-
Neuro-oncology Advances 2024This retrospective study compares the real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD).
BACKGROUND
This retrospective study compares the real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD).
METHODS
Consecutive patients with suspected LMD who underwent lumbar punctures for CSF cytology and CNSide™ from January 2020 to December 2022 were reviewed. LMD was classified by EANO criteria. Descriptive statistics, confusion matrix, Kaplan-Meier curves, and Cox proportional regression were used.
RESULTS
Median age for 87 evaluable patients was 63 years (range: 23-93); 82 (94%) met EANO criteria for possible/probable/confirmed LMD (EANO/LMD). The commonest primary cancers were breast (36,44.0%) and lung (34,41.5%). Primary lung harbored actionable mutations in 18 (53.0%); primary breast expressed hormone receptors in 27 (75%), and HER2 amplification in 8 (22%). Uncontrolled systemic disease was detected in 35 (40%), while 25 (46%) received systemic therapy with medium/high CNS penetrance at LMD diagnosis. The median time from initial cancer to LMD diagnosis was 31 months (range: 13-73). LMD was confirmed by CSF cytology in 23/82 (28%), all identified by CNSide™. CNSide™ identified 13 additional cases (36/82, 43.9%), increasing diagnostic yield by 56.5%. Median overall survival (mOS) was 31 weeks (95%CI: 21-43), significantly worse for CNSide™ positive versus negative: 4.0 versus 16.0 weeks, respectively (HR = 0.50, = .010). While survival since LMD diagnosis did not differ by histology, time to LMD diagnosis from initial cancer diagnosis was longer for breast (48.5 months, IQR: 30.0-87.5) versus lung (8 months, IQR:0.5-16.0) cohorts. mOS was longer for patients eligible for intrathecal chemotherapy (HR: 0.189, 95%CI: 0.053-0.672, = .010).
CONCLUSIONS
This retrospective, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant molecular CSF analyses.
PubMed: 38957163
DOI: 10.1093/noajnl/vdae071 -
Scandinavian Journal of Gastroenterology Jul 2024: International guidelines currently recommend the use of molecular testing in patients with advanced pancreatic cancer. The rate of actionable molecular alterations is...
Molecular testing for personalized therapy is underutilized in patients with borderline resectable and locally advanced pancreatic cancer - real world data from the NORPACT-2 study.
: International guidelines currently recommend the use of molecular testing in patients with advanced pancreatic cancer. The rate of actionable molecular alterations is low. The utility of molecular testing in patients with borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer in real world clinical practice is unclear. 188 consecutive patients included in a prospective, population-based study (NORPACT-2) in patients with BRPC and LAPC (2018-2020) were reviewed. Molecular testing was performed at the discretion of the treating oncologist and was not recommended as a routine investigation by the national guidelines. All patients were considered fit to undergo primary chemotherapy and potential surgical resection. The frequency and the results of molecular testing (microsatellite instability (MSI) and/or KRAS status) were assessed. Thirty patients (16%) underwent molecular testing. MSI tumour was detected in one (3.6%) of 28 tested patients. The patient received immunotherapy and subsequently underwent surgical resection. Histological assessment of the resected specimen revealed a complete response. KRAS wild type was detected in one (14.3%) of seven tested patient. Patients who initiated FOLFIRINOX as the primary chemotherapy regimen ( = 0.022), or were being treated at one of the eight hospital trusts ( = 0.001) were more likely to undergo molecular testing. Molecular testing was rarely performed in patients with BRPC or LAPC. Routine molecular testing for all patients with BRPC and LAPC should be considered to increase identification of targetable mutations and improve outcomes.
PubMed: 38957079
DOI: 10.1080/00365521.2024.2373115 -
Ophthalmic Genetics Jul 2024This case report explores the relationship between genetics and phenotypic variability in autosomal dominant vitreoretinochoroidopathy (ADVIRC). The study focuses on a...
BACKGROUND
This case report explores the relationship between genetics and phenotypic variability in autosomal dominant vitreoretinochoroidopathy (ADVIRC). The study focuses on a case presenting a novel mutation in the gene and its phenotype in the case's relatives, shedding light on the structural and functional intricacies underlying this rare ophthalmologic disorder.
CASE PRESENTATION
A 33-year-old female presented for consultation with a history of bilateral retinal damage accompanied by a complaint of decreased visual acuity, progressive visual field deficit, and night blindness over the past year. Ophthalmic examination revealed a distinctive phenotype, including fibrillar vitreous, pigmented cells, and atrophic hyperpigmented retina in the periphery which was suggestive of a diagnosis of ADVIRC. Genetic testing revealed a heterozygous c.1101-1 G>T variant in , a novel splice site mutation. Functional analysis confirmed its impact on pre-mRNA splicing, resulting in an in-frame deletion (p(Ser367_Asn579del)). Family investigation revealed varying degrees of ophthalmologic impairment in the patient's mother and half-sister, both carrying the same mutation.
