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The Cochrane Database of Systematic... Feb 2022Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has... (Review)
Review
BACKGROUND
Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women with advanced disease will relapse. PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi), are a type of anticancer treatment that works by preventing cancer cells from repairing DNA damage, especially in those with breast cancer susceptibility gene (BRCA) variants. PARPi offer a different mechanism of anticancer treatment from conventional chemotherapy.
OBJECTIVES
To determine the benefits and risks of poly (ADP-ribose) polymerase) inhibitors (PARPi) for the treatment of epithelial ovarian cancer (EOC).
SEARCH METHODS
We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (Central 2020, Issue 10), Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to October 2020), Embase (1990 to October 2020), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials, the National Research Register (NRR), FDA database and pharmaceutical industry biomedical literature.
SELECTION CRITERIA
We included trials that randomised women with EOC to PARPi with no treatment, or PARPi versus conventional chemotherapy, or PARPi together with conventional chemotherapy versus conventional chemotherapy alone.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data. Outcomes included overall survival (OS), objective response rate (ORR), quality of life (QoL) and rate of adverse events.
MAIN RESULTS
We included 15 studies (6109 participants); four (3070 participants) with newly-diagnosed, advanced EOC and 11 (3039 participants) with recurrent EOC. The studies varied in types of comparisons and evaluated PARPi. Eight studies were judged as at low risk of bias in most of the domains. Quality of life data were generally poorly reported. Below we present six key comparisons. The majority of participants had BRCA mutations, either in their tumour (sBRCAmut) and/or germline (gBRCAmut), or homologous recombination deficiencies (HRD) in their tumours. Newly diagnosed EOC Overall, four studies evaluated the effect of PARPi in newly-diagnosed, advanced EOC. Two compared PARPi with chemotherapy and chemotherapy alone. OS data were not reported. The combination of PARPi with chemotherapy may have little to no difference in progression-free survival (PFS) (two studies, 1564 participants; hazard ratio (HR) 0.82, 95% confidence interval (CI 0).49 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months' 63% with PARPi versus 69% for placebo). PARPi with chemotherapy likely increases any severe adverse event (SevAE) (grade 3 or higher) slightly (45%) compared with chemotherapy alone (51%) (two studies, 1549 participants, risk ratio (RR) 1.13, 95% CI 1.07 to 1.20; high-certainty evidence). PARPi combined with chemotherapy compared with chemotherapy alone likely results in little to no difference in the QoL (one study; 744 participants, MD 1.56 95% CI -0.42 to 3.54; moderate-certainty evidence). Two studies compared PARPi monotherapy with placebo as maintenance after first-line chemotherapy in newly diagnosed EOC. PARPi probably results in little to no difference in OS (two studies, 1124 participants; HR 0.81, 95%CI 0.59 to 1.13; moderate-certainty evidence) (alive at 12 months 68% with PARPi versus 62% for placebo). However, PARPi may increase PFS (two studies, 1124 participants; HR 0.42, 95% CI 0.19 to 0.92; low-certainty evidence) (no evidence of disease progression at 12 months' 55% with PARPi versus 24% for placebo). There may be an increase in the risk of experiencing any SevAE (grade 3 or higher) with PARPi (54%) compared with placebo (19%)(two studies, 1118 participants, RR 2.87, 95% CI 1.65 to 4.99; very low-certainty evidence), but the evidence is very uncertain. There is probably a slight reduction in QoL with PARPi, although this may not be clinically significant (one study, 362 participants; MD -3.00, 95%CI -4.48 to -1.52; moderate-certainty evidence). Recurrent, platinum-sensitive EOC Overall, 10 studies evaluated the effect of PARPi in recurrent platinum-sensitive EOC. Three studies compared PARPi monotherapy with chemotherapy alone. PARPi may result in little to no difference in OS (two studies, 331 participants; HR 0.95, 95%CI 0.62 to 1.47; low-certainty evidence) (percentage alive at 36 months 18% with PARPi versus 17% for placebo). Evidence is very uncertain about the effect of PARPi on PFS (three studies, 739 participants; HR 0.88, 95%CI 0.56 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months 26% with PARPi versus 22% for placebo). There may be little to no difference in rates of any SevAE (grade 3 or higher) with PARPi (50%) than chemotherapy alone (47%) (one study, 254 participants; RR 1.06, 95%CI 0.80 to 1.39; low-certainty evidence). Four studies compared PARPi monotherapy as maintenance with placebo. PARPi may result in little to no difference in OS (two studies, 560 participants; HR 0.88, 95%CI 0.65 to 1.20; moderate-certainty evidence)(percentage alive at 36 months 21% with PARPi versus 17% for placebo). However, evidence suggests that PARPi as maintenance therapy results in a large PFS (four studies, 1677 participants; HR 0.34, 95% CI 0.28 to 0.42; high-certainty evidence)(no evidence of disease progression at 12 months 37% with PARPi versus 5.5% for placebo). PARPi maintenance therapy may result in a large increase in any SevAE (51%) (grade 3 or higher) than placebo (19%)(four studies, 1665 participants, RR 2.62, 95%CI 1.85 to 3.72; low-certainty evidence). PARPi compared with chemotherapy may result in little or no change in QoL (one study, 229 participants, MD 1.20, 95%CI -1.75 to 4.16; low-certainty evidence). Recurrent, platinum-resistant EOC Two studies compared PARPi with chemotherapy. The certainty of evidence in both studies was graded as very low. Overall, there was minimal information on the QoL and adverse events.
