Patient With a Diffuse Large B-Cell Non-Hodgkin Lymphoma in the Right Heart Chamber That Caused Cardiogenic Shock Was Well-Responded to Corticosteroids and Chemotherapy.

Heart tumors are sporadic. Secondary heart tumors are 30 times more common than primary ones. Depending on the location and origin of the tumor, clinical pictures vary from asymptomatic to severe manifestations such as arrhythmia, heart failure, pericardial effusion, and cardiogenic shock. We report hereby a rare case who presented with faint clinical symptoms, rapidly progressing to right heart failure within a month. Echocardiography and computed tomography of the chest revealed a tumor in the right heart chamber of 72.0 × 43.0 mm, in addition to large mediastinal lymph and left supraclavicular lymph nodes, cardiogenic shock appeared 4 days after admission. Through examination, it was suspected that this was a cardiac lymphoma. The patient was treated with 2 mg methylprednisolone per kg body weight. Symptoms of cardiogenic shock improved significantly and disappeared after 6 hours of treatment. After supraclavicular lymph node biopsy and immunohistochemistry, the final result was diagnosed as diffuse large B-cell non-Hodgkin lymphoma with large lymphoma in the right heart. The patient received chemotherapy with the R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone). Re-examination before the 5th chemotherapy cycle showed no signs of right heart failure, normal self-activity, and no dyspnea on exertion, and the tumor size in the heart on the echocardiogram was 23.8 × 19.1 mm. The report shows that a large right heart tumor with a clinical picture of cardiogenic shock in a patient with diffuse large B-cell non-Hodgkin's lymphoma was well-responded to initial treatment with methylprednisolone at a dose of 2 mg/kg body weight and R-CHOP chemotherapy.

CD4+ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection.

Immunological priming-in the context of either prior infection or vaccination-elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrated that prior Mtb infection elicited a long-lasting protective response against subsequent Mtb exposure and was CD4+ T cell dependent. By analyzing data from primary infection, reinfection, and reinfection-CD4+ T cell-depleted granulomas, we found that the presence of CD4+ T cells during reinfection resulted in a less inflammatory lung milieu characterized by reprogrammed CD8+ T cells, reduced neutrophilia, and blunted type 1 immune signaling among myeloid cells. These results open avenues for developing vaccines and therapeutics that not only target lymphocytes but also modulate innate immune cells to limit tuberculosis (TB) disease.

Detraining after short-term exercise induces hyperphagia and obesity with fatty liver and brown adipose tissue whitening in young male OLETF rats.

This study examined the effects of exercise and detraining at a young age on fat accumulation in various organs. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were assigned to either the non-exercise sedentary (OLETF Sed) or exercise groups. The exercise group was subdivided into two groups: exercise between 4 and 12 weeks of age (OLETF Ex) and exercise between 4 and 6 weeks of age followed by non-exercise between 6 and 12 weeks of age (OLETF DT). Body weight was significantly lower in the OLETF Ex group than in the OLETF Sed group at 12 weeks of age. Fat accumulation in the epididymal white adipose tissue, liver, and brown adipose tissue was suppressed in the OLETF Ex group. During the exercise period, body weight and food intake in the OLETF DT group were significantly lower than those in the OLETF Sed group. However, food intake was significantly higher in the OLETF DT group than in the OLETF Sed group after exercise cessation, resulting in extreme obesity with fatty liver and brown adipose tissue whitening. Detraining after early-onset exercise promotes hyperphagia, causing extreme obesity. Overeating should be avoided during detraining periods in cases of exercise cessation at a young age.

Long-term outcome of retroperitoneoscopic one-trocar-assisted pyeloplasty: a single-center and single-surgeon experience.