CONCLUSIONS
This case report provides the first clinical description of the c.1101-1 G>T mutation in the gene associated with ADVIRC. The presence of intrafamilial variability, as evidenced by the differing clinical features observed in the index case and her half-sister, suggests the potential involvement of mechanisms influencing phenotype expression.: ADVIRC : autosomal dominant vitreoretinochoroidopathy; RNA : ribonucleic acid; RPE : retinal pigment epithelium.
PubMed: 38957071
DOI: 10.1080/13816810.2024.2368797 -
Australian Journal of General Practice Jul 2024Cardiovascular diseases (CVDs) pose significant global health challenges, with genetics increasingly recognised as a key factor alongside traditional risk factors. This...
BACKGROUND
Cardiovascular diseases (CVDs) pose significant global health challenges, with genetics increasingly recognised as a key factor alongside traditional risk factors. This presents an opportunity for general practitioners (GPs) to refine their approaches.
OBJECTIVE
This article explores the impact of genetics on CVDs and its implications for GPs. It discusses monogenic disorders like inherited cardiomyopathies and polygenic risks, as well as pharmacogenetics, aiming to enhance risk assessment and personalised care.
DISCUSSION
Monogenic disorders, driven by single gene mutations, exhibit predictable inheritance patterns, including inherited cardiomyopathies and channelopathies such as Long QT syndrome. Polygenic risks involve multiple genetic variants influencing CVD susceptibility, addressed through polygenic risk scores for precise risk assessment. Pharmacogenetics tailor drug interventions based on genetic profiles, though challenges like accessibility and ethical considerations persist. Integrating genetics into cardiovascular care holds promise for alleviating the global CVD burden and improving patient outcomes.
Topics: Humans; General Practitioners; Heart Diseases; Genetic Predisposition to Disease; Pharmacogenetics; Cardiovascular Diseases; Risk Assessment; Risk Factors
PubMed: 38957060
DOI: 10.31128/AJGP-10-23-6986 -
Chemical Communications (Cambridge,... Jul 2024Benzo[a]pyrene-modified oligonucleotides were developed for the detection of RNAs with a point mutation. The probes produced two distinct fluorescence signals in...
Benzo[a]pyrene-modified oligonucleotides were developed for the detection of RNAs with a point mutation. The probes produced two distinct fluorescence signals in response to single nucleotide differences in the RNA sequences, allowing for discrimination between the matched and single base mismatched RNA sequences in colorimetric and ratiometric manners.
PubMed: 38957007
DOI: 10.1039/d4cc02188f -
Biotechnology and Bioengineering Jul 20246-Aminocaproic acid (6ACA) and 1,6-hexamethylenediamine (HMDA) are key precursors for nylon synthesis, and both are produced using petroleum-based chemical processes....
Metabolic engineering combined with site-directed saturated mutations of α-keto acid decarboxylase for efficient production of 6-aminocaproic acid and 1,6-hexamethylenediamine.
6-Aminocaproic acid (6ACA) and 1,6-hexamethylenediamine (HMDA) are key precursors for nylon synthesis, and both are produced using petroleum-based chemical processes. However, the utilization of bio-based raw materials for biological production of monomers is crucial for nylon industry. In this study, we demonstrated that metabolic engineering of Escherichia coli and selected mutations of α-keto acid decarboxylase successfully synthesized 6ACA and HMDA. An artificial iterative cycle from l-lysine to chain-extended α-ketoacids was introduced into Escherichia coli BL21 (DE3). Then, the extended α-ketoacids were decarboxylated and oxidized for 6ACA production. Overexpression of catalase (KatE) combined with the site-directed mutations of α-isopropylmalate synthase (LeuA) contributed synergistic enhancement effect on synthesis of 6ACA, resulting in a 1.3-fold increase in 6ACA titer. Selected mutations in α-keto acid decarboxylase (KivD) improved its specificity and 170.00 ± 5.57 mg/L of 6ACA with a yield of 0.13 mol/mol (6ACA/ l-lysine hydrochloride) was achieved by shake flask cultivation of the engineered strain with the KivD# (F381Y/V461I). Meanwhile, the engineered E. coli could accumulate 84.67 ± 4.04 mg/L of HMDA with a yield of 0.08 mol/mol (HMDA/ l-lysine hydrochloride) by replacing aldehyde dehydrogenase with bi-aminotransferases. This achievement marks a significant advancement in the biological synthesis of 6-carbon compounds, since the biosynthetic pathways of HMDA are rarely identified.
