Citations

PURPOSE Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

Abstract Acute graft-versus-host disease (GVHD), a serious complication of allogeneic hematopoietic cell transplantation (HCT), frequently involves the skin. Since clinicopathologic features of GVHD can mimic those of certain drug eruptions, accurate diagnosis can be challenging. We aimed to develop a tissue-based molecular assay to improve differentiation of GVHD from vacuolar interface drug eruption in the post-HCT period. After identifying 62 putative tissue-based biomarkers using unbiased molecular methods, we incorporated 26 into a quantitative RT-PCR assay. We tested skin biopsy specimens showing vacuolar interface changes attributable to either acute GVHD (n=67) or drug reaction (n=17), as classified by meticulous review of clinical features and course. Data were incorporated into clinical-molecular fusion diagnostic models. Significant differences in the expression of several genes, including MX1, MNDA, OAS, LIMA1, GSTM5, and SPP1, were detected between the two diagnostic groups (p<0.05). The optimal fusion model, which incorporated quantitative expression of MX1, MNDA, OAS, and GSTM5, as well as the clinical feature of diarrhea, imparted high diagnostic accuracy (receiver operating characteristic area-under-curve: 0.89). This novel tissue-based diagnostic molecular assay and fusion model demonstrates potential to improve distinction of GVHD from drug eruptions in the post-HCT setting. Multicenter validation studies are required.

AbstractThe pathologic assessment of lung cancers provides essential guidance to the surgeon and oncologist who are considering the best treatment strategies for patients with both early and advanced‐stage disease. The management of patients with lung cancer is predicated first and foremost on access to an accurate diagnosis, even when the sample size is limited, as is often the case with use of modern, minimally invasive sampling techniques. Once the diagnosis and disease stage are established, predictive biomarker testing may be essential, particularly for those patients with nonsmall cell lung carcinoma (NSCLC) being considered for immunotherapy or genomic biomarker‐driven targeted therapy. This review will discuss the best practices for the diagnosis of NSCLC using morphology and immunohistochemistry, thus providing the surgeon with needed information to understand and critically evaluate pathology reports. Controversial and evolving topics including tumor spread through airspaces, evaluation of multiple tumors, and staging based on invasive tumor size will be addressed. Clinical genomic profiling in NSCLC is driven by published guidelines and reflects evidence based on clinical trials and regulatory approvals. In this fast‐moving space, surgeons should be aware of the critical immunohistochemical and genomic biomarkers that drive systemic therapy decisions and anticipate when such testing will be required, both to ensure adequate sampling and to advise the pathologist when tumor material will be required for biomarker analysis. The basic approaches to and sample requirements for molecular biomarker testing will be addressed. As biomarker testing moves exclusively from advanced‐stage patients into earlier stage disease, the surgeon should be aware of the relevant markers and work with the pathologist and oncologist to ensure that this information is available to facilitate timely access to therapies not just in the advanced setting, but in consideration of neoadjuvant and adjuvant care.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

Androgenic alopecia (AGA) is a genetically predetermined condition that occurs as a result of stepwise miniaturization of the dermal papilla. During this process, the hair follicle suffers from increasing malnutrition and eventually dies, causing progressive hair loss. We recently highlighted that HIF-1α modulation may counteract hair loss. Here, we aim to demonstrate the positive influence of Tomorrowlabs HIF strengthening factor [HSF] hair restoration technology on hair biology in a monocentric blinded clinical trial over a total period of 9 months. A trial with 20 subjects (4 female and 16 male) and once-daily application of [HSF] hair restoration technology to the scalp was conducted. To assess the tolerability and efficacy of [HSF], testing included dermatological assessment, determination of hair loss by counting after combing, macro images of the head and TrichoScan evaluation of hair density as well as the proportion of anagen hair versus telogen hair. The clinical data show Tomorrowlabs [HSF] hair restoration to be safe and effective to counteract AGA. The use of Tomorrowlabs [HSF] hair restoration resulted in improvements in the clinical parameters of hair quality such as thickness (+7.2%), hair density (+14.3%) and shine and elasticity (+20.3%) during the test period. The effectiveness of the test product was further determined by a significant reduction in hair loss of an average of 66.8% in treatment-responsive subjects after 6 months and an increase in hair growth reaching up to 32.5%, with an average percentage change of 8.4% in all participants and 10.8% in the responsive patients (85% of the study cohort) after 9 months on TrichoScan evaluation. The hair growth cycle was harmonized with the result of an average anagen hair percentage increase of +8.0% and telogen hair percentage reduction of −14.0% shown in the test area. Applicable for both sexes in an alcohol-free formulation, beneficial to scalp health and free of complications or side effects, this novel product provides objectively measurable results counteracting hair loss paired with an improved look and feel of the hair.

Abstract The transcription factor Runx1 is critical for T cell development and maturation. CD4-Cre Runx1 conditional knockout mice have a block in T cell maturation, leading to complement deposition on CD4+ recent thymic emigrants, leaving very few CD4+ T cells in peripheral lymphoid organs. Consistent with a block in maturation, peripheral Runx1-deficient CD4+ T cells fail to produce normal levels of TNF-a upon stimulation. These CD4+ T cells that persist in CD4-Cre Runx1 cKO mice possess a phenotype not found in other genetically modified mice with a block in T cell maturation. Thymic- and splenic-derived T cells from the CD4-Cre Runx1 cKO exhibit altered expression of markers indicative of anergy including FR4 and CD73. This suggests Runx1 plays a role in regulating the development of T cell tolerance which is disrupted upon deletion of Runx1 in CD4+ T Cells. To test this, we have generated a mixed bone marrow chimera (BMC) system with Estrogen Receptor-Cre Runx1 knockout and B6.SJL bone marrow to knock out Runx1 in mature T cells. Surprisingly, in the mixed BMC both the ER-Cre Runx1 cKO and the B6.SJL peripheral T cells acquire a functionally hyporesponsive phenotype, suggesting that Runx1 regulates an extrinsic signaling mechanism controlling tolerance. Moving forward, this BMC model allows us to investigate the development of this anergic phenotype in mature T cells, and tests the hypothesis that Runx1 plays a critical role in regulating T cell tolerance.

