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Current Genomics Apr 2011Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide, and the incidence of this fatal disease is still on rise. The majority of HCCs...
Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide, and the incidence of this fatal disease is still on rise. The majority of HCCs emerge in the background of a chronic liver disease, such as chronic hepatitis and liver cirrhosis. The current understanding is that majority of HCCs evolve as a consequence of chronic inflammation and due to the presence of infection with hepatitis viruses. These underlying pathogenic stimuli subsequently induce a spectrum of genetic and epigenetic alterations in several cancer-related genes, which are involved in cell-cycle regulation, cell growth and adhesion. Such widespread genomic alterations cause disruption of normal cellular signaling and finally lead to the acquisition of a malignant phenotype in HCC. In general, the type of gene alterations, such as point mutations, deletion of chromosomal regions and abnormal methylation of gene promoters differ according to the individual targeted gene. In HCC, incidence of genetic alterations is relatively rare and is limited to a subset of few cancer-specific genes, such as the tumor suppressor p53, RB genes and oncogenes such as the CTNNB1. In contrast, epigenetic changes that involve aberrant methylation of genes and other post-transcriptional histone modifications occur far more frequently, and some of these epigenetic alterations are now being exploited for the development of molecular diagnostic signatures for HCC. In addition, recent findings of unique microRNA expression profiles also provide an evidence for the existence of novel mechanisms for gene expression regulation in HCC. In this review article, we will review the current state of knowledge on the activation of various oncogenic pathways and the inactivation of tumor suppressor pathways in HCC that result in the disruption of cancer-related gene function. In addition, we will specifically emphasize the clinical implication of some of these genetic and epigenetic alterations in the management of hepatocarcinogenesis.
PubMed: 21966251
DOI: 10.2174/138920211795564359 -
The Annals of Pharmacotherapy Jan 2022Earlier trials on the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in platinum-sensitive relapsed ovarian cancer used the hazard ratio (HR) as an efficacy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Earlier trials on the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in platinum-sensitive relapsed ovarian cancer used the hazard ratio (HR) as an efficacy parameter.
OBJECTIVE
The present meta-analysis was focused on improving the robustness and clinical interpretability of the efficacy evaluation of PARP inhibitors using the restricted mean survival time (RMST).
METHODS
A search for relevant studies published up to July 31, 2020, was performed in electronic databases to identify eligible trials comparing PARP inhibitors with placebo. The difference in RMST was used as a PARP inhibitor efficacy parameter. Combined differences in RMST with 95% CIs across studies were calculated using a random-effects model.
RESULTS
Four trials (6 articles) were assessed, including 1079 patients treated with PARP inhibitors and 598 with placebo. The combined RMST differences for up to 360 days (PARP inhibitors minus placebo: point estimate and 95% CI) among all patients and the patients of subgroups with mutations, homologous recombination-deficient (HRD) carcinoma, and wild-type carcinoma were 87 days (95% CI = 71, 102), 112 days (95% CI = 96, 129), 99 days (95% CI = 80, 119), and 69 days (95% CI = 47, 92), respectively. The combined RMST differences for up to 660 and 720 days were also larger among patients with mutations than among those with HRD carcinoma.
CONCLUSION AND RELEVANCE
Based on using the RMST difference as an alternative measure to the HR, this meta-analysis suggests that PARP inhibitors are the most effective for patients with mutations, followed by patients with HRD carcinoma.
Topics: Carcinoma, Ovarian Epithelial; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Survival Rate
PubMed: 33926263
DOI: 10.1177/10600280211013489 -
Frontiers in Endocrinology 2024Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic,... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs.
METHODS
A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25 of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package.
RESULTS
Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was , with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in , , , , , , and/or ) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The point mutations/indels were distributed throughout . Overall, (16%, 37/225) and -variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. mutations occurred more frequently in PNETs with mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways.
DISCUSSION
The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).
Topics: Humans; Pancreatic Neoplasms; Neuroendocrine Tumors; Sequence Analysis, DNA; Mutation
PubMed: 38868744
DOI: 10.3389/fendo.2024.1351624 -
The Cochrane Database of Systematic... Dec 2019Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a point mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. By definition, children with SMA type I are never able to sit without support and usually die or become ventilator dependent before the age of two years. There have until very recently been no drug treatments to influence the course of SMA. We undertook this updated review to evaluate new evidence on emerging treatments for SMA type I. The review was first published in 2009 and previously updated in 2011.
OBJECTIVES
To assess the efficacy and safety of any drug therapy designed to slow or arrest progression of spinal muscular atrophy (SMA) type I.
SEARCH METHODS
We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. We also searched two trials registries to identify unpublished trials (October 2018).
