Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

An update on oral cavity cancer: epidemiological trends, prevention strategies and novel approaches in diagnosis and prognosis.

In the UK, the incidence of oral cavity cancer continues to rise, with an increase of around 60% over the past 10 years. Many patients still present with advanced disease, often resulting in locoregional recurrence and poor outcomes, which has not changed significantly for over four decades. Changes in aetiology may also be emerging, given the decline of smoking in developed countries. Therefore, new methods to better target prevention, improve screening and detect recurrence are needed. High-throughput 'omics' technologies appear promising for future individual-level diagnosis and prognosis. However, given this is a relatively rare cancer with significant intra-tumour heterogeneity and variation in patient response, reliable biomarkers have been difficult to elucidate. From a public health perspective, implementing these novel technologies into current services would require substantial practical, financial and ethical considerations. This may be difficult to justify and implement at present, therefore focus remains on early detection using new patient-led follow-up strategies. This paper reviews the latest evidence on epidemiological trends in oral cavity cancer to help identify at risk groups, population-based approaches for prevention, in addition to potential cutting-edge approaches in the diagnosis and prognosis of this disease.

Plasma tumor gene conversions after one cycle abiraterone acetate for metastatic castration-resistant prostate cancer: a biomarker analysis of a multicenter international trial.

BACKGROUND: Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment. PATIENTS AND METHODS: Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS). RESULTS: Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients. CONCLUSIONS: Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.

Outcomes and complications associated with malar onlays: literature review and case series of 119 implants.

Alloplastic malar onlays have been used by surgeons to correct or enhance the midfacial skeleton for over 40 years. Case series have shown respectable results using different alloplastic materials in various maxillofacial subsites. However, these articles include small numbers of patients with limited follow up. We present a literature review specifically concentrating on porous polyethylene (Medpor, Stryker) and polyethyl ether ketone (PEEK) malar onlays. We illustrate the technique used by a single oral and maxillofacial surgeon for placement of 119 implants in 61 patients over a 14-year period, and show the results of this work with long-term follow up. A complication rate of 2.5% in this cohort was reported, with follow up of three years, demonstrating that this technique for midfacial correction is successful in both the short and the long term.

Value-driven attentional capture is modulated by the contents of working memory: An EEG study.

Attention and working memory (WM) have previously been shown to interact closely when sensory information is being maintained. However, when non-sensory information is maintained in WM, the relationship between WM and sensory attention may be less strong. In the current study, we used electroencephalography to evaluate whether value-driven attentional capture (i.e., allocation of attention to a task-irrelevant feature previously associated with a reward) and its effects on either sensory or non-sensory WM performance might be greater than the effects of salient, non-reward-associated stimuli. In a training phase, 19 participants learned to associate a color with reward. Then, participants were presented with squares and encoded their locations into WM. Participants were instructed to convert the spatial locations either to another type of sensory representation or to an abstract, relational type of representation. During the WM delay period, task-irrelevant distractors, either previously-rewarded or non-rewarded, were presented, with a novel color distractor in the other hemifield. The results revealed lower alpha power and larger N2pc amplitude over posterior electrode sides contralateral to the previously rewarded color, compared to ipsilateral. These effects were mainly found during relational WM, compared to sensory WM, and only for the previously rewarded distractor color, compared to a previous non-rewarded target color or novel color. These effects were associated with modulations of WM performance. These results appear to reflect less capture of attention during maintenance of specific location information, and suggest that value-driven attentional capture can be mitigated as a function of the type of information maintained in WM.

A Rare Fourth Branch of the Marginal Mandibular Nerve.

This report describes a good example of the rare fourth branch of the marginal mandibular nerve. This case emphasizes the need for respecting the variation in the marginal mandibular nerve when carrying out surgery.

A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone.

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/ß-catenin pathway were more frequently mutated and negative regulators of Wnt/ß-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/ß-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Integrin α4-positive human trophoblast progenitors: functional characterization and transcriptional regulation.