PURPOSE: The aim of this study was to assess the long-term outcomes of retroperitoneoscopic one-trocar-assisted pyeloplasty (OTAP) for ureteropelvic junction obstruction (UPJO) in children. METHODS: This retrospective analysis included 70 pediatric cases, all under the age of 5, diagnosed with UPJO and treated with the OTAP technique between May 2011 and June 2013 by a single surgeon. A single 10 mm operative scope with a 5 mm working channel was utilized to mobilize the ureteropelvic junction (UPJ) and exteriorize it through the trocar insertion site. Subsequently, conventional Anderson-Hynes dismembered pyeloplasty was conducted extracorporeally. Patient's demographics, operative time, hospital stay, complications, and success rate were evaluated. RESULTS: Seventy pediatric patients (65 males and 5 females) underwent OTAP, with ages at the time of operation ranging from 1 month to 5 years (mean = 22.6 ± 18.6 months). The mean operative time was 74.8 ± 15.2 min. There was a significant reduction in the mean renal pelvis size from 34.3 ± 8.1 mm preoperatively to 13.8 ± 4.7 mm postoperatively (p < 0.05). Moreover, the mean differential renal function (DRF) increased from 47.9 ± 9.8% preoperatively to 51.2 ± 5.9% postoperatively (p < 0.05). All patients experienced an uneventful postoperative recovery, with a median hospital stay of 3.4 days. The success rate was 95.7%, with a median follow-up time of 75 months (range: 6-125 months). CONCLUSION: OTAP is a safe and feasible minimally invasive technique to correct ureteropelvic junction obstruction in children. It could be considered as a treatment of choice for children under the age of 5 as it combines the advantages of open and retroperitoneoscopic pyeloplasty and presents excellent long-term outcomes. TRIAL REGISTRATION NUMBER: NCT06349161 April 4th, 2024, retrospectively registered.

Condensate-Promoting ENL Mutation Drives Tumorigenesis In Vivo Through Dynamic Regulation of Histone Modifications and Gene Expression.

Gain-of-function mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL), found in acute myeloid leukemia (AML) and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of the mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis and demonstrates the potential of targeting pathogenic condensates in cancer treatment. Significance: A direct link between ENL mutations, condensate formation, and tumorigenesis is lacking. This study elucidates the function and mechanism of ENL mutations in leukemogenesis, establishing these mutations as bona fide oncogenic drivers. Our results also support the role of condensate dysregulation in cancer and reveal strategies to target pathogenic condensates.

Structural Characterization of a Pathogenic Antibody Underlying Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT).

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but dangerous side effect of adenoviral-vectored COVID-19 vaccines. VITT had been linked to production of autoantibodies recognizing platelet factor 4 (PF4). Here, we characterize anti-PF4 antibodies obtained from a VITT patient's blood. Intact mass measurements indicate that a significant fraction of these antibodies represent a limited number of clones. MS analysis of large antibody fragments (the light chain and the Fc/2 and Fd fragments of the heavy chain) confirms the monoclonal nature of this component of the anti-PF4 antibodies repertoire and reveals the presence of a mature complex biantennary N-glycan within the Fd segment. Peptide mapping using two complementary proteases and LC-MS/MS was used to determine the amino acid sequence of the entire light chain and over 98% of the heavy chain (excluding a short N-terminal segment). The sequence analysis allows the monoclonal antibody to be assigned to the IgG2 subclass and verifies that the light chain belongs to the λ-type. Incorporation of enzymatic de-N-glycosylation into the peptide mapping routine allows the N-glycan in the Fab region of the antibody to be localized to the framework 3 region of the VH domain. This novel N-glycosylation site is the result of a single mutation within the germline sequence. Peptide mapping also provides information on lower-abundance (polyclonal) components of the anti-PF4 antibody ensemble, revealing the presence of all four subclasses (IgG1-IgG4) and both types of the light chain (λ and κ). This case study demonstrates the power of combining the intact, middle-down, and bottom-up MS approaches for meaningful characterization of ultralow quantities of pathogenic antibodies extracted directly from patients' blood.

Machine Learning Prediction of Lymph Node Metastasis in Breast Cancer: Performance of a Multi-institutional MRI-based 4D Convolutional Neural Network.

