Pathological Variants Research Articles

Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10.

The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-- Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10Q108P proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools. This study presents the foundational characterization of the structural features of CHCHD10Q108P and compares them with those of the wild-type counterpart. We conducted multiple run molecular dynamics simulations and bioinformatics analyses. Our findings reveal distinct differences in structural properties, free energy surfaces, and the outputs of principal component analysis between these two proteins. These results contribute significantly to the comprehension of CHCHD10 and its Q108P variant in terms of pathology, biochemistry, and structural biology. The reported structural properties hold promise for informing the development of more effective treatments for ALS.

DICER1 Mutations Enable Rare Tumor Formation

Abstract Introduction/Objective DICER1 is a tumor suppressor gene that imparts a slight increase in tumor formation when mutated. The protein plays a role in processing miRNA that silences transcription. Germline mutations of DICER1 predispose to tumors in a known set of organs and rarely in other locations. However the presence of additional genetic aberrations further increases the likelihood of tumor formation. Acting as a compounding factor, DICER1 mutations can present a constantly shifting cancer phenotype of affected patients. Of particular interest here is the development of both Pineoblastoma and Malignant spindle cell sarcoma in a young patient. Sarcomas are estimated to make up only 10% of pediatric cancers and Pineal masses only 3%. Methods/Case Report This case involves an 8 year old male with a history of Pineoblastoma who originally presented with slowly worsening ataxia. A screening ultrasound on following visits identified an abdominal mass that was confirmed with computed tomography. Subsequent biopsies showed malignant spindle cells arranged in a herringbone pattern. Additionally these cells displayed high mitotic activity and hyperchromatic nuclei. Surprisingly, they also demonstrated extramedullary hematopoiesis. Multiple stains were performed however no significant conclusion could be made. The appearance of this tumor and its rarity prompted a request for a Complete Comprehensive Sarcoma Panel via Next Generation Sequencing. This confirmed the presence of pathologic BRAF and DICER1 genes. From that the diagnosis of DICER1 associated Malignant Spindle Cell Sarcoma was made. BRAF V600E is the most common genetic variant and is seen in multiple cancers but only seen in 1-3% of sarcomas. Pathologic variants of the DICER1 gene exist on exons 13 and 25. The presence of these exon mutations in some way affect DICER1 protein function and compound the effects of the mutated BRAF gene. This situation is unique as such neoplasms are rarely found in the anterior abdominal wall and showcases the effects of DICER1 on rare tumor phenotypes. Results (if a Case Study enter NA) NA Conclusion Continuing research into both DICER1 protein pathways is essential for isolating a diagnosis and guiding treatment. It would seem screening images and genetic testing would benefit pediatric or even adult patients with common and rare cancers. Extra effort made toward this would not be outside the norm as personalized medicine is gradually becoming the standard for cancer treatment.

Uncovering etiologic genes through whole exome sequencing in pediatric epilepsy: A case series from Thailand

Introduction Developmental and epileptic encephalopathy (DEE) is characterized by seizures that are difficult to control for a long time and affect development in children who are previously normal or delayed. Therefore, children with DEE should be diagnosed promptly because certain types of the disease respond well to specific medications. In developing countries with limited universal coverage for whole exome sequencing (WES), identifying key clinical features in this patient group will help us make more accurate selections for investigations. The purpose of this study was to determine the prevalence of WES and its common clinical features in children with epileptic encephalopathy. Methods Ten volunteers aged 0-15 years were diagnosed with epilepsy with two or more symptoms of drug-resistant epilepsy, developmental delays, and abnormal nervous system/or dysmorphic features, and their electroencephalogram (EEG) showed abnormal background or specific patterns of epileptiform discharges. These were subjected to WES for the standard > 400 genes in the epilepsy panel. Results The established diagnosis was 4/10. Two known pathogenic variants, SCN2A and PCDH19. Two novel pathological variants, CHD2 and SCN1A. These are drug-resistant epilepsy, which is initially difficult to control and cannot stop antiseizure medications. Out of the 2/4 had moderate to severe intellectual disability. 3/4 had generalized epileptiform discharge activities. Conclusions This study showed a similar detection rate to that of a previous WES study. All the patients had difficult-to-treat epilepsy. For those who have not found abnormalities with the same clinical symptoms, further examinations using other methods should be conducted.