AUTHORS' CONCLUSIONS
PARPi maintenance treatment after chemotherapy may improve PFS in women with newly-diagnosed and recurrent platinum-sensitive EOC; there may be little to no effect on OS, although OS data are immature. Overall, this is likely at the expense of an increase in SevAE. It is disappointing that data on quality of life outcomes are relatively sparse. More research is needed to determine whether PARPi have a role to play in platinum-resistant disease.
Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 35170751
DOI: 10.1002/14651858.CD007929.pub4 -
Heliyon Sep 2023Operating room workers are at risk of experiencing adverse effects due to occupational exposure to waste anesthetic gases (WAGs). One of the consequences of long-term...
INTRODUCTION
Operating room workers are at risk of experiencing adverse effects due to occupational exposure to waste anesthetic gases (WAGs). One of the consequences of long-term WAGs exposure is the probability of developing deoxyribonucleic acid (DNA) damage. This systematic review investigated the link between WAGs and DNA damage in operating room workers.
METHODS
PubMed, Science Direct, ProQuest, Scopus, and EbscoHost, as well as hand-searching, were used to find literature on the relationship between WAGs and DNA damage. Three independent reviewers independently assessed the study's quality. Meta-analysis was conducted for several DNA damage indicators, such as comet assay (DNA damage score, tail's length, tail's DNA percentage), micronuclei formation, and total chromosomal aberration.
RESULTS
This systematic review included 29 eligible studies (2732 participants). The majority of the studies used a cross-sectional design. From our meta-analysis, which compared the extent of DNA damage in operating room workers to the unexposed group, operating room workers exposed to WAGs had a significantly higher DNA damage indicator, including DNA damage score, comet tail's length, comet tail's DNA percentage, micronuclei formation, and total chromosomal aberration (p < 0.05) than non-exposed group.
CONCLUSION
Waste anesthetic gases have been found to significantly impact DNA damage indicators in operating room personnel, including comet assay, micronuclei development, and chromosomal aberration. To reduce the impact of exposure, hospital and operating room personnel should take preventive measures, such as by adapting scavenger method.
PubMed: 37810053
DOI: 10.1016/j.heliyon.2023.e19988 -
International Journal of Environmental... Jan 2020Antineoplastic drugs (ANDs) are a broad group of chemicals showing, at the same time, carcinogenic effects. The potential, albeit true, risk of side effects cannot be... (Review)
Review Meta-Analysis
BACKGROUND
Antineoplastic drugs (ANDs) are a broad group of chemicals showing, at the same time, carcinogenic effects. The potential, albeit true, risk of side effects cannot be accepted, especially if resulting from occupational exposure. The aim of this study was to evaluate the association between occupational exposure to ANDs and the extent of primary DNA damage in health professionals.
METHODS
A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed/Medline, Web of Science, and Scopus were used to perform the literature search. The databases were examined in July 2019. Sub-group, moderator, and cumulative analyses were conducted. The trim and fill method was used in the case of potential publication bias.
RESULTS
Twenty studies were included in the qualitative analysis, and 19 in quantitative evaluation. The pooled effect size was 1.27 [(95% confidence interval (CI) = 0.66-1.88), = 0.000] based on 1569 subjects. The moderator analysis by duration of exposure showed a positive association between duration of exposure and primary DNA damage.