Purpose To develop a custom deep convolutional neural network (CNN) for noninvasive prediction of breast cancer nodal metastasis. Materials and Methods This retrospective study included patients with newly diagnosed primary invasive breast cancer with known pathologic (pN) and clinical nodal (cN) status who underwent dynamic contrast-enhanced (DCE) breast MRI at the authors' institution between July 2013 and July 2016. Clinicopathologic data (age, estrogen receptor and human epidermal growth factor 2 status, Ki-67 index, and tumor grade) and cN and pN status were collected. A four-dimensional (4D) CNN model integrating temporal information from dynamic image sets was developed. The convolutional layers learned prognostic image features, which were combined with clinicopathologic measures to predict cN0 versus cN+ and pN0 versus pN+ disease. Performance was assessed with the area under the receiver operating characteristic curve (AUC), with fivefold nested cross-validation. Results Data from 350 female patients (mean age, 51.7 years ± 11.9 [SD]) were analyzed. AUC, sensitivity, and specificity values of the 4D hybrid model were 0.87 (95% CI: 0.83, 0.91), 89% (95% CI: 79%, 93%), and 76% (95% CI: 68%, 88%) for differentiating pN0 versus pN+ and 0.79 (95% CI: 0.76, 0.82), 80% (95% CI: 77%, 84%), and 62% (95% CI: 58%, 67%), respectively, for differentiating cN0 versus cN+. Conclusion The proposed deep learning model using tumor DCE MR images demonstrated high sensitivity in identifying breast cancer lymph node metastasis and shows promise for potential use as a clinical decision support tool. Keywords: MR Imaging, Breast, Breast Cancer, Breast MRI, Machine Learning, Metastasis, Prognostic Prediction Supplemental material is available for this article. Published under a CC BY 4.0 license.

Pathogenic/likely pathogenic mutations identified in Vietnamese children diagnosed with autism spectrum disorder using high-resolution SNP genotyping platform.

Among the most prevalent neurodevelopmental disorders, Autism Spectrum Disorder (ASD) is highly diverse showing a broad phenotypic spectrum. ASD also couples with a broad range of mutations, both de novo and inherited. In this study, we used a proprietary SNP genotyping chip to analyze the genomic DNA of 250 Vietnamese children diagnosed with ASD. Our Single Nucleotide Polymorphism (SNP) genotyping chip directly targets more than 800 thousand SNPs in the genome. Our primary focus was to identify pathogenic/likely pathogenic mutations that are potentially linked to more severe symptoms of autism. We identified and validated 23 pathogenic/likely pathogenic mutations in this initial study. The data shows that these mutations were detected in several cases spanning multiple biological pathways. Among the confirmed SNPs, mutations were identified in genes previously known to be strongly associated with ASD such as SLCO1B1, ACADSB, TCF4, HCP5, MOCOS, SRD5A2, MCCC2, DCC, and PRKN while several other mutations are known to associate with autistic traits or other neurodevelopmental disorders. Some mutations were found in multiple patients and some patients carried multiple pathogenic/likely pathogenic mutations. These findings contribute to the identification of potential targets for therapeutic solutions in what is considered a genetically heterogeneous neurodevelopmental disorder.

Results of acute cerebral infarction treatment with hyperbaric oxygen therapy, 2020-2022.

