-
Biochimica Et Biophysica Acta.... Dec 2020Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55-200 CGG repeats at 5UTR of FMR1 gene, known...
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55-200 CGG repeats at 5UTR of FMR1 gene, known as premutation. The main clinical and neuropathological features of FXTAS include progressive intention tremor, gait ataxia, neuronal cell loss and presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes. Various mitochondrial dysfunctions are reported in in vitro/vivo models of FXTAS; however, the molecular mechanisms underlying such mitochondrial dysfunctions are unclear. CGG expansions are pathogenic through distinct mechanisms involving RNA gain of function, impaired DNA damage repair and FMRpolyG toxicity. Here, we have systematically reviewed the reports of mitochondrial dysfunctions under premutation condition. We have also focused on potential emerging mechanisms to understand mitochondrial associated pathology in FXTAS. This review highlights the important role of mitochondria in FXTAS and other related disorders; and suggests focus of future studies on mitochondrial dysfunction along with other prevailing mechanisms to alleviate neurodegeneration.
Topics: Animals; Ataxia; Fragile X Syndrome; Humans; Mitochondria; Tremor
PubMed: 32800941
DOI: 10.1016/j.bbadis.2020.165918 -
European Journal of Medical Research Dec 2022Charged particle beams from protons to carbon ions provide many significant physical benefits in radiation therapy. However, preclinical studies of charged particle... (Review)
Review
BACKGROUND
Charged particle beams from protons to carbon ions provide many significant physical benefits in radiation therapy. However, preclinical studies of charged particle therapy for prostate cancer are extremely limited. The aim of this study was to comprehensively investigate the biological effects of charged particles on prostate cancer from the perspective of in vitro studies.
METHODS
We conducted a systematic review by searching EMBASE (OVID), Medline (OVID), and Web of Science databases to identify the publications assessing the radiobiological effects of charged particle irradiation on prostate cancer cells. The data of relative biological effectiveness (RBE), surviving fraction (SF), standard enhancement ratio (SER) and oxygen enhancement ratio (OER) were extracted.
RESULTS
We found 12 studies met the eligible criteria. The relative biological effectiveness values of proton and carbon ion irradiation ranged from 0.94 to 1.52, and 1.67 to 3.7, respectively. Surviving fraction of 2 Gy were 0.17 ± 0.12, 0.55 ± 0.20 and 0.53 ± 0.16 in carbon ion, proton, and photon irradiation, respectively. PNKP inhibitor and gold nanoparticles were favorable sensitizing agents, while it was presented poorer performance in GANT61. The oxygen enhancement ratio values of photon and carbon ion irradiation were 2.32 ± 0.04, and 1.77 ± 0.13, respectively. Charged particle irradiation induced more G0-/G1- or G2-/M-phase arrest, more expression of γ-H2AX, more apoptosis, and lower motility and/or migration ability than photon irradiation.
CONCLUSIONS
Both carbon ion and proton irradiation have advantages over photon irradiation in radiobiological effects on prostate cancer cell lines. Carbon ion irradiation seems to have further advantages over proton irradiation.
Topics: Male; Humans; Protons; Gold; Dose-Response Relationship, Radiation; Metal Nanoparticles; Prostatic Neoplasms; Carbon; Oxygen; Phosphotransferases (Alcohol Group Acceptor); DNA Repair Enzymes
PubMed: 36572945
DOI: 10.1186/s40001-022-00942-2 -
Frontiers in Pharmacology 2021Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis... (Review)
Review
Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis of current clinical trials to evaluate the efficacy of PARP inhibitors in mCRPC patients based on their genetic status. On August 2020, PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for phase II/III clinical studies on PARP inhibitors in mCRPC patients. Data were extracted independently by two investigators and analyzed using Review Manager software version 5.3. Primary endpoints included overall response rate (ORR) and progression-free survival (PFS). Nine clinical trials were identified and analyzed for the clinical benefit of PARP inhibitors in mCRPC patients ( = 1,219). Pooled analyses demonstrated that PARP inhibitors could provide a significant improvement of ORR and PFS in patients with homologous recombination deficiency (HRD) when compared with non-HRD patients. Within the HRD subgroup, mutation patients achieved significantly higher ORR [odds ratio (OR): 9.97, 95% confidence interval (CI): 6.08-16.35] and PFS rates at 12 months (OR: 3.23, 95% CI: 1.71-6.10) when compared with wild-type patients. Furthermore, patients harboring HRD without mutations have a higher objective response after PARP inhibitor treatment compared with non-HRD patients. PARP inhibitor is an effective treatment option for mCRPC patients with mutations in genes related to the HR DNA repair pathway when compared with non-HRD patients. In addition to mutations, other HRD-related gene aberrations may also be used as novel biomarkers to predict the efficacy of PARP inhibitors.
