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PubMed2025

Pathogenicity assessment of genetic variants identified in patients with severe hypertriglyceridemia: Novel cases of familial chylomicronemia syndrome from the Dyslipidemia Registry of the Spanish Atherosclerosis Society.

PURPOSE: Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. METHODS: 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. RESULTS: Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. CONCLUSION: The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.

Humans↗

PubMed2025

Opportunistic screening for broad range of medically relevant secondary findings: Laboratory benefits and burdens.

PURPOSE: Exome and genome sequencing enable opportunistic screening for secondary findings (SFs). We report on exome analysis for a broad range of medically relevant SFs in the setting of the Incidental Genomics randomized clinical trial (NCT03597165). METHODS: Participants had exome sequencing and were randomized to receive only primary cancer findings (control) or cancer findings and a choice of SFs (intervention). RESULTS: Across 279 participants, there were 4441 unique variants in SF genes: 5.0% (221) were reportable pathogenic/likely pathogenic variants, and 81.4% (3615) were nonreportable variants of uncertain significance (VUS). Intervention arm participants had on average 2.6 (SD 1.66, range 0-9) pathogenic/likely pathogenic variants and 29.5 VUS (SD 13.2, range 2-74). SFs for monogenic disease risk were reported in 35.3% (49/139) of participants (American College of Medical Genetics and Genomics non-cancer subset in 1.4%) and carrier status in 89.3% (117/131). In the intervention arm, variant filtration was 7.7 times longer per case (95% CI 5.3 to 11.3, P < .0001), variant classification was 13.3 times longer (95% CI 10.6 to 16.5, P < .0001), and report preparation was 3.3 times longer (95% CI 2.6 to 4.1, P < .0001). CONCLUSION: Although the yield of reportable SFs was high, this was accompanied by many nonreportable VUS and increased efforts for exome analysis.

Humans↗

PubMed1983

Correlated reduction of velocity of shortening and the rate of energy utilization in mouse fast-twitch muscle during a continuous tetanus.

Isometric tetani of slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles of the mouse were studied at 20 degrees C. The total energy cost for 3- and 9-s isometric tetani was measured as a function of length above L0 and partitioned into a filament overlap-dependent fraction and a smaller filament overlap-independent fraction. In both muscles, the rate of filament overlap-independent energy cost did not change with tetanic duration. In the EDL, but not in the soleus, the rate of filament overlap-dependent energy utilization was greater in a 3-s tetanus than in a 9-s tetanus. The force-velocity relationships were studied after 3 and 9 s of isometric tetanus. In the soleus, Vmax was 2 fiber lengths/s and was not dependent on the duration of isometric tetanus. In contrast, in the EDL, Vmas decreased from 5.9 fiber lengths/s at 3 s to 3.9 fiber lengths/s at 9 s. The velocity of unloaded shortening (Vus) was examined by the slack test method as a function of the duration of isometric tetanus duration over the range of 1-15 s. In the soleus, Vus did not change, whereas in the EDL, Vus declined progressively from 6.4 to 3.2 fiber lengths/s after an isometric tetanus of increasing duration from 1 to 15 s. These results cannot exclude the hypothesis that in a maintained tetanus there is a decrease in the intrinsic cross-bridge turnover rate in the fast-twitch EDL, but not in the slow-twitch soleus muscle.

Animals↗

PubMed2026

Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.

BACKGROUND AND AIMS: Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine. METHODS: All 252 missense and in-frame insertion/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD. RESULTS: Most variants (146/252) were functionally abnormal (Z ≤ -2), with 100 having severe loss-of-function (Z ≤ -4). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z ≤ -6 had penetrance of 24.5% (15.9%-37.7% CI) and an odds ratio of 501 for BrS. CONCLUSIONS: This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.

Humans↗

PubMed2000

Contractile properties and proteins of smooth muscles of a calponin knockout mouse.