PubMed: 38956978
DOI: 10.1002/bit.28795 -
Obesity Reviews : An Official Journal... Jul 2024Patients with monogenic obesity display numerous medical features on top of hyperphagic obesity, but no study to date has provided an exhaustive description of their... (Review)
Review
Patients with monogenic obesity display numerous medical features on top of hyperphagic obesity, but no study to date has provided an exhaustive description of their semiology. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to January 2022 to identify studies that described symptoms of patients carrying pathogenic mutations in at least one of eight monogenic obesity genes (ADCY3, LEP, LEPR, MC3R, MC4R, MRAP2, PCSK1, and POMC). Of 5207 identified references, 269 were deemed eligible after title and abstract screening, full-text reading, and risk of bias and quality assessment. Data extraction included mutation spectrum and mode of inheritance, clinical presentation (e.g., anthropometry, energy intake and eating behaviors, digestive function, puberty and fertility, cognitive features, infectious diseases, morphological characteristics, chronic respiratory disease, and cardiovascular disease), biological characteristics (metabolic profile, endocrinology, hematology), radiological features, and treatments. The review provides an exhaustive description of mandatory, non-mandatory, and unique symptoms in heterozygous and homozygous carriers of mutation in eight monogenic obesity genes. This information is critical to help clinicians to orient genetic testing in subsets of patients with suspected monogenic obesity and provide actionable treatments (e.g., recombinant leptin and MC4R agonist).
PubMed: 38956946
DOI: 10.1111/obr.13797 -
Ophthalmic Genetics Jul 2024-related spliceosomeopathy is a rare autosomal recessive disorder with only 14 patients have been reported. It is characterized by retinal degeneration, short stature,...
BACKGROUND
-related spliceosomeopathy is a rare autosomal recessive disorder with only 14 patients have been reported. It is characterized by retinal degeneration, short stature, skeletal anomalies, and neurological defects. We described the clinical features of a Chinese patient with -related spliceosomeopathy and identified the pathogenic variant.
METHODS
The affected subject underwent detailed ophthalmic examinations. Systemic abnormalities were assessed, including body height, craniofacial morphology, oral cavity, hands, feet, hair and skin. Genomic DNA was isolated from peripheral blood and sequenced by next-generation sequencing. Sanger sequencing was performed for validation and segregation.
RESULTS
The patient had poor vision, nyctalopia and nystagmus from childhood. Fundoscopy revealed extensive chorioretinal atrophy with numerous scattered greyish pigmentation. Severe circular areas of macular atrophy were observed. Optical coherent tomography showed reduced retinal thickness with nearly absent ellipsoid zone and retinal pigment epithelium. In addition, craniofacial abnormalities, short statue, brachydactyly, dental anomalies, cafe-au-lait spots, scant hair, absent eyebrows and thin eyelashes were documented. Genetic analysis revealed a novel homozygous novel small deletion c.1133delG(p.G378Efs*12) in (NM_005869.2).
CONCLUSIONS
We present a patient with early-onset retinitis pigmentosa and marked syndromic features. A novel pathogenic variant was identified. Our findings broaden the clinical and mutation spectrum of -related spliceosomeopathy, and could be helpful in diagnosis of this rare disease.
PubMed: 38956876
DOI: 10.1080/13816810.2024.2368791 -
Otology & Neurotology : Official... Jul 2024To characterize the pattern of hearing loss in Charcot-Marie-Tooth (CMT) disease to help guide clinical management.
OBJECTIVE
To characterize the pattern of hearing loss in Charcot-Marie-Tooth (CMT) disease to help guide clinical management.
DATABASES REVIEWED
CINAHL, PubMed, and Scopus.
METHODS
Two independent investigators selected studies on CMT patients with pure-tone average (PTA) and auditory brainstem response (ABR) data. Case reports, case series <5 patients, and data that overlapped with another study were excluded. Investigators performed data extraction, quality rating, and risk-of-bias assessment using the Newcastle-Ottawa Scale. Meta-analysis of mean difference using fixed/random effects models was used. Also, data were analyzed using a weighted one-way analysis of variance, with post-hoc Tukey's test for comparison.
RESULTS
Ultimately, 6 prospective studies (N = 197) were included. The most common demyelinating subtype (CMT1A) had significantly prolonged ABR latency values across wave III (0.20 ms, 95% confidence interval [CI]: 0.05-0.35), wave V (0.20 ms, 95% CI: 0.01-0.39), waves I-III (0.20 ms, 95% CI: 0.01-0.39), and waves I-V (0.20 ms, 95% CI: 0.01-0.39) when compared to matched controls. The autosomal recessive demyelinating subtype (CMT4C) had significantly worse PTA when compared to the most common subtype (CMT1A) (Δ 28.93 dB, 95% CI 18.34-39.52) and nondemyelinating subtype (CMT2A) (Δ 28.3 dB, 95% CI: 15.98-40.62).
CONCLUSIONS
Patients with CMT can present with a variety of phenotypes depending on the causative mutation. The ABR interpeak latency values for the most common demyelinating form of CMT are delayed when compared to matched controls. Most subtypes have normal hearing thresholds, apart from CMT4C, which presents with mild hearing loss on average.
PubMed: 38956759
DOI: 10.1097/MAO.0000000000004243 -
Annals of Pediatric Endocrinology &... Jun 2024
PubMed: 38956755
DOI: 10.6065/apem.2346236.118