STUDY QUESTION: What are the functional characteristics and transcriptional regulators of human trophoblast progenitor cells (TBPCs)? SUMMARY ANSWER: TBPC lines established from the human smooth chorion by cell sorting for integrin α4 expressed markers of stemness and trophoblast (TB) stage-specific antigens, invaded Matrigel substrates and contributed to the cytotrophoblasts (CTBs) layer of smooth chorion explants with high-mobility group protein HMGI-C (HMGA2) and transcription factor GATA-4 (GATA4) controlling their progenitor state and TB identity. WHAT IS KNOWN ALREADY: Previously, we reported the derivation of TBPC lines by trypsinization of colonies that formed in cultures of chorionic mesenchyme cells that were treated with an activin nodal inhibitor. Microarray analyses showed that, among integrins, α4 was most highly expressed, and identified HMGA2 and GATA4 as potential transcriptional regulators. STUDY DESIGN, SIZE, DURATION: The aim of this study was to streamline TBPC derivation across gestation. High-cell surface expression of integrin α4 enabled the use of a fluorescence-activated cell sorter (FACS) approach for TBPC isolation from the human smooth chorion (n = 6 lines). To confirm their TBPC identity, we profiled their expression of stemness and TB markers, and growth factor receptors. At a functional level, we assayed their invasive capacity (n = 3) and tropism for the CTB layer of the smooth chorion (n = 3). At a molecular level, we studied the roles of HMGA2 and GATA4. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Cells were enzymatically disassociated from the human smooth chorion across gestation. FACS was used to isolate the integrin α4-positive population. In total, we established six TBPC lines, two per trimester. Their identity was determined by immunolocalization of a suite of antigens. Function was assessed via Matrigel invasion and co-culture with explants of the human smooth chorion. An siRNA approach was used to down-regulate HMGA2 and GATA4 expression and the results were confirmed by immunoblotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses. The endpoints analyzed included proliferation, as determined by 5-bromo-2'-deoxyuridine (BrDU) incorporation, and the expression of stage-specific antigens and hormones, as determined by qRT-PCR and immunostaining approaches. MAIN RESULTS AND THE ROLE OF CHANCE: As with the original cell lines, the progenitors expressed a combination of human embryonic stem cell and TB markers. Upon differentiation, they primarily formed CTBs, which were capable of Matrigel invasion. Co-culture of the cells with smooth chorion explants enabled their migration through the mesenchyme after which they intercalated within the chorionic CTB layer. Down-regulation of HMGA2 showed that this DNA-binding protein governed their self-renewal. Both HMGA2 and GATA4 had pleitropic effects on the cells' progenitor state and TB identity. LIMITATIONS, REASONS FOR CAUTION: This study supported our hypothesis that TBPCs from the chorionic mesenchyme can contribute to the subpopulation of CTBs that reside in the smooth chorion. In the absence of in vivo data, which is difficult to obtain in humans, the results have the limitations common to all in vitro studies. WIDER IMPLICATIONS OF THE FINDINGS: The accepted view is that progenitors reside among the villous CTB subpopulation. Here, we show that TBPCs also reside in the mesenchymal layer of the smooth chorion throughout gestation. We theorize that they can contribute to the CTB layer in this region. This phenomenon may be particularly important in pathological situations when CTBs of the smooth chorion might provide a functional reserve for CTBs of the placenta proper. STUDY FUNDING/COMPETING INTERESTS: Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award P50HD055764. O.G., N.L., K.O., A.P., T.G.-G., M.K., A.B., M.G. have nothing to disclose. S.J.F. received licensing fees and royalties from SeraCare Life Sciences for trisomic TBPC lines that were derived according to the methods described in this manuscript. TRIAL REGISTRATION NUMBER: N/A.

A genomics-based framework for identifying biomarkers of human neurodevelopmental toxicity.

Human embryonic stem cell (hESC) neural differentiation models have tremendous potential for evaluating environmental compounds in terms of their ability to induce neurodevelopmental toxicity. Genomic based-approaches are being applied to identify changes underlying normal human development (in vitro and in vivo) and the effects of environmental exposures. Here, we investigated whether mechanisms that are shared between hESC neural differentiation model systems and human embryos are candidate biomarkers of developmental toxicities for neurogenesis. We conducted a meta-analysis of transcriptomic datasets with the goal of identifying differentially expressed genes that were common to the hESC-model and human embryos. The overlapping NeuroDevelopmental Biomarker (NDB) gene set contained 304 genes which were enriched for their roles in neurogenesis. These genes were investigated for their utility as candidate biomarkers in the context of toxicogenomic studies focused on the effects of retinoic acid, valproic acid, or carbamazepine in hESC models of neurodifferentiation. The results revealed genes, including 13 common targets of the 3 compounds, that were candidate biomarkers of neurotoxicity in hESC-based studies of environmental toxicants.

Antisynthetase syndrome: two cases presenting orofacial manifestations.

Antisynthetase syndrome is a rare autoimmune disease that is characterised by inflammatory myositis, and interstitial lung disease or chronic arthropathy, or both. To the best of our knowledge, orofacial manifestations have not previously been reported. We present 2 patients with orofacial disease: one with aphthous-like oral ulceration and the other with hyposalivation.

Impact of speed change on estimated journey time: failure of drivers to appreciate relevance of initial speed.

Higher speeds are associated with increases in the probability of crashing and the severity of the outcome. Logically drivers speed to save time, and research evidence supports this assertion. It is therefore important to investigate drivers' understanding of how speed change impacts on journey time. Since it is likely that drivers do not appreciate the reciprocal nature of the function which links these two variables, and its implications, two predictions can be made: the impact of a speed change will be underestimated at low speeds and overestimated at high speeds. This issue was addressed through four questions generated by manipulating Speed Change (increase versus decrease) and Starting Speed (30 mph versus 60 mph) with the participants being asked how they felt these variables would impact on journey time. These were included in a large survey addressing speed-related issues. Participants were a representative quota sample of 1005 UK drivers, interviewed by questionnaire. The findings indicated that three of the four questions produced results consistent with the predictions made. Furthermore, a repeated measures factorial ANOVA indicated that there was no real appreciation of how starting speed impacted on journey time. A disordinal interaction provided evidence that drivers wrongly believed that as starting speed increased the impact of a speed rise also increased; the opposite is true. For speed decreases, drivers appeared to think that starting speed had little impact on the amount of time saved. It is recommended that these findings be integrated into driver training and speed awareness courses.