The role of h1-calponin in regulating the contractile properties of smooth muscle was investigated in bladder and vas deferens of mice carrying a targeted mutation in both alleles designed to inactivate the basic calponin gene. These calponin knockout (KO) mice displayed no detectable h1-calponin in their smooth muscles. The amplitudes of Ca2+ sensitization, force and Ca2+ sensitivity were not significantly different in permeabilized smooth muscle of KO compared with wild-type (WT) mice, nor were the delays in onset and half-times of Ca2+ sensitization, initiated by flash photolysis of caged GTPgammaS, different. The unloaded shortening velocity (Vus) of thiophosphorylated fibres was significantly (P<0.05) faster in the smooth muscle of KO than WT animals, but could be slowed by exogenous calponin to approximate WT levels; the concentration dependence of exogenous calponin slowing of Vus was proportional to its actomyosin binding in situ. Actin expression was reduced by 25-50%, relative to that of myosin heavy chain, in smooth muscle of KO mice, without any change in the relative distribution of the actin isoforms. We conclude that the faster Vus of smooth muscle of the KO mouse is consistent with, but does not prove without further study, physiological regulation of the crossbridge cycle by calponin. Our results show no detectable role of calponin in the signal transduction of the Ca2+-sensitization pathways in smooth muscle.

Animals↗

PubMed2006

Influence of different treatment approaches on non-submerged and submerged healing of ligature induced peri-implantitis lesions: an experimental study in dogs.

OBJECTIVE: [corrected] The aim of the present study was to evaluate non-submerged and submerged healing of ligature induced peri-implantitis in dogs. MATERIAL AND METHODS: Peri-implantitis was induced by ligature placement in five beagle dogs (n = 30 implants). The defects were randomly and equally allocated in a split-mouth design to either closed treatment + non-submerged healing (CNS), or open treatment + submerged healing (OS) using an Er:YAG laser (ERL), an ultrasonic device (VUS), or plastic curettes + local application of metronidazole gel (PCM), respectively. The animals were sacrificed after 3 months. Clinical, radiological and histological (e.g. new bone-to-implant contact (BIC)) parameters were assessed. RESULTS: All treatment procedures resulted in statistically significant improvements of all clinical parameters at both CNS and OS implants. Radiological improvements were merely observed at OS implants. Histomorphometrical analysis revealed that all CNS implants exhibited comparable low amounts of new BIC (1.0-1.2%), while mean BIC was statistically significant higher in the respective OS groups [ERL (44.8%), PCM (14.8%), VUS (8.7%)]. CONCLUSION: Within the limits of the present study, it was concluded that (i) OS improved the outcome of treatment in comparison with CNS and (ii) ERL seemed to be more suitable to promote re-osseointegration than PCM and VUS.

Aluminum Silicates↗

PubMed1988

Role of magnesium in activation of smooth muscle.

We studied the effects of Mg2+-free solutions on isometric force (F0) and unloaded shortening velocity (Vus) in contractions elicited by Ca2+ or by ATP after thiophosphorylation by adenosine 5'-O-(3-thiotriphosphate (ATP gamma S) in chemically skinned guinea pig taenia coli smooth muscle. In Mg2+-free solutions, increasing Ca2+ did not increase Fo above resting levels. At the peak of a control contraction elicited by Ca2+, transfer to Mg2+-free (but Ca2+-containing) solutions resulted in a rapid relaxation and concomitant dephosphorylation of myosin. After ATP gamma S, a contracture required neither Mg2+ nor Ca2+ in the solutions for control levels of Fo. Vus in the Mg2+-free solutions after ATP gamma S was approximately 50% of control and could be restored to near control levels by addition of Mg2+ but not Ca2+. After ATP gamma S, pretreatment with 4 mM EDTA and contracture in 0.1 mM EDTA-containing solutions decreased Fo to 70-80% of control and Vus to 50-60% of control. Our results suggest that the relatively high requirement for Mg2+ for contraction in skinned smooth muscle largely reflects the Mg2+ dependence of myosin kinase and not for actin-myosin interaction. The dependence of Fo on Mg2+ (in the presence of excess ATP) in taenia coli is less than that reported for skeletal muscle. Appreciable force can be maintained with no added Mg2+ in the presence of 4 mMEDTA, and thus it appears that ATP4- can be a substrate for contraction after ATP gamma S treatment. In addition, our data imply that any Ca2+-dependent regulatory mechanism that does not involve myosin phosphorylation/dephosphorylation, if present, requires Mg2+ for expression.