PubMed: 34975480
DOI: 10.3389/fphar.2021.777663 -
Genetics in Medicine : Official Journal... May 2022Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to provide accurate estimates of the true prevalence of LS.
METHODS
MEDLINE (Ovid), Embase, and Web of Science were searched. Prevalence was calculated by random effects meta-analysis models. I score was used to assess heterogeneity across studies. Meta-regression was performed for between-study variance.
RESULTS
A total of 51 studies were included in this review. The overall pooled yield of LS screening was 2.2% based on all methods of detection. Studies performing germline tests on all participants with CRC reported higher prevalence (5.1%) as opposed to studies only performing germline tests on participants with tumors with mismatch repair deficiency (1.6%) or microsatellite instability (1.1%). Selected cohorts of CRC had a higher prevalence of germline LS diagnoses.
CONCLUSION
LS prevalence across multiple ethnic, geographic, and clinical populations is remarkably similar. Universal germline testing of patients presenting with cancer identifies that most CRCs are attributed to LS. Young patients presenting with CRC and those who fulfill criteria for a familial risk provide the highest returns for LS identification. Our study supports the universal germline CRC screening for LS.
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Microsatellite Instability; Prevalence
PubMed: 35177335
DOI: 10.1016/j.gim.2022.01.014 -
Urology Jul 2022To review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome... (Review)
Review
OBJECTIVE
To review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome diagnostics.
MATERIALS AND METHODS
Studies were identified through PubMed on December 1, 2021. Eligibility criteria were universal immunohistochemical analyses for at least 2 MMR proteins in unselected, consecutively collected UTUC cohorts. Exclusion criteria included reviews, case-reports, non-English language, and non-humans. Risk of bias was assessed using a modified Newcastle-Ottawa scale. Meta-analyses were performed to compare the association between clinical criteria and Lynch syndrome diagnoses.
RESULTS
From 12 included studies, 1628 surgically removed UTUC from 1626 patients were screened for MMR protein loss. In 11 studies, 140 of the 1559 patients had tumors with loss (9.0%) with 80.7% showing loss of MSH2, MSH6, or both. In 7 studies, genetic testing confirmed Lynch syndrome diagnosis for 20 of 970 patients (2.1%). In 8 studies, 31 patients were given a clinical Lynch syndrome diagnosis (2.6%). In total, 51 assumed or verified Lynch syndrome patients were identified among 1087 patients (4.7%). Meta-analyses of 3 studies showed significant association between previous cancer diagnosis and Lynch syndrome-associated UTUC (P = .038).
CONCLUSION
Despite the few studies conducted and lack of genetic testing, current data suggests that universal screening for MMR protein loss in UTUC may result in Lynch syndrome diagnoses in 4.7%. However, for the screening to be effective for Lynch syndrome diagnostics, follow-up investigations, such as genetic testing for MMR variants, are needed.
Topics: Carcinoma, Transitional Cell; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Immunohistochemistry; MutL Protein Homolog 1; Urinary Bladder Neoplasms
PubMed: 35217028
DOI: 10.1016/j.urology.2022.02.006 -
BMC Neurology Mar 2024MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT...
BACKGROUND
MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated with greater overall and progression free survival with alkylating agent regimens. To date, there is marked heterogeneity in how MGMT promoter methylation is tested and which CpG sites are interrogated.