7655 Genetic Mysteries Unveiled: Unusual Mutation Unraveled In Hypophosphatasia

Abstract Disclosure: A. Sharma: None. P. Katikaneni: None. S. Tanveer: None. K. Selk: None. Introduction: Hypophosphatasia (HPP), an inherited dental-osseous metabolic illness, is caused by inactivating mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), which leads to a decrease in TNSALP enzymatic activity. Patients with HPP typically experience dental and skeletal mineralization issues as their most common symptoms; musculoskeletal abnormalities, numerous fractures, tiredness, and migraines are less common clinical presentations. Case Report: Our 75-year-old male patient initially presented 1.5 years prior following a spontaneous T12 vertebral fracture. A bone biopsy was performed and did not reveal evidence of malignancy. Testing for SPEP/UPEP was not consistent with myeloma, and thyroid testing was also unrevealing. His alkaline phosphatase level was consistently <40 IU/L since 1999. An evaluation was done for low alkaline phosphatase and secondary reasons for bone loss. This testing did not reveal vitamin D deficiency, parathyroid disease, hypophosphatemia, laboratory evidence of celiac disease, hypogonadism, or hypomagnesemia. A vitamin b6 level was markedly elevated at 119 ng/mL (ref range 2.1-21.7) while not on supplementation. He had noticed multiple fractures as a child, but he had written them off as minor injuries. He could clearly remember breaking his right wrist and clavicle. As an adult, he had rib fractures and a foot fracture. He was unable to recollect losing his primary teeth. Almost all his teeth are crowns or implants despite taking exceptional care of them. He did not have joint hypermobility. Genetic testing revealed the patient was heterozygous for an ALPL gene variant, c.876_882delinsT. It was a variant of undetermined significance at that time. His daughter also was found to have a low alkaline phosphatase and the same genetic test result. She also has experienced dental carries and joint pain. Our patient initiated teriparatide due to the need for more urgent therapy for extensive spinal surgery. He was later transitioned to asfotase alfa therapy and has not had any further fractures at the time of this report. Discussion: Hypophosphatasia is a rare inborn disorder due to mutations in the tissue nonspecific alkaline phosphatase gene ALPL and is characterized by low ALP levels. Affected individuals will also have elevated vitamin b6 levels and urinary phosphoethanolamine (PEA) levels. Early diagnosis of HPP is necessary to prevent bone fracture pain and improve quality of life. Inaccurate assessments can miss diagnoses of parents and other family members and even lead to lost opportunities to treat a patient with a substantial illness burden. This case highlights the mutation c.876_882delinsT as a likely pathologic variant in the ALPL gene. It also supports that patients with HPP can also respond to teriparatide treatment. Presentation: 6/2/2024

Fabry Disease with Genetic Variants of Unknown Significance and Concomitant Immunoglobulin A Nephropathy