BACKGROUND: Cerebral stroke is the third leading cause of death after cardiovascular disease, cancer and the leading cause of disability for patients. Hyperbaric oxygen is a non-drug treatment that has the potential to improve brain function for patients with ischaemic stroke. The objective of this study was to evaluate the results of treatment of acute cerebral infarction with hyperbaric oxygen therapy (HBOT). MATERIALS AND METHODS: This was a case-control study. One hundred ninety-five patients diagnosed with cerebral infarction, with signs of onset within 24 hours, were treated at the Centre for Underwater Medicine and Hyperbaric Oxygen of Vietnam National Institute of Maritime Medicine during the period from January 2020 to December 2022. Study group included 100 patients with acute cerebral infarction treated with a combination of HBOT and medication and reference group included 95 patients treated by medication only (antiplatelets drugs, statins, control of associated risks factors) RESULTS: After 7 days of treatment with hyperbaric oxygen (HBO), symptoms such as headache, dizziness, nausea, sensory disturbances, and Glasgow score of the study group improved better than that of the reference group (p < 0.01). Movement recovery in the study group was better than the reference group: the percentage of patients with mild and moderate paralysis in the study group increased higher than that of the reference group (86.0% and 68.4%), the degree of complete paralysis of the study group decreased more than that of the reference group (14.0% and 31.6%). The degree of independence in daily activities in the study group was better than the reference group. In the study group, the percentage of patients with complete independence in daily life increased from 27.0% to 84.0%. In the reference group, the rate of patients who were independent in their daily activities increased from 37.9% to 51.6%. The average number of treatment days of the study group was 10.32 ± 2.41 days and it the reference group 14.51 ± 3.24 days. CONCLUSIONS: Hyperbaric oxygen therapy is a non-drug treatment with many good effects in the treatment of cerebral infarction, especially acute cerebral infarction. HBOT reduces and improves functional symptoms, improves mobility, and reduces treatment time for patients.

A retrospective study of endogenous endophthalmitis-related pyogenic liver abscess: An increasing complication in North Vietnam.

Introduction: Endogenous endophthalmitis-related Klebsiella pyogenic liver abscess is a rare complication of metastatic infection. In most cases, visual acuity results are often impaired, even blind, and even with aggressive treatment with topical antibiotics, the final results are unsatisfactory. The objective of this study is to retrospectively based on medical records to describe clinical features, risk factors, and visual outcomes of patients with endogenous endophthalmitis-related pyogenic liver abscesses. Methods: We reported a case series of 12 endogenous endophthalmitis-related pyogenic liver abscess patients from March 2021 to 2023. All cases of endogenous endophthalmitis were diagnosed at admission or during the hospital stay. Results: From the medical records of 588 pyogenic liver abscess patients, we found 12 cases of endogenous endophthalmitis with 2.0%. The result showed a mean age of 61.5 ± 12.0 (41-78), diabetes mellitus (7 of 12), right lobe (7 of 12), single abscess (9 of 12), and the mean largest abscess diameter of 5.8 ± 1.7 cm (3.3-9). All patients had ocular symptoms such as eye pain (9 of 12), pus discharge (3 of 12), hypopyon (1 of 12), swollen eyelids (2 of 12), and corneal edema (2 of 12), pyogenic liver abscess before endogenous endophthalmitis (10 of 12), the median interval between endogenous endophthalmitis and pyogenic liver abscess 6.1 ± 1.9 days, ocular symptoms before diagnosis endogenous endophthalmitis 4.4 ± 2.3 days. All affected eyes were injected intravitreously with ceftazidime, amikacin, and vancomycin. Two patients underwent evisceration. Conclusions: Endogenous endophthalmitis has permanent morbidity, reducing visual acuity, poor quality of life, and lacks the warning signs, so it is essential for early detection of symptoms and referral to ophthalmologists.

N-terminal pro-B-type Natriuretic peptide levels and left atrial appendage thrombosis in patients with persistent atrial fibrillation / Niveles de péptido natriurético N-terminal pro-B y trombosis de la orejuela auricular izquierda en pacientes con fibrilación auricular persistente