CONCLUSIONS
This systematic review clearly shows a significant association between occupational exposure to ANDs and the extent of primary DNA damage in health professionals. Considering these results, health professionals should be warned against this potential occupational risk.
Topics: Antineoplastic Agents; Comet Assay; DNA Damage; Health Personnel; Humans; Occupational Exposure
PubMed: 31947621
DOI: 10.3390/ijerph17020523 -
Frontiers in Physiology 20238-Hydroxy-2'-deoxyguanosine (8-OHdG) is a byproduct of DNA oxidation resulting from free radical attacks. Paradoxically, treatment with 8-OHdG accelerates tissue...
8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a byproduct of DNA oxidation resulting from free radical attacks. Paradoxically, treatment with 8-OHdG accelerates tissue healing. The aim of this study is to quantify the 8-OHdG response after a single session of exercise in both trained and untrained adults. A systematic review and meta-analysis of exercise intervention studies measuring changes in blood 8-OHdG following resistance exercise and aerobic exercise were conducted. The literature search included Web of Science, PubMed, BASE, and Scopus, with publications up to February 2023 included. Subgroup analysis of training status was also conducted. Sixteen studies involving 431 participants met the eligibility criteria. Resistance exercise showed a medium effect on increasing circulating 8-OHdG levels (SMD = 0.66, < 0.001), which was similar for both trained and untrained participants. However, studies on aerobic exercise presented mixed results. For trained participants, a small effect of aerobic exercise on increasing circulating 8-OHdG levels was observed (SMD = 0.42; < 0.001). In contrast, for untrained participants, a large effect of decreasing circulating 8-OHdG levels was observed, mostly after long-duration aerobic exercise (SMD = -1.16; < 0.05). Similar to resistance exercise, high-intensity aerobic exercise (5-45 min, ≥75% VO) significantly increased circulating 8-OHdG levels, primarily in trained participants. Pooled results from the studies confirm an increase in circulating 8-OHdG levels after resistance exercise. However, further studies are needed to fully confirm the circulating 8-OHdG response to aerobic exercise. Increases in 8-OHdG after high-intensity aerobic exercise are observed only in trained individuals, implicating its role in training adaptation. : [https://Systematicreview.gov/], identifier [CRD42022324180].
PubMed: 38028771
DOI: 10.3389/fphys.2023.1275867 -
Future Oncology (London, England) Mar 2021Ongoing clinical trials are investigating PARP inhibitors to target the DNA damage repair (DDR) pathway in prostate cancer. DDR mutation screening will guide treatment...
Ongoing clinical trials are investigating PARP inhibitors to target the DNA damage repair (DDR) pathway in prostate cancer. DDR mutation screening will guide treatment strategy and assess eligibility for clinical trials. This systematic review estimated the rate of DDR mutation testing or genetic counseling among men with or at risk of prostate cancer. From 6856 records, one study fulfilled the inclusion criteria and described men undiagnosed with prostate cancer with a family history of mutation who received DDR mutation testing. With only one study included in this first systematic review of DDR mutation testing or genetic counseling in men with or at risk of prostate cancer, more research is warranted.
Topics: BRCA1 Protein; BRCA2 Protein; Consensus; DNA Mutational Analysis; DNA Repair; Drug Resistance, Neoplasm; Genetic Counseling; Genetic Testing; Humans; Male; Medical History Taking; Mutation; Poly(ADP-ribose) Polymerase Inhibitors; Practice Guidelines as Topic; Prostatic Neoplasms
PubMed: 33263430
DOI: 10.2217/fon-2020-0569 -
International Journal of Occupational... Jan 2016Unintended occupational exposure to antineoplastic drugs (ANDs) may occur in medical personnel. Some ANDs are known human carcinogens and exposure can be monitored by... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Unintended occupational exposure to antineoplastic drugs (ANDs) may occur in medical personnel. Some ANDs are known human carcinogens and exposure can be monitored by genotoxic biomarkers.
OBJECTIVE
To evaluate the obstacles to obtaining conclusive results from a comet assay test to determine DNA damage among AND exposed healthcare workers.
METHODS
We systematically reviewed studies that used alkaline comet assay to determine the magnitude and significance of DNA damage among health care workers with potential AND exposure. Fifteen studies were eligible for review and 14 studies were used in the meta-analysis.