Introduction: The diagnosis of Fabry disease (FD) with genetic variants of unknown significance (VUSs) is relatively difficult. We explored patients with novel VUS variants and concomitant immunoglobulin A nephropathy (IgAN) to improve the understanding of VUS. Methods: The study retrospectively investigated patients with genetically confirmed FD. Probands with VUS were selected from the database of FD patients who underwent genetic analysis. Demographic, clinicopathological, and laboratory data from probands and family members were collected and analyzed. Results: Fourteen probands and their family members were included in the study. The probands were divided into group 1 (patients with VUS, n = 5) and group 2 (patients with pathologic/likely pathologic variants, n = 9). The group 1 included 2 missense mutations and 1 deletion mutation, while the group 2 included 6 missense mutations and 2 deletion mutations. There were no significant differences in gender, age, serum creatinine, eGFR, and proteinuria between the two groups. IgA deposition with myeloid bodies was found in all VUS patients. The cardiac involvement in group 2 was more severe than that in group 1. Seven families performed the pedigree analysis, and after the comprehensive evaluation, two GLA variants (c.479C>A, p.Ala160Asp; c.1032-1058 del, p.Ser345_Met353del) were upgraded from VUS to the likely pathogenic. Conclusion: The clinical manifestations of FD are heterogeneous. FD often coexists with nephrotic disorders, such as IgAN and MCD. Comprehensive evaluation, especially tissue-specific biopsy, is necessary for patients with GLA-VUSs. Two GLA variants (c.479C>A, p.Ala160Asp; c.1032-1058 del, p.Ser345_Met353del) were upgraded from VUS to the likely pathogenic after the comprehensive evaluation.

Shiga toxin-producing Escherichia coli infection as a precipitating factor for atypical hemolytic-uremic syndrome.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis. It can be classified as either typical, primarily caused by Shiga toxin-producing Escherichia coli (STEC) infection, or as atypical HUS (aHUS), which results from uncontrolled complement activation. We report the case of a 9-year-old boy with aHUS due to compound heterozygous complement factor H-related genes (CFHR) 1/3 and CFHR1-CFHR4 deletions, leading to the development of anti-complement factor H (CFH) autoantibodies. The patient presented nephrological and neurological thrombotic microangiopathy with STEC positivity. Additionally, we provide an extensive literature review of aHUS cases initially classified as typical. A total of 11 patients were included, 73% of whom were pediatric. Kidney replacement therapy was required in 73% of patients. The recurrence rate was 55%. All cases were found positive for pathological variants of the complement system genes. The most commonly implicated gene was CFH, while the CFHR genes were involved in 36% of cases, although none exhibited anti-CFH autoantibodies. Anti-complement therapy was administered in 54% of cases, and none of the patients who received it early progressed to kidney failure. STEC infection does not exclude aHUS diagnosis, and early use of anti-complement therapy might be reasonable in life-threatening conditions. Genetic testing can be helpful in patients with atypical presentations and can confirm the necessity of prolonged anti-complement therapy.

QSOX2 Deficiency-induced short stature, gastrointestinal dysmotility and immune dysfunction.

Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease.

The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome.

Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.

Lipoma: An Unusual Iodine-131 Uptake on Whole-Body Scanning: A Case Report

Whole-body radioiodine scintigraphy plays a major role in detecting metastases or recurrence of differentiated thyroid cancers. However, radioactive iodine uptake is not specific to thyroid tissue, and many physiological and pathological variants can bind radioactive iodine, resulting in false positives that can compromise the correct interpretation of results. We report the case of a 73-year-old patient with papillary thyroid carcinoma who underwent surgery 2 years ago, and whose whole-body scan, performed in the face of rising thyroglobulin levels, revealed abnormal fixation on the thigh, and further investigations suggested a lipoma. Our aim in reporting this case is to contribute to the knowledge of new false positives linked to iodine-131 fixation, in order to avoid unusual diagnostic errors that can lead to the unnecessary administration of therapeutic doses of iodine-131 or to aberrant surgical interventions.

Ciliary Function, Antigen Stasis and Asthma.

The prevalence of asthma exceeds 3% of the population. Asthma is observed to be more common in children following severe viral lower respiratory illnesses that affect ciliary function, but mechanisms linking ciliary function to asthma pathogenesis have been obscure. Recent data regarding primary ciliary dyskinesia (PCD) may help us to understand the association. Here, I will review what is known about the relationship between ciliary function and asthma. PCD is caused by pathologic variants in over 50 different genes that affect the structure and function of motile cilia. At the cellular level, a characteristic feature shared by most PCD patients is that antigens and other particles are not cleared from the epithelial surface. Poor antigen clearance results in pro-oxidant pathway activation and airway epithelial damage and may predispose PCD patients to DUOX1- and IL33-mediated asthma. Secondary ciliary dysfunction, such as that caused by viruses or by smoking, can also contribute to asthma development. Moreover, variants in genes that affect the function of cilia can be associated with poor lung function, even in the absence of PCD, and with increased asthma severity. The role of antigen stasis on the surface of dysfunctional airway cilia in the pathophysiology of asthma is a novel area for research, because specific airway clearance techniques and other therapeutic interventions, such as antioxidants, could be of value in preventing the development of asthma.