Muscle fiber orientation in muscles commonly injected with botulinum toxin: an anatomical pilot study.

The endplate zone is assumed to be at about the midpoint of a muscle fiber. This study was designed to locate the middle of the muscle fibers of commonly injected muscles, thus identifying the endplate zone of these muscles. The proximal and distal musculotendinous junctions in muscles of the upper and lower extremities were identified. Orientation of muscle fibers was determined. Measurements using common surface landmarks were used to determine the relationship of these muscles with the landmarks (e.g., biceps muscle bulk extends from the upper fourth to the lower fourth of the humerus). Figures were developed using these measurements so as to be able to extrapolate these measurements to other patients of varying sizes. Illustrations of muscle fiber orientation were done and the assumed location of motor endplate bands marked. Color illustrations will be shown. With the thought that the endplate zone is at the middle of the muscle fiber, this detailed study of muscle fibers helps identify assumed location of motor endplates of specific muscles, thereby improving technique and efficacy of botulinum toxin injections.

Treatment of neuromuscular and musculoskeletal problems in cerebral palsy.

Cerebral palsy typically involves a variety of neuromuscular and musculoskeletal problems. These problems include spasticity, dystonia, contractures, abnormal bone growth, poor balance, and loss of selective motor control. These problems can interfere with function and treating them can improve function. The treatments include physical and occupational therapy, bracing, oral medications, neurolytic blocks, neurosurgical procedures, orthopaedic surgery and others. Using a multidisciplinary treatment team with a good understanding of cerebral palsy, the best treatment options can be determined and functional outcomes maximized.

Use of botulinum toxin type A in pediatric patients with cerebral palsy: a three-center retrospective chart review.

Over the last several years, botulinum toxin type A has gained widespread use for the management of focal spasticity in children with cerebral palsy. To assess the current patterns of botulinum toxin type A use in the clinical setting, the dose, muscles injected, age at injection, and interval between injections of botulinum toxin type A treatments were examined in a retrospective chart review of children with cerebral palsy (N = 270) over a 2-year period at three major treatment centers. The average dose of botulinum toxin type A across the three centers ranged from 7.7 to 10.8 U/kg body weight, and the average total amount of botulinum toxin type A injected at a single visit ranged from 154 to 205 U. The majority of botulinum toxin type A injections were to the muscles to the lower limbs. The average age at first injection was 6.2 years, and the average interval between injections ranged from 134 to 199 days.

Spasticity management in the child with spastic quadriplegia.

In children with spastic quadriplegia, also described as 'whole body involvement', spasticity can interfere with motor function, contributes to the development of deformities and adversely impacts on care, positioning, and comfort. In this population, spasticity interventions address goals such as improving comfort, reducing pain, easing the burden of carers, slowing the progression of musculoskeletal deformities and perhaps improving function. Children with severe diplegia are distinguished from those with quadriplegia by their ability to ambulate, as well as by a greater emphasis being placed on functional motor goals even though similar treatment modalities are often employed to manage spasticity. The many treatment options currently available include, but are not limited to, botulinum toxin type A, phenol neurolysis, oral medications, intrathecal baclofen, selective dorsal rhizotomy, and orthopaedic surgery. The integration of these treatment modalities can help to optimize the overall care and function for a child with spastic quadriplegia or severe diplegia. However, the development of a management programme is complex and needs to take into account many factors, including age, weight and nutritional status, rate of progression of musculoskeletal deformities, developmental potential, comorbid conditions, current functional status and prognosis, and family and patient treatment goals. Children with marked spasticity are likely to benefit from a combination of interventions, rather than a single treatment modality. Because of these complexities, management should be planned and coordinated by a multidisciplinary team of medical and allied health professionals which recognizes the central role of the family in all decisions. Once the special characteristics of the child with spastic quadriplegia and the various treatment options are understood, outcomes can be maximized.

Recommendations for the use of botulinum toxin type A in the management of cerebral palsy.

Botulinum toxin type A (BTX-A) is increasingly being used for the treatment of childhood spasticity, particularly cerebral palsy. However, until very recently, all such use in this indication has been unapproved with no generally accepted treatment protocols, resulting in considerable uncertainty and variation in its use as a therapeutic agent. In view of the increasing awareness of, and interest in, this approach to the treatment of spasticity, and also the recent licensing in a number of countries of a BTX-A preparation for treating equinus deformity in children, it would seem timely to establish a framework of guidelines for the safe and efficacious use of BTX-A for treating spasticity in children. This paper represents an attempt, by a group of 15 experienced clinicians and scientists from a variety of disciplines, to arrive at a consensus and produce detailed recommendations as to appropriate patient selection and assessment, dosage, injection technique and outcome measurement. The importance of adjunctive physiotherapy, orthoses and casting is also stressed.