SELECTION CRITERIA
We sought all randomised controlled trials (RCTs) or quasi-RCTs that examined the efficacy of drug treatment for SMA type I. Included participants had to fulfil clinical criteria and have a genetically confirmed deletion or mutation of the SMN1 gene (5q11.2-13.2). The primary outcome measure was age at death or full-time ventilation. Secondary outcome measures were acquisition of motor milestones, i.e. head control, rolling, sitting or standing, motor milestone response on disability scores within one year after the onset of treatment, and adverse events and serious adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1 gene replacement with viral vectors are out of the scope of this review.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodology.
MAIN RESULTS
We identified two RCTs: one trial of intrathecal nusinersen in comparison to a sham (control) procedure in 121 randomised infants with SMA type I, which was newly included at this update, and one small trial comparing riluzole treatment to placebo in 10 children with SMA type I. The RCT of intrathecally-injected nusinersen was stopped early for efficacy (based on a predefined Hammersmith Infant Neurological Examination-Section 2 (HINE-2) response). At the interim analyses after 183 days of treatment, 41% (21/51) of nusinersen-treated infants showed a predefined improvement on HINE-2, compared to 0% (0/27) of participants in the control group. This trial was largely at low risk of bias. Final analyses (ranging from 6 months to 13 months of treatment), showed that fewer participants died or required full-time ventilation (defined as more than 16 hours daily for 21 days or more) in the nusinersen-treated group than the control group (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.32 to 0.89; N = 121; a 47% lower risk; moderate-certainty evidence). A proportion of infants in the nusinersen group and none of 37 infants in the control group achieved motor milestones: 37/73 nusinersen-treated infants (51%) achieved a motor milestone response on HINE-2 (risk ratio (RR) 38.51, 95% CI 2.43 to 610.14; N = 110; moderate-certainty evidence); 16/73 achieved head control (RR 16.95, 95% CI 1.04 to 274.84; moderate-certainty evidence); 6/73 achieved independent sitting (RR 6.68, 95% CI 0.39 to 115.38; moderate-certainty evidence); 7/73 achieved rolling over (RR 7.70, 95% CI 0.45 to 131.29); and 1/73 achieved standing (RR 1.54, 95% CI 0.06 to 36.92; moderate-certainty evidence). Seventy-one per cent of nusinersen-treated infants versus 3% of infants in the control group were responders on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) measure of motor disability (RR 26.36, 95% CI 3.79 to 183.18; N = 110; moderate-certainty evidence). Adverse events and serious adverse events occurred in the majority of infants but were no more frequent in the nusinersen-treated group than the control group (RR 0.99, 95% CI 0.92 to 1.05 and RR 0.70, 95% CI 0.55 to 0.89, respectively; N = 121; moderate-certainty evidence). In the riluzole trial, three of seven children treated with riluzole were still alive at the ages of 30, 48, and 64 months, whereas all three children in the placebo group died. None of the children in the riluzole or placebo group developed the ability to sit, which was the only milestone reported. There were no adverse effects. The certainty of the evidence for all measured outcomes from this study was very low, because the study was too small to detect or rule out an effect, and had serious limitations, including baseline differences. This trial was stopped prematurely because the pharmaceutical company withdrew funding. Various trials and studies investigating treatment strategies other than nusinersen, such as SMN2 augmentation by small molecules, are ongoing.
AUTHORS' CONCLUSIONS
Based on the very limited evidence currently available regarding drug treatments for SMA type 1, intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with SMA type I. It is also probable that a greater proportion of infants treated with nusinersen than with a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and CHOP INTEND). The proportion of children experiencing adverse events and serious adverse events on nusinersen is no higher with nusinersen treatment than with a sham procedure, based on evidence of moderate certainty. It is uncertain whether riluzole has any effect in patients with SMA type I, based on the limited available evidence. Future trials could provide more high-certainty, longer-term evidence to confirm this result, or focus on comparing new treatments to nusinersen or evaluate them as an add-on therapy to nusinersen.
Topics: Child, Preschool; Humans; Infant; Neuroprotective Agents; Oligonucleotides; Randomized Controlled Trials as Topic; Spinal Muscular Atrophies of Childhood
PubMed: 31825542
DOI: 10.1002/14651858.CD006281.pub5 -
Advances in Therapy Dec 2019Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy...
Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy due to retinal ganglion cell (RGC) loss. It is a maternally inherited (or sporadic) mitochondrial disorder caused primarily by mutations in genes that encode components of respiratory complex (RC)1 in mitochondria. Mitochondrial deficiency of RC1 compromises ATP production and oxidative stress management in RGCs. The most common LHON-causing mutations are 11778G>A, 3460G>A, and 14484T>C point mutations in MT-ND4, MT-ND1, and MT-ND6. The unusually high mitochondrial load of RGCs makes them particularly sensitive to these mutations. Patients with LHON may be prescribed ubiquinone (a component of RC3) or idebenone, a ubiquinone analogue with enhanced bioavailability to act downstream of RC1. The challenge of accessing the inner mitochondrial membrane with gene therapy for LHON, and other mitochondrial diseases, may be overcome by incorporation of a specific mitochondrion-targeting sequence (MTS) that enables allotropic expression of a nucleus-transcribed ND4 transgene. Because LHON penetrance is incomplete among carriers of the aforementioned mutations, identification of environmental factors, such as heavy smoking, that interact with genetics in the phenotypic expression of LHON may be helpful toward preventing or delaying disease development. LHON has become a model for mitochondrial and neurogenerative diseases owing to it having a clearly identified genetic cause and its early onset and rapid progression characteristics. Hence, LHON studies and genetic treatment advances may inform research of other diseases.
Topics: DNA, Mitochondrial; Electron Transport Complex I; Genetic Therapy; Humans; Mutation; Optic Atrophy, Hereditary, Leber; Phenotype; Point Mutation
PubMed: 31605306
DOI: 10.1007/s12325-019-01113-2 -
Journal of the International AIDS... 2014There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical... (Review)
Review
There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended.
Topics: Anti-HIV Agents; Disease Progression; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Mutation; Treatment Outcome
PubMed: 24998532
DOI: 10.7448/IAS.17.1.18944 -
Blood May 2009Recent studies suggested that JAK2V617F mutation is frequent in patients with splanchnic vein thrombosis (SVT) but not in patients with other venous thromboembolic... (Meta-Analysis)
Meta-Analysis
Recent studies suggested that JAK2V617F mutation is frequent in patients with splanchnic vein thrombosis (SVT) but not in patients with other venous thromboembolic events (VTE). However, whether screening for the JAK2V617F mutation in VTE patients is justified remains unclear. Therefore, we performed a systematic review to assess the frequency of JAK2 mutation in VTE patients and the role of JAK2V617F mutation in the diagnosis of myeloproliferative neoplasms. MEDLINE and EMBASE databases were searched. Two reviewers independently performed study selection and extracted study characteristics. Pooled odds ratios of case-control studies and weighted mean proportion of the prevalence of JAK2V617F mutation of uncontrolled series were calculated. Twenty-four studies involving 3123 patients were included. Mean prevalence of JAK2 mutation was 32.7% (95% confidence interval, 25.5%-35.9%) in SVT patients. JAK2 mutation was associated with increased risk of SVT (odds ratio, 53.98; 95% confidence interval, 13.10-222.45). Mean prevalence of JAK2 mutation in other VTE patients was low (range, 0.88%-2.57%). Presence of JAK2V617F mutation in SVT patients was associated with a subsequent diagnosis of myeloproliferative neoplasm in many patients. JAK2 mutation is strongly associated with SVT, and routine screening of JAK2 mutation appears to be indicated in these patients.
Topics: Algorithms; Amino Acid Substitution; Biomarkers, Tumor; Case-Control Studies; Early Detection of Cancer; Female; Gene Frequency; Humans; Janus Kinase 2; Male; Myeloproliferative Disorders; Neoplasms; Phenylalanine; Philadelphia Chromosome; Point Mutation; Valine; Venous Thromboembolism
PubMed: 19273837
DOI: 10.1182/blood-2008-12-196014 -
Alzheimer's Research & Therapy Jan 2018The MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer's...
BACKGROUND
The MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer's disease-like clinical features.
METHODS
We compiled clinical data from a new Swedish kindred with R406W mutation. Seven family members were followed longitudinally for up to 22 years. Radiological examinations were performed in six family members and neuropathological examinations in three. We systematically reviewed the literature and compiled clinical, radiological, and neuropathological data on 63 previously described R406W heterozygotes and 3 homozygotes.
RESULTS
For all cases combined, the median age of onset was 56 years and the median disease duration was 13 years. Memory impairment was the most frequent symptom, behavioral disturbance and language impairment were less common, and Parkinsonism was rare. Disease progression was most often slow. The most frequent clinical diagnosis was Alzheimer's disease. R406W homozygotes had an earlier age at onset and a higher frequency of behavioral symptoms and Parkinsonism than heterozygotes. In the new Swedish kindred, a consistent imaging finding was ventromedial temporal lobe atrophy, which was evident also in early disease stages as a widening of the collateral sulcus with ensuing atrophy of the parahippocampal gyrus. Unlike previously published R406W carriers, all three autopsied patients from the novel family showed neuropathological similarities with progressive supranuclear palsy, with predominant four-repeat (exon 10+) tau isoform (4R) tauopathy and neurofibrillary tangles accentuated in the basal-medial temporal lobe. Amyloid-β pathology was absent.