Introduction: In hospitalized patients, atrial fibrillation is the most common arrhythmia, and leading cause of cardio-embolic stroke. Objective: To evaluate the association between N-terminal b-type natriuretic peptide pro (NT-proBNP) and left atrial appendage thrombus in persistent atrial fibrillation patients. Methods: A cross-sectional study, enrolled 139 patients with persistent non-valvular atrial fibrillation. Transthoracic and trans-esophageal echocardiographs were performed in all patients. Results: Mean age was 70.5 ( 10.6 years, 80.6% male. In patients with LAAT, NT-proBNP was positively correlated with left ventricular end diastolic diameter (LVEDD) (r=0.345), left ventricular end-systolic diameter (LVEDS) (r= 0.449), E/e' (r=0.445), and left atrial spontaneous echo contrast (LA SEC) (r=0.478), and negatively correlated with left ventricular ejection fraction (LVEF) (r=-0.473), left atrial strain (r= -0.301), strain rate (r= -0.283), and e'(r= -0.458). In patients without LAAT, NT-proBNP was positively correlated with LVEDD (r= 0.333), LVESD (r= 0.358), E (r= 0.318), E/e' (r= 0.411), left atrial volume index (LAVI) (r= 0.421), and negatively correlated with LVEF (r= -0.307). Plasma NT-proBNP (> 1279 pg/mL) could be used to predict LAAT (AUC= 0.639; Se= 67.7 percent, Sp= 60.2 percent). In patients with ejection fraction > 50 percent, the cutoff value of NT-proBNP to predict LAAT was 1325 pg/mL (AUC= 0.572; Se= 57.9 percent , Sp= 78.3 percent). Multiple logistic regression analysis showed that prior stroke, E/e' index, and NT-proBNP correlated with LAAT (r= 0.887; p< 0.001; r= -0.092, p= 0.035 and 0.022; p= 0.004, respectively). Conclusion: Plasma NT-proBNP levels and E/e' index are associated with LAAT in patients with persistent atrial fibrillation(AU)

Introducción: En pacientes hospitalizados, la fibrilación auricular es la arritmia más común y causa principal de ictus cardioembólico. Objetivo: Evaluar la asociación entre el péptido natriurético NT proBNP y el trombo en la orejuela auricular izquierda en pacientes con fibrilación auricular persistente. Métodos: Se reclutaron prospectivamente 139 pacientes con fibrilación auricular no valvular persistente. Se realizaron ecocardiografías transtorácicas y transesofágicas en todos los pacientes. Resultados: Edad media, 70,5±10,6 años; 80,6 por ciento hombres. En pacientes con LAAT, NT-proBNP correlacionó positivamente con el diámetro telediastólico del ventrículo izquierdo (DDVI) (r=0,345), diámetro sistólico final del ventrículo izquierdo (DSVI) (r=0,449), E/e' (r=0,445) y contraste de eco espontáneo auricular izquierdo (LA SEC) (r=0,478), y negativamente con la fracción de eyección del ventrículo izquierdo (FEVI) (r=-0,473), tensión auricular izquierda (r=-0,301), tasa de tensión (r=0,283) y e' (r=-0,458). En pacientes sin LAAT, NT-proBNP correlacionó positivamente con LVEDD (r= 0,333), LVESD (r=0,358), E (r=0,318), E/e' (r=0,411), índice de volumen auricular izquierdo (LAVI) (r=0,421), y negativamente con FEVI (r=-0,307). NT-proBNP plasmático (>1279 pg/mL) podría usarse para predecir LAAT (AUC=0,639; Se=67,7 por ciento, Sp=60,2 por ciento). En pacientes con fracción de eyección >50 por ciento; valor de corte de NT-proBNP para predecir LAAT fue 1325 pg/mL (AUC=0,572; Se=57,9 por ciento, Sp=78,3 por ciento). Según regresión logística múltiple, el accidente cerebrovascular previo, el índice E/e' y NT-proBNP se correlacionaron con LAAT (r=0,887; p<0,001; r=0,092, p=0,035 y 0,022; p=0,004, respectivamente). Conclusiones: Los niveles plasmáticos de NT-proBNP y el índice E/e' se asocian con el OAI en pacientes con FA persistente(AU)

Statement from the Asia Summit: Current state of arrhythmia care in Asia.