METHODS
To further elucidate which MGMT promoter CpG sites are of greatest interest, we performed comprehensive searches in PubMed, Web of Science, and Embase and reviewed 2,925 article abstracts. We followed the GRADE scoring system to assess risk of bias and the quality of the studies we included.
RESULTS
We included articles on adult glioblastoma that examined significant sites or regions within MGMT promoter for the outcomes: overall survival, progression free survival, and/or MGMT expression. We excluded systemic reviews and articles on lower grade glioma. fifteen articles met inclusion criteria with variable overlap in laboratory and statistical methods employed, as well as CpG sites interrogated. Pyrosequencing or BeadChip arrays were the most popular methods utilized, and CpG sites between CpG's 70-90 were most frequently investigated. Overall, there was moderate concordance between the CpG sites that the studies reported to be highly predictive of prognosis. Combinations or means of sites between CpG's 73-89 were associated with improved OS and PFS. Six studies identified CpG sites associated with prognosis that were closer to the transcription start site: CpG's 8, 19, 22, 25, 27, 32,38, and CpG sites 21-37, as well as low methylation level of the enhancer regions.
CONCLUSION
The following systematic review details a comprehensive investigation of the current literature and highlights several potential key CpG sites that demonstrate significant association with OS, PFS, and MGMT expression. However, the relationship between extent of MGMT promoter methylation and survival may be non-linear and could be influenced by potential CpG hotspots, the extent of methylation at each CpG site, and MGMT enhancer methylation status. There were several limitations within the studies such as smaller sample sizes, variance between methylation testing methods, and differences in the various statistical methods to test for association to outcome. Further studies of high impact CpG sites in MGMT methylation is warranted.
Topics: Humans; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Glioma; Prognosis; Tumor Suppressor Proteins
PubMed: 38521933
DOI: 10.1186/s12883-024-03605-3 -
Advances in Nutrition (Bethesda, Md.) Sep 2020Caloric starvation, as well as various diets, has been proposed to increase the oxidative DNA damage induced by radiotherapy (RT). However, some diets could have dual...
Caloric starvation, as well as various diets, has been proposed to increase the oxidative DNA damage induced by radiotherapy (RT). However, some diets could have dual effects, sometimes promoting cancer growth, whereas proposing caloric restriction may appear counterproductive during RT considering that the maintenance of weight is a major factor for the success of this therapy. A systematic review was performed via a PubMed search on RT and fasting, or caloric restriction, ketogenic diet (>75% of fat-derived energy intake), protein starvation, amino acid restriction, as well as the Warburg effect. Twenty-six eligible original articles (17 preclinical studies and 9 clinical noncontrolled studies on low-carbohydrate, high-fat diets popularized as ketogenic diets, representing a total of 77 patients) were included. Preclinical experiments suggest that a short period of fasting prior to radiation, and/or transient caloric restriction during treatment course, can increase tumor responsiveness. These regimens promote accumulation of oxidative lesions and insufficient repair, subsequently leading to cancer cell death. Due to their more flexible metabolism, healthy cells should be less sensitive, shifting their metabolism to support survival and repair. Interestingly, these regimens might stimulate an acute anticancer immune response, and may be of particular interest in tumors with high glucose uptake on positron emission tomography scan, a phenotype associated with poor survival and resistance to RT. Preclinical studies with ketogenic diets yielded more conflicting results, perhaps because cancer cells can sometimes metabolize fatty acids and/or ketone bodies. Randomized trials are awaited to specify the role of each strategy according to the clinical setting, although more stringent definitions of proposed diet, nutritional status, and consensual criteria for tumor response assessment are needed. In conclusion, dietary interventions during RT could be a simple and medically economical and inexpensive method that may deserve to be tested to improve efficiency of radiation.
Topics: Caloric Restriction; Diet, High-Fat; Diet, Ketogenic; Energy Intake; Fasting; Humans
PubMed: 32492154
DOI: 10.1093/advances/nmaa062 -
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 -
Frontiers in Pharmacology 2020The introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with either oxaliplatin or mitomycin C for patients with...
Genetic Variants in DNA Repair Pathways as Potential Biomarkers in Predicting Treatment Outcome of Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: A Systematic Review.