Genetic basis and imaging findings of neurofibromatosis 1 and other somatic overgrowth disorders.

Somatic overgrowth disorders comprise a wide range of rare conditions that present with focal enlargement of one or more tissue types. The PI3K-AKT-mTOR pathway is a signalling pathway that induces angiogenesis and cell proliferation, and is one of the most commonly overactivated signalling pathways in cancer. The PI3K-AKT-mTOR pathway can be up-regulated by genetic variants that code for proteins in this pathway, or down-regulated by proteins that inhibit the pathway. Mosaic genetic variations can result in cells that proliferate excessively in specific anatomical locations. The PIK3CA-related overgrowth spectrum (PROS) disorders include CLOVES syndrome, macrodystrophia lipomatosa, and Klippel-Trenaunay syndrome among many. The neurofibromatosis type 1 (NF1) gene encodes neurofibromin which down-regulates the PI3K-AKT-mTOR pathway. Thousands of pathological variants in the NF1 gene have been described which can result in lower-than-normal levels of neurofibromin and therefore up-regulation of the PI3K-AKT-mTOR pathway promoting cellular overgrowth. Somatic overgrowth is a rare presentation in NF1 with a wide range of clinical and radiological presentations. Hypertrophy of all ectodermal and mesodermal elements has been described in NF1 including bone, muscle, fat, nerve, lymphatics, arteries and veins, and skin. The shared signalling pathway for cellular overgrowth means that these radiological appearances can overlap with other conditions in the PIK3CA-related overgrowth spectrum. The aim of this review is to describe the genetic basis for the radiological features of NF1 and in particular compare the appearances of the somatic overgrowth disorders in NF1 with other conditions in the PIK3CA-related overgrowth spectrum.

Intratumoral heterogeneity of oncogenic drivers in mixed histology lung adenocarcinomas: How tissue selection impacts molecular testing?

Majority of the lung adenocarcinomas show a mixture of different histological patterns. The possibility of histologically heterogeneous areas of the adenocarcinoma showing genetic heterogeneity and harboring different driver mutations, with potentially significant clinical impact, has not been adequately addressed. Currently, there are no guidelines to suggest how to submit tumor tissue in adenocarcinomas with mixed histological features for molecular testing.The objective of this study is to assess intra-tumoral heterogeneity in prominent driver mutations among different morphological patterns of lung adenocarcinoma, its implications on the future of molecular testing as well as its potential impact on patient management.Twenty-three cases of mixed histology lung adenocarcinoma resected between 2018 and 2023 were retrieved from the archives. H&E slides were reviewed to identify the predominant and second most predominant histological patterns. The morphologically different tumor areas were manually macro-dissected for DNA extraction. Next-Generation Sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 (Thermo Fisher Scientific, USA).Thirteen cases showed the same pathological variant in both histological components tested. Three cases (13 %) exhibited disparities in the variants detected across the different histological patterns tested (p=0.025). The discrepant findings had a direct therapeutic impact in 4.3 % cases. Seven cases showed no pathogenic variants detected on either of the histological components tested.This study elucidates the presence of infrequent yet significant intra-tumoral heterogeneity in the molecular profiles of mixed histology adenocarcinomas, highlighting the need for guidelines directing tissue selection for molecular testing to avoid missed therapeutic opportunities and mitigate disease relapse.