RESULTS
Under random effect assumption, the estimated standardized mean difference (SMD) in the DNA damage of health care workers was 1.93 (95% CI: 1.15-2.71, p < 0.0001). The resulting SMD was reduced to 1.756 (95% CI: 0.992-2.52, p < 0.0001) when the analysis only included nurses. In subgroup analyses based on gender and smoking, heterogeneity was observed. Only for studies reporting comet moment, I2 test results, as a measure of heterogeneity, dropped to zero. Heterogeneity analysis showed that date of study publication was a possible source of heterogeneity (B = -0.14; p < 0.0001).
CONCLUSIONS
A mixture of personal parameters, comet assay methodological variables, and exposure characteristics may be responsible for heterogenic data from comet assay studies and interfere with obtaining conclusive results. Lack of quantitative environmental exposure measures and variation in comet assay protocols across studies are important obstacles in generalization of results.
Topics: Antineoplastic Agents; Comet Assay; DNA Damage; Health Personnel; Humans; Mutagens; Occupational Exposure
PubMed: 27110842
DOI: 10.1080/10773525.2015.1123380 -
Journal of Assisted Reproduction and... May 2011Sperm DNA damage is common amongst infertile men and may adversely impact natural reproduction, IUI-assisted reproduction and to a lesser degree IVF pregnancy. The... (Review)
Review
PURPOSE
Sperm DNA damage is common amongst infertile men and may adversely impact natural reproduction, IUI-assisted reproduction and to a lesser degree IVF pregnancy. The objective of this study was to examine the influence of sperm DNA damage on embryo quality and/or development at IVF and ICSI.
METHODS
We conducted a systematic review of studies that evaluated sperm DNA damage and embryo development and/or quality after IVF and/or ICSI.
RESULTS
We identified 28 studies (8 IVF, 12 ICSI and 8 mixed IVF-ICSI studies) that evaluated the relationship between sperm DNA damage and embryo quality. These 28 studies evaluated 3226 treatment cycles (1033 IVF and 873 ICSI, 1320 mixed IVF-ICSI cycles) and demonstrated highly variable characteristics. In 11 of the 28 studies (1/8 IVF, 5/12 ICSI and 5/8 mixed IVF-ICSI studies), sperm DNA damage was associated with poor embryo quality and/or development, whereas the remaining 17 studies showed no relationship between sperm DNA damage and embryo quality and/or development.
CONCLUSIONS
This systematic review indicates that the evaluable studies are heterogeneous and that overall, there is no consistent relationship between sperm DNA damage and embryo quality and/or development. The data also suggest that the influence of sperm DNA damage on embryo quality/development may be more significant in ICSI compared to IVF cycles.
Topics: DNA Damage; Embryo, Mammalian; Embryonic Development; Fertilization in Vitro; Humans; Male; Sperm Injections, Intracytoplasmic; Spermatozoa
PubMed: 21327499
DOI: 10.1007/s10815-011-9544-6 -
Andrology Sep 2016Existing literature suggests evidence that protamine deficiency is related to DNA damage and male fertility. In this meta-analysis, we analyzed the relationship between... (Meta-Analysis)
Meta-Analysis Review
Existing literature suggests evidence that protamine deficiency is related to DNA damage and male fertility. In this meta-analysis, we analyzed the relationship between the ratio of protamine-1 and protamine-2 with male fertility and the association of protamine deficiency with sperm DNA damage. Quality of available cohort studies was evaluated using the Newcastle-Ottawa Scale checklist. Summary effect estimates with 95% confidence intervals (CI) were derived using a random effects model. The effect of the protamine ratio on male fertility was analyzed in nine studies demonstrating a significantly higher value of the protamine ratio in subfertile men (n = 633) when compared with controls (n = 453, SMD = 0.46, 95% CI 0.25-0.66, Z = 4.42, p < 0.00001). Both protamine mRNA (SMD = 0.45, 95% CI 0.11-0.79, Z = 2.63, p = 0.009) and protein ratio (SMD = 0.46, 95% CI 0.25-0.68, Z = 4.22, p < 0.0001) showed significantly increased values in subfertile patients. The association between protamine deficiency and DNA damage was analyzed in 12 studies (n = 845) exhibiting a combined overall correlation coefficient (COR) of 0.53 (95% CI 0.28-0.71, Z = 3.87, p < 0.001). Protamine deficiency measured by CMA3 staining was significantly associated with sperm DNA damage (COR = 0.71, 95% CI 0.48-0.85, Z = 4.87, p < 0.001), whereas the P1/P2 ratio was not (COR = 0.17, 95% CI -0.16 to 0.46, Z = 0.99, p = 0.33). It is concluded that the protamine ratio represents a suitable biomarker for the assessment of sperm quality and protamine deficiency is closely related with sperm DNA damage.
