; DNA Damage; Air Pollutants, Occupational; Mutagens
PubMed: 38600397
DOI: 10.1007/s00204-024-03744-z -
Brazilian Oral Research 2023The aim of this systematic review was to evaluate published papers regarding the micronucleus assay in oral mucosal cells of patients undergoing orthodontic therapy... (Meta-Analysis)
Meta-Analysis
The aim of this systematic review was to evaluate published papers regarding the micronucleus assay in oral mucosal cells of patients undergoing orthodontic therapy (OT). A search of the scientific literature was made in the PubMed, Scopus, and Web of Science databases for all data published until November, 2021 using the combination of the following keywords: "fixed orthodontic therapy," "genetic damage", "DNA damage," "genotoxicity", "mutagenicity", "buccal cells", "oral mucosa cells," and "micronucleus assay". The systematic review was designed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Nine studies were retrieved. Some authors demonstrated that OT induces cytogenetic damage in oral mucosal cells. Out of the nine studies included, two were classified as strong, five as moderate, and two as weak, according to the quality assessment components of the Effective Public Health Practice Project (EPHPP). Meta-analysis data revealed no relationship between mutagenicity in oral cells and OT in different months of treatment. At one month, the SMD = 0.65 and p = 0.08; after three months of OT, the SMD = 1.21 and p = 0.07; and after six months of OT, the SMD = 0.56 and p = 0.11. In the analyzed months of OT, I2 values were >75%, indicating high heterogeneity. In summary, this review was not able to demonstrate that OT induces genetic damage in oral cells. The study is important for the protection of patients undergoing fixed OT, given that mutagenesis participates in the multi-step process of carcinogenesis.
Topics: Humans; Micronucleus Tests; DNA Damage; Mouth Mucosa
PubMed: 37970936
DOI: 10.1590/1807-3107bor-2023.vol37.0116 -
Journal of Applied Toxicology : JAT Jul 2024The present systematic review (SR) aims to evaluate manuscripts in order to help further elucidate the following question: is the micronucleus assay (MA) also a useful... (Review)
Review
Is micronucleus assay a useful marker in gingiva, tongue, and palate for evaluating cytogenetic damage induced by chemical, physical, and biological agents in vivo? A systematic review with meta-analysis.
The present systematic review (SR) aims to evaluate manuscripts in order to help further elucidate the following question: is the micronucleus assay (MA) also a useful marker in gingiva, tongue, and palate for evaluating cytogenetic damage in vivo? A search was performed through the electronic databases PubMed/Medline, Scopus, and Web of Science, all studies published up to December 2023. The comparisons were defined as standardized mean difference (SMD), and 95% confidence intervals (CIs) were established. Full manuscripts from 34 studies were carefully selected and reviewed in this setting. Our results demonstrate that the MA may be a useful biomarker of gingival tissue damage in vivo, and this tissue could be a useful alternative to the buccal mucosa. The meta-analysis analyzing the different sites regardless of the deleterious factor studied, the buccal mucosa (SMD = 0.69, 95% CI, - 0.49 to 1.88, p = 0.25) and gingiva (SMD = 0.31, 95% CI, - 0.11 to 0.72, p = 0.15), showed similar results and different outcome for the tongue (SMD = 1.19, 95% CI, 0.47 to 1.91, p = 0.001). In summary, our conclusion suggests that the MA can be a useful marker for detecting DNA damage in gingiva in vivo and that this tissue could be effective site for smearing.
PubMed: 38951124
DOI: 10.1002/jat.4662 -
International Journal of Environmental... Mar 2024The goal of this study was to perform systematic review (SR) to investigate the scientific literature regarding the genotoxicity effects of fluoride exposure (FE). The... (Meta-Analysis)
Meta-Analysis Review
The goal of this study was to perform systematic review (SR) to investigate the scientific literature regarding the genotoxicity effects of fluoride exposure (FE). The search of databases used for this study was PubMed/Medline, SCOPUS and Web of Science. The quality of included studies was assessed using the EPHPP (Effective Public Health Practice Project). A total of 20 potentially relevant studies were selected for evaluating the genotoxicity induced by fluoride. Few studies have revealed that FE induces genotoxicity. A total of 14 studies demonstrated negative results whereas 6 studies did not. After reviewing the twenty studies, 1 was classified as weak, 10 were considered moderate and 9 were considered strong, according to the EPHPP. Taken together, it has been established that genotoxicity of fluoride is limited.
Topics: Fluorides; DNA Damage; Databases, Factual; Comet Assay
PubMed: 36994717
DOI: 10.1080/09603123.2023.2194616 -
Toxics Apr 2024Biomonitoring of human populations exposed to chemical substances that can act as potential mutagens or carcinogens, may enable the detection of damage and early disease... (Review)
Review
Biomonitoring of human populations exposed to chemical substances that can act as potential mutagens or carcinogens, may enable the detection of damage and early disease prevention. In recent years, the comet assay has become an important tool for assessing DNA damage, both in environmental and occupational exposure contexts. To evidence the role of the comet assay in human biomonitoring, we have analysed original research studies of environmental or occupational exposure that used the comet assay in their assessments, following the PRISMA-ScR method (preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews). Groups of chemicals were designated according to a broad classification, and the results obtained from over 300 original studies (n = 123 on air pollutants, n = 14 on anaesthetics, n = 18 on antineoplastic drugs, n = 57 on heavy metals, n = 59 on pesticides, and n = 49 on solvents) showed overall higher values of DNA strand breaks in the exposed subjects in comparison with the unexposed. In summary, our systematic scoping review strengthens the relevance of the use of the comet assay in assessing DNA damage in human biomonitoring studies.
PubMed: 38668493
DOI: 10.3390/toxics12040270