T2-relaxometry in a large cohort of hereditary transthyretin amyloidosis with polyneuropathy

Background Previously, T2-relaxation time (T2app) and proton spin density (ρ) detected nerve injury in a small group of ATTRv amyloidosis. Here, we aim to quantify peripheral nerve impairment in a large cohort of symptomatic and asymptomatic ATTRv amyloidosis and correlate T2-relaxometry markers with clinical parameters and nerve conduction studies (NCS). Methods Eighty participants with pathologic variants of the transthyretin gene (TTRv) and 40 controls prospectively underwent magnetic resonance neurography. T2-relaxometry was performed, allowing to calculate tibial ρ, T2app and cross-sectional-area (CSA). Detailed clinical examinations and NCS of tibial and peroneal nerves were performed. Results Forty participants were classified as asymptomatic TTRv-carriers, 40 as symptomatic patients with polyneuropathy. ρ, T2app and CSA were significantly higher in symptomatic ATTRv amyloidosis (484.2 ± 14.8 a.u.; 70.6 ± 1.8 ms; 25.7 ± 0.9 mm2) versus TTRv-carriers (413.1 ± 9.4 a.u., p < 0.0001; 62.3 ± 1.3 ms, p = 0.0002; 19.0 ± 0.8 mm2, p < 0.0001) and versus controls (362.6 ± 7.5 a.u., p < 0.0001; 59.5 ± 1.0 ms, p < 0.0001; 15.4 ± 0.5 mm2, p < 0.0001). Only ρ and CSA differentiated TTRv-carriers from controls. ρ and CSA correlated with NCS in TTRv-carriers, while T2app correlated with NCS in symptomatic ATTRv amyloidosis. Both ρ and T2app correlated with clinical score. Conclusion ρ and CSA can detect early nerve injury and correlate with electrophysiology in asymptomatic TTRv-carriers. T2app increases only in symptomatic ATTRv amyloidosis in whom it correlates with clinical scores and electrophysiology. Our results suggest that T2-relaxometry can provide biomarkers for disease- and therapy-monitoring in the future.

Real-world assessment of comprehensive genome profiling impact on clinical outcomes: A single-institution study in Japan.

Comprehensive genome profiling (CGP) has revolutionized healthcare by offering personalized medicine opportunities. However, its real-world utility and impact remain incompletely understood. This study examined the extent to which CGP leads to genomically matched therapy and its effectiveness. We analyzed data from advanced solid tumor patients who underwent CGP panel between December 2019 and May 2023 at the Osaka International Cancer Institute. Patient demographics, specimen details, and expert panel assessments were collected. Turnaround time (TAT) and genomically matched therapy outcomes were analyzed. Gene alterations and their co-occurrence patterns were also assessed. Among 1437 patients, 1096 results were available for analysis. The median TAT was 63 [28-182] days. There were 667 (60.9%) cases wherein recommended clinical trials were presented and there were 12 (1.1%) cases that could be enrolled in the trial and 25 (2.3%) cases that could lead to therapies under insurance reimbursement. The median progression free survival of the trial treatment was 1.58 months (95% CI: 0.66-4.37) in clinical trials and 3.66 months (95% CI: 2.14-7.13) in treatment under insurance. Pathologic germline variants were confirmed in 15 patients (1.3%). Co-alteration of CDKN2A, CDKN2B, and MTAP was significantly observed in overall population. The effectiveness of the genomically matched therapy based on the CGP panel was unsatisfactory. Expansion of clinical trials and utilization of remote clinical trials are required to ensure that the results of the CGP panel can be fully returned to patients.

Active Immunotherapy for the Prevention of Alzheimer's and Parkinson's Disease.