CONCLUSIONS
Dominance of 4R over three-repeat (exon 10-) tau isoforms contrasts with earlier reports of R406W patients and was not sufficiently explained by the presence of H1/H2 haplotypes in two of the autopsied patients. R406W patients often show a long course of disease with marked memory deficits. Both our neuropathological results and our imaging findings revealed that the ventromedial temporal lobes were extensively affected in the disease. We suggest that this area may represent the point of origin of tau deposition in this disease with relatively isolated tauopathy.
Topics: Age of Onset; Aged; Brain; Dementia; Disease Progression; Family; Female; Humans; Longitudinal Studies; Male; Middle Aged; Mutation; tau Proteins
PubMed: 29370822
DOI: 10.1186/s13195-017-0330-2 -
World Neurosurgery Nov 2019Epithelioid glioblastoma (eGBM) is a very rare histologic variant of glioblastoma that has not been studied in isolation and, therefore, its optimal management has been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Epithelioid glioblastoma (eGBM) is a very rare histologic variant of glioblastoma that has not been studied in isolation and, therefore, its optimal management has been largely assumed, but not confirmed. The aim of this study was to analyze all reported cases describing the presentation and clinical features to better understand the clinical significance of this histologic diagnosis.
METHODS
A comprehensive literature search was conducted from 2005 to April 2019 identifying cases of eGBM that satisfied selection criteria for analysis. Survival was investigated using Kaplan-Meier estimations, and then univariate and multivariate logistic regression analyses for primary end point overall survival (OS) and second end point progression-free survival (PFS).
RESULTS
A total cohort of 59 eGBM cases from 28 articles were included for final analysis. Median age of patients at diagnosis was 30 years, with 29 (46%) female patients. When reported, 100% (37/37) cases were IDH1-wild-type and 63% (19/30) were positive for the BRAF V600E mutation by immunohistochemistry. Median OS and PFS were estimated to be 11.0 months (95% confidence interval, 6.5-13.0) and 7.0 months (95% confidence interval, 3.0-10.0), respectively. Surgical extent of resection, radiation therapy, and chemotherapy all predicted superior OS and PFS on multivariate analysis (P < 0.05). No biomarkers prognosticated survival.
CONCLUSIONS
These findings indicate that the histologic diagnosis of eGBM does not deviate from the clinical course of the broader glioblastoma diagnosis, despite being a unique histologic identity. These results argue against the temptation to deviate from the traditional management paradigm of surgery, radiation, and chemotherapy for glioblastoma based on this histology alone.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Child; Child, Preschool; Disease-Free Survival; Female; Glioblastoma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Rare Diseases; Treatment Outcome; Young Adult
PubMed: 31404694
DOI: 10.1016/j.wneu.2019.08.007 -
The Lancet. Infectious Diseases Jul 2009Antiretroviral-therapy rollout in resource-poor countries is often associated with limited, if any, HIV-RNA monitoring. The effect of variable monitoring on the... (Meta-Analysis)
Meta-Analysis
Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis.
Antiretroviral-therapy rollout in resource-poor countries is often associated with limited, if any, HIV-RNA monitoring. The effect of variable monitoring on the emergence of resistance after therapy with commonly used drug combinations was assessed by systematic review of studies reporting resistance in patients infected with HIV with a CD4 count of fewer than 200 cells per muL treated with two nucleoside analogues (including a thymidine analogue) and a non-nucleoside reverse transcriptase inhibitor. 8376 patients from eight cohorts and two prospective studies were analysed. Resistance at virological failure to non-nucleoside reverse transcriptase inhibitors at 48 weeks was 88.3% (95% CI 82.2-92.9) in infrequently monitored patients, compared with 61.0% (48.9-72.2) in frequently monitored patients (p<0.001). Lamivudine resistance was 80.5% (72.9-86.8) and 40.3% (29.1-52.2) in infrequently and frequently monitored patients, respectively (p<0.001); the prevalence of at least one thymidine analogue mutation was 27.8% (21.2-35.2) and 12.1% (5.9-21.4), respectively (p<0.001). Genotypic resistance at 48 weeks to lamivudine, nucleoside reverse transcriptase inhibitors (thymidine analogue mutations), and non-nucleoside reverse transcriptase inhibitors appears substantially higher in less frequently monitored patients. This Review highlights the need for cheap point-of-care viral-load tests to identify early viral failures and limit the emergence of resistance.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Monitoring; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; RNA, Viral; Treatment Failure; Treatment Outcome; Viral Load
PubMed: 19555900
DOI: 10.1016/S1473-3099(09)70136-7