Adenosine Triphosphate↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed2025

Homologous Recombination Deficiency and Survival in Ovarian High-Grade Serous Carcinoma by Self-Reported Race.

BACKGROUND: Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race. METHODS: HRD features were identified using matched tumor-normal whole-exome and RNA sequencing in an HGSC cohort. We calculated age- and stage-adjusted HR and 95% confidence intervals (CI) for survival, comparing individuals with a feature to those without, separately by self-reported race. RESULTS: Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR = 0.68; 95% CI, 0.43-1.09; White HR = 0.38; 95% CI, 0.14-1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% vs. 45%; somatic 62% vs. 50%). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% vs. 49.6%; family history 68.4% vs. 34.6%). CONCLUSIONS: HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals. IMPACT: Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.

Adult↗

PubMed2026

Comprehensive Genomic Profiling Reveals the Mutational Spectrum and Clinical Significance of BRCA1/2 and Other Cancer-Susceptibility Genes in Breast Cancer Patients from Southern Tunisia.

BACKGROUND/OBJECTIVES: This study aims to investigate the mutational spectrum of BRCA1 and BRCA2 genes in a cohort of breast cancer (BC) patients from southern Tunisia, and to evaluate their clinical and prognostic significance. Additionally, this study explores the contribution of other cancer predisposition genes and the prevalence of variants of uncertain significance (VUS). RESULTS: Among the 165 patients included, pathogenic or likely pathogenic variants (P/LPVs) in BRCA1/BRCA2 were identified in 19 cases (11.51%), including 8 in BRCA1 and 11 in BRCA2. The presence of BRCA P/LPVs associated with young patients (p = 0.006) and those with TNBC (p = 0.036). Beyond BRCA1/2, PV/LPVs were detected in other cancer-related genes, including TP53 (n = 3), CHEK2, RAD50 (n = 2 cases each), and MUTYH, BARD1, and BRIP1 (one case each). Furthermore, 56 VUS were identified; among them, 7 were prioritized based on in silico predictive analyses, suggesting a potential deleterious effect. However, these VUS should not be used for clinical decision-making without additional evidence from functional and familial segregation studies. CONCLUSIONS: Our findings provide novel insights into the genetic landscape of breast cancer in southern Tunisia, highlighting the clinical relevance of BRCA1/2 mutations and the contribution of other susceptibility genes. These results support the personalized management of breast cancer patients and the implementation of expanded multigene panel testing in routine clinical practice to improve genetic counseling.

BRCA1↗

PubMed1990

Effects of modulators of myosin phosphorylation on isometric force and shortening velocity in skinned smooth muscle.

Using different modulators of myosin phosphorylation, we were able to demonstrate several different relations between Fo and Vus. The data from our studies using phosphatase indicate that force and velocity may be similarly influenced by high concentration of this enzyme which is known to modulate phosphorylation. H8, however, generated a relation in which Vus is sensitive to this modulator of myosin phosphorylation and Po is relatively insensitive except at high concentrations of H8. Whether these relations are attributable to changes in phosphorylation is still questionable and under investigation. Because H8 is competitive with respect to ATP and the effect is calcium-insensitive, it may instead have a direct effect on the actin-myosin interaction. ML9, a compound which has been reported to have effects upon MLCK through a mechanism similar to that of H8, yields a relation different than H8 but similar to the phosphatase, that is, both force and velocity decreased in a nearly parallel manner. Using these modulators, we have found that the relation between Po and Vus is not unique, reinforcing the hypothesis that crossbridge number and cycle rate may be independently modulated in smooth muscle. (Paul, 1989).

Animals↗

PubMed2026

Severe Early-Onset Fetal Growth Restriction: The Yield of Antenatal and Postnatal Genetic Testing.