BACKGROUND
The introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with either oxaliplatin or mitomycin C for patients with colorectal peritoneal metastasis (CPM) has resulted in a major increase in overall survival. Nonetheless, despite critical patient selection, the majority of patients will develop recurrent disease within one year following CRS + HIPEC. Therefore, improvement of patient and treatment selection is needed and may be achieved by the incorporation of genetic biomarkers. This systematic review aims to provide an overview of genetic biomarkers in the DNA repair pathway that are potentially predictive for treatment outcome of patients with colorectal peritoneal metastases treated with CRS + HIPEC with oxaliplatin or mitomycin C.
METHODS
A systematic review was conducted according to the PRISMA guidelines. Given the limited number of genetic association studies of intraperitoneal mitomycin C and oxaliplatin in patients with CPM, we expanded the review and extrapolated the data from biomarker studies conducted in colorectal cancer patients treated with systemic mitomycin C- and oxaliplatin-based chemotherapy.
RESULTS
In total, 43 papers were included in this review. No study reported potential pharmacogenomic biomarkers in patients with colorectal cancer undergoing mitomycin C-based chemotherapy. For oxaliplatin-based chemotherapy, a total of 26 genetic biomarkers within 14 genes were identified that were significantly associated with treatment outcome. The most promising genetic biomarkers were rs11615, rs1043953, rs13181, rs17655, rs3783819/rs973063/rs4151330, MMR status, ATM protein expression, tandem repeat D17S5, and rs2233678.
CONCLUSION
Several genetic biomarkers have proven predictive value for the treatment outcome of systemically administered oxaliplatin. By extrapolation, these genetic biomarkers may also be predictive for the efficacy of intraperitoneal oxaliplatin. This should be the subject of further investigation.
PubMed: 33117169
DOI: 10.3389/fphar.2020.577968 -
International Journal of Colorectal... Mar 2023The 12-gene recurrence score (RS) is a clinically validated assay which predicts recurrence risk in patients with stage II/III colon cancer. Decisions regarding adjuvant... (Meta-Analysis)
Meta-Analysis Review
Impact of the 12-gene recurrence score in influencing adjuvant chemotherapy prescription in mismatch repair proficient stage II/III colonic carcinoma-a systematic review and meta-analysis.
INTRODUCTION
The 12-gene recurrence score (RS) is a clinically validated assay which predicts recurrence risk in patients with stage II/III colon cancer. Decisions regarding adjuvant chemotherapy may be guided using this assay or based on the judgement of tumour board.
AIMS
To assess the concordance between the RS and MDT decisions regarding adjuvant chemotherapy in colon cancer.
METHODS
A systematic review was performed in accordance with PRISMA guidelines. Meta-analyses were performed using the Mantel-Haenszel method using the Review Manager version 5.4 software.
RESULTS
Four studies including 855 patients with a mean age of 68 years (range: 25-90 years) met inclusion criteria. Overall, 79.2% had stage II disease (677/855) and 20.8% had stage III disease (178/855). For the entire cohort, concordant results between the 12-gene assay and MDT were more likely than discordant (odds ratio (OR): 0.38, 95% confidence interval (CI): 0.25-0.56, P < 0.001). Patients were more likely to have chemotherapy omitted than escalated when using the RS (OR: 9.76, 95% CI: 6.72-14.18, P < 0.001). For those with stage II disease, concordant results between the 12-gene assay and MDT were more likely than discordant (OR: 0.30, 95% CI: 0.17-0.53, P < 0.001). In stage II disease, patients were more likely to have chemotherapy omitted than escalated when using the RS (OR: 7.39, 95% CI: 4.85-11.26, P < 0.001).
CONCLUSIONS
The use of the 12-gene signature refutes the decision of tumour board in 25% of cases, with 75% of discordant decisions resulting in omission of adjuvant chemotherapy. Therefore, it is possible that a proportion of such patients are being overtreated when relying on tumour board decisions alone.
Topics: Humans; Aged; DNA Mismatch Repair; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Staging; Colonic Neoplasms; Chemotherapy, Adjuvant; Carcinoma
PubMed: 36912973
DOI: 10.1007/s00384-023-04364-2