Neurodegenerative diseases (ND) give rise to significant declines in motor, autonomic, behavioral, and cognitive functions. Of these conditions, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent, impacting over 55 million people worldwide. Given the staggering financial toll on the global economy and their widespread manifestation, NDs represent a critical issue for healthcare systems worldwide. Current treatment options merely seek to provide symptomatic relief or slow the rate of functional decline and remain financially inaccessible to many patients. Indeed, no therapy has yet demonstrated the potential to halt the trajectory of NDs, let alone reverse them. It is now recognized that brain accumulation of pathological variants of AD- or PD-associated proteins (i.e., amyloid-β, Tau, α-synuclein) begins years to decades before the onset of clinical symptoms. Accordingly, there is an urgent need to pursue therapies that prevent the neurodegenerative processes associated with pathological protein aggregation long before a clinical diagnosis can be made. These therapies must be safe, convenient, and affordable to ensure broad coverage in at-risk populations. Based on the need to intervene long before clinical symptoms appear, in this review, we present a rationale for greater investment to support the development of active immunotherapy for the prevention of the two most common NDs based on their safety profile, ability to specifically target pathological proteins, as well as the significantly lower costs associated with manufacturing and distribution, which stands to expand accessibility to millions of people globally.

Management of bilateral head and neck paragangliomas at a single-institution across four decades.

Bilateral head and neck paragangliomas (HNPGLs) require nuanced management to balance tumor control with functional preservation. All patients seen at a single-institution for bilateral paraganglioma between 1983 and 2023 were retrospectively reviewed. Demographics, genetic testing results, and tumor characteristics were analyzed and compared to treatment modality and cranial nerve outcomes. There were 49 patients with 116 tumors (90 carotid body tumors [CBTs], 15 vagal paragangliomas [VPs], and 11 jugular paragangliomas [JPs]). Twenty-six patients had SDH pathologic variants (PV). Surgical management was more commonly utilized in younger patients (OR: 0.97, 95% CI: 0.950-0.992) and for JPs (OR: 9, 95% CI: 1.386-58.443). In surgical cases, CBTs had a lower risk of postoperative cranial nerve deficits compared to JPs and VPs (OR: 0.095, 95% CI: 0.013-0.692). Younger patients with bilateral HNPGLs, especially those with JP and CBT, are more often treated with surgery. CBTs have lowest risk of cranial nerve deficits after surgery.

Novel tau filament folds in individuals with MAPT mutations P301L and P301T.

Mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological MAPT variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common MAPT mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick's disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.

Experimental Study: The Development of a Novel Treatment for Chemotherapy-Resistant Tongue Cancer with the Inhibition of the Pathological Periostin Splicing Variant 1-2 with Exon 21.

Tongue squamous cell carcinoma (TSCC) occurs frequently in the oral cavity, and because of its high proliferative and metastatic potential, it is necessary to develop a novel treatment for it. We have reported the importance of the inhibition of the periostin (POSTN) pathological splicing variant, including exon 21 (PN1-2), in various malignancies, but its influence is unclear in tongue cancer. In this study, we investigated the potential of POSTN exon 21-specific neutralizing antibody (PN21-Ab) as a novel treatment for TSCC. Human PN2 was transfected into the human TSCC (HSC-3) and cultured under stress, and PN2 was found to increase cell viability. PN2 induced chemotherapy resistance in HSC-3 via the phosphorylation of the cell survival signal Akt. In tissues from human TSCC and primary tumors of an HSC-3 xenograft model, PN1-2 was expressed in the tumor stroma, mainly from fibroblasts. The intensity of PN1-2 mRNA expression was positively correlated with malignancy. In the HSC-3 xenograft model, CDDP and PN21-Ab promoted CDPP's inhibition of tumor growth. These results suggest that POSTN exon 21 may be a biomarker for tongue cancer and that PN21-Ab may be a novel treatment for chemotherapy-resistant tongue cancer. The treatment points towards important innovations for TSCC, but many more studies are needed to extrapolate the results.

Challenges of liquid panel in genomic profiling of esophageal squamous cell carcinoma (ESCC): Insights from an analysis of over 1000 cases.