OBJECTIVES: We evaluated the diagnostic yield of karyotype (KT) and chromosomal microarray (CMA) with isolated severe FGR diagnosed before 32 weeks' gestation. Exome and genome sequencing (ES/GS) level data were available in a subset of this population. METHOD: We performed a retrospective review of singleton pregnancies (delivered 2022-2025) with estimated fetal weight or abdominal circumference < 3rd percentile before 32 weeks' gestation, no sonographic structural anomalies, and diagnostic testing (KT, CMA, ES, or GS) via amniocentesis or cord blood. Cases with abnormal cell-free DNA were excluded. RESULTS: Forty cases were included (mean diagnosis 26.8 weeks). Testing was performed via amniocentesis in 42% and cord blood in 58%. All KT (27/40) were normal. CMA (39/40) identified one pathogenic CNV (2.5%) and three (7.5%) variants of uncertain significance (VUS). Four (10%) showed ≥ 1 region of absence of heterozygosity (AOH) > 10Mb; one revealed maternal uniparental disomy of chromosome 6. Sequencing (N = 10) detected one VUS in COL1A1. Acute viral infection was not observed in any of the cases. CONCLUSIONS: CMA was diagnostic in 2/39 (5.1%) cases, a pathogenic CNV implicating the SHOX gene, and maternal UPD 6, which were consistent with FGR. There was a remarkable rate (10%) of AOH. Further investigation, including placental studies and genome sequencing, may elucidate whether AOH is a contributing factor for FGR.

Humans↗

PubMed2002

Diagnosis of vesicoureteral reflux with ultrasonography.

The primary diagnostic procedure for evaluation of vesicoureteral reflux (VUR) in children is fluoroscopic voiding cystourethrography (VCUG). Radionuclide cystography (RNC) is an alternative, sensitive method for diagnosing VUR, but it lacks spatial resolution. Over the past 2 decades, in an effort to eliminate the radiation exposure intrinsic to these methods, many endeavors had been made to use ultrasonography (US) for the diagnosis of VUR. The various attempts that have been undertaken are reviewed. The real breakthrough in the US diagnostic option has come with the availability of stable US contrast media that can be administered intravesically. Comparison between contrast-enhanced sonographic reflux examination (voiding urosonography, VUS) and VCUG/RNC has revealed the high concordance between these imaging modalities regarding the diagnosis or exclusion of VUR. Imaging of the urethra still necessitates the performance of VCUG. VUS is used in routine imaging primarily for follow-up cases, girls, and screening high-risk groups for reflux. Using these selection criteria, the number of VCUG investigations can be reduced by over half and, consequently, a significant reduction of radiation exposure in children can be achieved. With the emergence of harmonic US imaging, the sonographic reflux examination will gain further diagnostic potential and widespread application. The whole field of sonographic diagnosis of reflux is still in the process of rapid development.

Forecasting↗

PubMed2026

Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy.

Variants of uncertain significance (VUS) in the LMNA gene represent a major challenge in clinical genetics, as insufficient functional evidence limits their interpretation and clinical decision-making in laminopathies, including dilated cardiomyopathy (DCM). Here, we generated two isogenic induced pluripotent stem cell (iPSC) lines carrying homozygous LMNA variants, c.293A > G (p.Glu98Gly) and c.439G > A (p.Ala147Thr) by prime editing of a healthy donor iPSC line. Both variants are located within Coil 1B domain of lamin A. The edited iPSC lines retain normal morphology, pluripotency, genomic integrity, and trilineage differentiation capacity, providing a valuable platform for functional characterization and potential clinical reclassification of LMNA VUS.

Humans↗

PubMed2000

Ovarian function during use of Nestorone(R) subdermal implants.

Nestorone(R) progestin (NES) is a potent 19-nor-progesterone derivative which is biologically inactive when administered orally; however, it is an excellent option for implant contraception. The objective of this study was to evaluate ovarian function during use of either one 4-cm or two 3-cm NES implants for 24 months. A total of 60 volunteers were enrolled in each dose group. Vaginal ultrasound (VUS) and blood sampling for determinations of estradiol (E(2)), progesterone (P) and NES serum levels were carried out twice a week for 6 consecutive weeks, beginning in months 1, 6, 12, 18, and 24 of implant use. Serum levels of NES declined with time, with a more pronounced decrease during the first 18 months of implant use; thereafter, NES levels remained stable until the end of the study at 24 months. Luteal activity was very infrequent during the first year of use (<3%) but increased during the second year, occurring in 27% and 35% of the sampling periods in the 1-implant group, and 2% and 16% of the sampling periods in the 2-implant group, at months 18 and 24 of use, respectively. No luteal activity was observed with NES levels above 80 pmol/L. Serum P levels in periods of luteal activity were significantly lower than those of controls. Persistent anovulatory follicles were the most common VUS finding and this was associated with E(2) levels that remained within the normal range (101-1500 pmol/L) in the majority of the sampling periods studied. Considering that a single implant offers advantage for insertion and removal, a new single NES implant is being developed with a slightly higher release rate, to reduce effectively the incidence of ovulation and provide a greater margin of safety beyond 2 years.