AbstractOral lichen planus (OLP) confers an approximately 1% risk of transformation to oral squamous cell carcinoma (OSCC). Early identification of high‐risk OLP would be very helpful for optimal patient management. We aimed to discover specific tissue‐based protein biomarkers in patients with OLP who developed OSCC compared to those who did not. We used laser capture microdissection– and nanoLC–tandem mass spectrometry to assess protein expression in fixed lesional mucosal specimens in patients with indolent OLP (no OSCC after at least 5‐year follow‐up, n = 6), transforming OLP (non‐dysplastic epithelium with lichenoid inflammation marginal to OSCC, n = 6) or normal oral mucosa (NOM, n = 5). Transforming OLP protein profile was enriched for actin cytoskeleton, mitochondrial dysfunction and oxidative phosphorylation pathways. CA1, TNNT3, SYNM and MB were overexpressed, and FBLN1 was underexpressed in transforming OLP compared with indolent OLP. Integrin signalling and antigen presentation pathways were enriched in both indolent and transforming OLP compared with NOM. This proteomic study provides potential biomarkers, such as CA1 overexpression, for higher‐risk OLP. While further validation studies are needed, we propose that epithelial–mesenchymal transition may be involved in OLP carcinogenesis.

ObjectiveThis study aimed to compare the prevalence and incidence of vocal fold pathologies among undergraduate classical, musical theatre, and contemporary commercial music (CCM) students over two‐time points.MethodsThis study is part of a longitudinal investigation. Videostroboscopic examinations were rated, with consensus among three of four expert blinded raters confirming the presence of pathology. Association between genre of singer and the presence of pathology, interrater reliability, and intra‐rater reliability were calculated. Prevalence and incidence of pathologies were compared across genres.ResultsDuring first‐year evaluations, 32% of musical theatre, 18% of CCM, and 0% of classical students had vocal pathologies. The prevalence at third‐year evaluations showed 22% of classical, 39% of musical theatre, and 27% of CCM participants having vocal fold pathologies. The incidence of pathologies was 67% of musical theatre students compared to 22% of classical students and 27% of CCM students. The four raters demonstrated fair to moderate interrater agreement. Singing Voice Handicap Index‐10 scores were normal for CCM singers at both time points but elevated for musical theatre and classical singers.ConclusionNo classical singers were found to have pathology during first‐year evaluations, although CCM and musical theatre singers showed evidence of vocal fold pathologies. At third‐year evaluations, all three genres had an apparent increase in prevalence of pathologies. Implications of this study suggest that more time in the field and intense voice usage may lead to a greater risk of pathology for all singers, regardless of genre.Level of Evidence2 Laryngoscope, 133:2317–2324, 2023

AbstractBackgroundTAR DNA‐binding protein 43 (TDP‐43) mislocalization is present in over 50% of patients with frontotemporal dementia and about 20% of patients with Alzheimer’s disease, but there is still an unmet need for clinical trials targeting sporadic TDP‐43 pathology in patients with dementia. The semantic variant of primary progressive aphasia (svPPA) is highly predictive of frontotemporal lobar degeneration with TDP‐43 mislocalization (FTLD‐TDP) and presents an ideal cohort in which to explore therapeutics with potential benefit across the spectrum of TDP‐43 pathology. Oxidative stress promotes mislocalization of TDP‐43 in neurons and may be a viable therapeutic target in svPPA and other FTLD‐TDP disorders. Verdiperstat is a potent, oral, CNS penetrant, myeloperoxidase inhibitor that reduces production of oxidative species from microglia. The Veri‐T trial (NCT05184569) explores the therapeutic potential of verdiperstat and is the first clinical trial to focus on patients suffering from svPPA.MethodsVeri‐T is a multisite, phase 1, randomized, double‐blind, placebo‐controlled trial. N = 64 participants with svPPA will be randomized 3:1 to oral verdiperstat (titrated to a dose of 600mg BID) or placebo for 6 months of double‐blind therapy. Neuropsychological assessments, plasma, CSF, and volumetric brain imaging are collected prior to and upon conclusion of treatment. Recruitment is ongoing at 5 ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) research network clinical centers.ResultsThe primary objective is to determine the safety and tolerability of verdiperstat in svPPA. The secondary objective is to determine the pharmacokinetic profile of verdiperstat in this cohort. Exploratory endpoints are focused on identifying potential pharmacodynamic effects and identifying endpoints for future efficacy trials including plasma myeloperoxidase activity, CSF biomarkers of glial activity (chitinase‐family proteins), neurodegeneration (neurofilament light chain), and unbiased CSF proteomics (Somalogics), as well volumetric MRI changes unique to svPPA, and cognitive and language impairments measured using the ALLFTD Mobile App.ConclusionThe Veri‐T trial examines the safety, tolerability and pharmacokinetic properties of verdiperstat in svPPA, and explores novel pharmacodynamic biomarkers and outcome measures that could be employed in future efficacy studies. Veri‐T is the first multicenter clinical trial of a potentially disease modifying agent for svPPA, and the first to leverage resources of the ALLFTD network.