86 Background: Genomic analysis of ctDNA from cancer patients can allow identification of actionable alterations of tumor without an invasive biopsy. ctDNA analysis has been reported to be superior for global summary of tumor heterogeneity and a short turnaround time compared to tissue analysis,however, there are potential issues including the detection sensitivity, threshold to determine TMB-H, and clonal hematopoiesis of indeterminate potential (CHIP). In order to elucidate the impact of ctDNA analysis on personalized cancer treatment, we decided to examine the genetic landscape and clinical outcomes of ESCC cohort registered in the C-CAT database. Methods: We retrospectively analyzed data from 1059 cases of ESCC registered in the C-CAT from June 2019 to February 2024. Clinical characteristics, TMB status, pathological gene variants, and time to treatment failure (TTF) of first-line treatment were examined. Results: The panels applied to eligible patients consisted of 925 tumor tissue panels (87.3%) and 134 liquid panels (12.7%). Pathological gene mutations were detected in 924 cases (99.8%) in tissue panels and 133 cases (99.2%) in liquid panels. The top 10 detected genes were TP53 (93.4%), CDKN2A (57.8%), CDKN2B (45.5%), CCND1 (43.9%), FGF19 (41.0%), PIK3CA (29.0%), NFE2L2 (28.3%), BCL6 (16.5%), NOTCH1 (13.5%), and KMT2D (12.2%). The detection rate for these genes excluding NOTCH1 and KMT2D were significantly higher in tissue panels than in liquid panels (P≤0.01). The median TMB was 5.00 Muts/Mb for both. In first-line treatment, the TTF for immune checkpoint inhibitors (ICIs) and chemotherapy was significantly longer in TMB-H (≧10 Muts/Mb) compared to TMB-L (3.1M vs. 1.9M, P&lt;0.01) in patients evaluated by tissue panels, but it was not proven in patients evaluated by liquid panels (P=0.38). Furthermore, the results suggest that patients with CDKN2A, CCND1, and FGF19 variants benefit more by adding ICIs to chemotherapy than patients without these variants and while the opposite was true for BCL6 and NOTCH1 and KMT2D. Conclusions: In this ESCC cohort, detection rates in the liquid panels were generally lower than in the tissue panels, suggesting that sufficient ctDNA could not be obtained in many cases. The appropriate patient selection for the liquid panels and the timing of blood collection should be discussed. Furthermore, the ideal threshold for determining TMB-H in the liquid panels needs to be further investigated.

Prevalence of Helicobacter pylori infection among patients with esophageal carcinoma.

Helicobacter pylori (H. pylori) is a widespread microorganism related to gastric adenocarcinoma (AC). In contrast, it has been reported that an inverse association exists between H. pylori infection and esophageal carcinoma. The mechanisms underlying this supposedly protective effect remain controversial. To determine the prevalence of H. pylori infection in esophageal carcinoma patients, we performed a retrospective observational study of esophageal tumors diagnosed in our hospital. We retrospectively reviewed the prevalence of H. pylori infection in a cohort of patients diagnosed with esophageal carcinoma. Concomitant or previous proton pump inhibitor (PPI) usage was also recorded. A total of 89 patients with esophageal carcinoma (69 males, 77.5%), with a mean age of 66 years (range, 26-93 years) were included. AC was the most frequent pathological variant (n = 47, 52.8%), followed by squamous cell carcinoma (n = 37, 41.6%). Fourteen ACs (29.8%) originated in the gastroesophageal junction and 33 (70.2%) in the esophageal body. Overall, 54 patients (60.7%) presented at stages III and IV. Previous H. pylori infection occurred only in 4 patients (4.5%), 3 with AC (6.3% of all ACs) and 1 with squamous cell carcinoma (2.7% of all squamous cell tumors). All patients with previous H. pylori infection had stage III-IV. Only one patient had received prior H. pylori eradication therapy, whereas 86 (96.6%) had received previous or concomitant PPI treatment. In our cohort of patients, and after histologic evaluation of paraffin-embedded primary tumors, we found a very low prevalence of previous H. pylori infection. We also reviewed the medical history of the patients, concluding that the majority had received or were on PPI treatment. The minimal prevalence of H. pylori infection found in this cohort of patients with esophageal carcinoma suggests a protective role.