Adolescent↗

PubMed2026

The importance of integrating genetic testing into reproductive medicine: a retrospective observational study investigating the monogenic causes of human infertility in couples considering ICSI.

The genetic landscape of human infertility is complex with diverse etiologies. Identifying the underlying etiology is crucial for guiding reproductive decisions and improving management for infertile couples. Here, we aim to report on the molecular spectrum of monogenic genetic causes of reproductive failure. Over a 3-year period, we recruited all infertile couples considering assisted reproductive technologies (ART) for whom the underlying genetic cause had been identified, in either partner, using exome sequencing (ES). Clinical data of all participants along with their hormonal profiles, sonographic findings and spermograms were recorded. The study included 50 couples with primary infertility. Clinically, male factor infertility was documented in 26 patients, female factor infertility in 10, while reproductive failure was unexplained in the remaining 14 couples. All participating couples had potentially disease-causing variants in infertility genes. ES identified variants related to male infertility in 26 men, while variants in female infertility-related genes were detected in the remaining couples (n = 24). According to ACMG classification criteria, 78% (39/50) of couples harbored pathogenic/likely pathogenic (P/LP) variants, whereas 22% (11/50) carried variants of uncertain significance (VUS). In view of the identified genetic etiologies, the cohort was stratified into two groups based on the predicted reproductive outcome: (1) couples with significantly impaired reproductive potential, and (2) couples who can have biological children using appropriate medical interventions. However, classifications involving VUS were interpreted cautiously and considered exploratory. This study provides further evidence for the molecular heterogeneity of human infertility and highlights the usefulness of genetic testing for infertile couples pursuing ARTs.

Humans↗

PubMed2021

Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Biomarkers, Tumor↗

PubMed2000

Computer-aided epiluminescence microscopy of pigmented skin lesions: the value of clinical data for the classification process.

Early melanoma is often difficult to differentiate from benign pigmented skin lesions (PSLs). Digital epiluminescence microscopy (DELM) and automated image analysis could represent possible aids for inexperienced clinicians. We designed an automated computerized image analysis system that has the potential for use as an additional tool for the differentiation of melanoma from dysplastic naevi and common naevi. The PC-based pilot system was attached to a common DELM system as the image source. Digital images of PSLs were automatically segmented and a panel of 107 morphological parameters were measured. Additionally, seven clinical parameters were evaluated and used as an additional source of information. Neural networks were then trained to distinguish melanoma from benign PSLs. One class of networks was trained solely based on the morphometric features, whereas the second class of networks was trained on the combination of morphometric and clinical features. The automatic segmentation algorithm was correct in 96% of cases. Using three-way receiver operating characteristic (ROC) analysis, for networks trained solely on morphometric features the volume under surface (VUS) was 0.617 (SD 0.036). The performance was significantly better for networks trained on the combination of both morphometric and clinical features (VUS = 0.682, SD 0.035). In a dichotomous model, distinguishing benign lesion (common naevi + dysplastic naevi) from melanoma, the area under the curve (AUC) from two-way ROC analysis was 0.942 (SD 0.018) for networks trained solely on morphometric features and 0.968 (SD 0.012) for those trained on the combination of clinical and morphometric data (P= NS). Automated feature extraction from PSLs and the training of neural networks as classifiers has thus shown satisfactory performance in a large scale experiment. The addition of clinical data significantly increases the diagnostic performance for distinguishing three classes of lesions (i.e. common naevi, dysplastic naevi and melanoma). Such integrated systems hold promise as a decision aid for the diagnosis of PSLs.

Algorithms↗