Topics: DNA Damage; DNA Fragmentation; Humans; Infertility, Male; Male; Protamines; Spermatozoa
PubMed: 27231200
DOI: 10.1111/andr.12216 -
Mutation Research. Reviews in Mutation... 2016Airborne particles are small, solid particles projected into the air either by natural forces, or by mechanical or man-made processes, and include fibers and dusts.... (Review)
Review
Airborne particles are small, solid particles projected into the air either by natural forces, or by mechanical or man-made processes, and include fibers and dusts. Their toxicity is usually subsequent to inhalation and can lead to pulmonary dysfunctions and diseases, including cancer. Cytochalasin B blocked micronucleus assay in lymphocytes (L-CBMN) has been shown as a sensitive and reliable technique in assessing genotoxic exposure, An extensive search of the PubMed and Web of Science databases allowed retrieval of 18 articles on occupational or environmental exposure evaluating L-CBMN in subjects exposed to fibers or dusts (asbestos, silica, rockwool, beryllium, tobacco, and wood). For each study, mean L-CBMN levels were compared in exposed subjects vs. unexposed controls providing a point estimate, the Mean Ratio (MR). The high heterogeneity among retrieved studies and their relatively limited number did not allow a quantitative meta-analysis. However, the inter-quartile range of all MRs fell within the interval between 1.25 and 2.23, supporting the hypothesis that exposure to airborne particles increases DNA damage, although mechanisms of genotoxicity should be further investigated. A borderline significant correlation was found with SCE, but not with chromosome aberrations or comet assay. Future research should focus on exposure assessment, in order to perform proper dose-response studies and disentangle the effect of different compounds in mixed exposures. To fully exploit the cytome assay, L-CBMN frequency should be integrated with other endpoints, such as nucleoplasmic bridges and nuclear buds. The use of alternative tissues, such as nasal and buccal mucosa, and the implementation of other cytogenetic assay, may help to understand the effects of this exposure.
Topics: Asbestos; Biomarkers; Dust; Environmental Exposure; Humans; Micronucleus Tests
PubMed: 27894680
DOI: 10.1016/j.mrrev.2016.05.004 -
Critical Reviews in Toxicology Aug 2021Intraoral fixed appliances remain in the potentially corrosive environment of the mouth for an average of two years. Over time, corrosion causes the release of metal...
Intraoral fixed appliances remain in the potentially corrosive environment of the mouth for an average of two years. Over time, corrosion causes the release of metal ions, such as nickel and chromium. These metals can become allergenic and cytotoxic, causing different conditions in the human body. The aim of this study therefore is to carry out a systematic review of the available scientific evidence on the accumulation of metal ions, and the genotoxic and cytotoxic effects in oral mucosa cells deriving from short- and long-term exposure to them. The systematic review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome (quantification of metal ion deposits and assessment of their genotoxic and/or cytotoxic effects) and secondary outcome (complementary analysis of cytotoxic and genotoxic effects) were examined. The Cochrane Collaboration tool and Toxicological data Reliability Assessment Tool (ToxRTool) were used for quality assessment. Once the search was performed, a total of seven articles met the inclusion criteria and were included in this study. Two main techniques were used to assess genotoxic effects: alkaline comet assay (6/7) and micronucleus method (1/7). Cytotoxicity was evaluated (4/7) using the trypan blue dye test. Accumulations of nickel (7/7), chromium (5/7), and other metals (zinc, cobalt, iron, manganese, molybdenum, titanium) were also quantified. The results allowed us to conclude that release of metal ions and acute cell and DNA damage in oral mucosa cells takes place in the early stages of treatment. However, more long-term studies are needed to evaluate chronic exposure to metals and DNA damage, as well as cellular capacity to recover DNA integrity.
Topics: Chromium; DNA Damage; Humans; Ions; Mouth Mucosa; Orthodontic Appliances; Reproducibility of Results
PubMed: 34738508
DOI: 10.1080/10408444.2021.1960271