On May 27, 2022, the Asia Pacific Heart Rhythm Society and the Heart Rhythm Society convened a meeting of leaders from different professional societies of healthcare providers committed to arrhythmia care from the Asia Pacific region. The overriding goals of the meeting were to discuss clinical and health policy issues that face each country for providing care for patients with electrophysiologic issues, share experiences and best practices, and discuss potential future solutions. Participants were asked to address a series of questions in preparation for the meeting. The format of the meeting was a series of individual country reports presented by the leaders from each of the professional societies followed by open discussion. The recorded presentations from the Asia Summit can be accessed at https://www.heartrhythm365.org/URL/asiasummit-22. Three major themes arose from the discussion. First, the major clinical problems faced by different countries vary. Although atrial fibrillation is common throughout the region, the most important issues also include more general issues such as hypertension, rheumatic heart disease, tobacco abuse, and management of potentially life-threatening problems such as sudden cardiac arrest or profound bradycardia. Second, there is significant variability in the access to advanced arrhythmia care throughout the region due to differences in workforce availability, resources, drug availability, and national health policies. Third, collaboration in the area already occurs between individual countries, but no systematic regional method for working together is present.

Reverse Engineering of a Pathogenic Antibody Reveals the Molecular Mechanism of Vaccine-Induced Immune Thrombotic Thrombocytopenia.

The massive COVID-19 vaccine roll-out campaign illuminated a range of rare side effects, the most dangerous of which─vaccine-induced immune thrombotic thrombocytopenia (VITT)─is caused by adenoviral (Ad)-vectored vaccines. VITT occurrence had been linked to the production of pathogenic antibodies that recognize an endogenous chemokine, platelet factor 4 (PF4). Mass spectrometry (MS)-based evaluation of the ensemble of anti-PF4 antibodies obtained from a VITT patient's blood indicates that the major component is a monoclonal antibody. Structural characterization of this antibody reveals several unusual characteristics, such as the presence of an N-glycan in the Fab segment and high density of acidic amino acid residues in the complementarity-determining regions. A recombinant version of this antibody (RVT1) was generated by transient expression in mammalian cells based on the newly determined sequence. It captures the key properties of VITT antibodies such as their ability to activate platelets in a PF4 concentration-dependent fashion. Homology modeling of the Fab segment reveals a well-defined polyanionic paratope, and the docking studies indicate that the polycationic segment of PF4 readily accommodates two Fab segments, cross-linking the antibodies to yield polymerized immune complexes. Their existence was verified with native MS by detecting assemblies as large as (RVT1)3(PF4)2, pointing out at FcγRIIa-mediated platelet activation as the molecular mechanism underlying VITT clinical manifestations. In addition to the high PF4 affinity, RVT1 readily binds other polycationic targets, indicating a polyreactive nature of this antibody. This surprising promiscuity not only sheds light on VITT etiology but also opens up a range of opportunities to manage this pathology.

Targeting of intracellular oncoproteins with peptide-centric CARs.

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

The diagnostic performance of AFP and PIVKA-II models for non-B non-C hepatocellular carcinoma.

OBJECTIVE: This study aims to describe the diagnostic performance of alpha-fetoprotein (AFP), alpha-fetoprotein L3 isoform (AFP-L3), protein induced by vitamin K absence II (PIVKA-II), and combined biomarkers for non-B non-C hepatocellular carcinoma (NBNC-HCC). RESULTS: A total of 681 newly-diagnosed primary liver disease subjects (385 non-HCC, 296 HCC) who tested negativity for the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV) enrolled in this study. At the cut-off point of 3.8 ng/mL, AFP helps to discriminate HCC from non-HCC with an area under the curve (AUC) value of 0.817 (95% confidence interval [CI]: 0.785-0.849). These values of AFP-L3 (cut-off 0.9%) and PIVKA-II (cut-off 57.7 mAU/mL) were 0.758 (95%CI: 0.725-0.791) and 0.866 (95%CI: 0.836-0.896), respectively. The Bayesian Model Averaging (BMA) statistic identified the optimal model, including patients' age, aspartate aminotransferase, AFP, and PIVKA-II combination, which helps to classify HCC with better performance (AUC = 0.896, 95%CI: 0.872-0.920, P < 0.001). The sensitivity and specificity of the optimal model reached 81.1% (95%CI: 76.1-85.4) and 83.2% (95%CI: 78.9-86.9), respectively. Further analyses indicated that AFP and PIVKA-II markers and combined models have good-to-excellent performance detecting curative resected HCC, separating HCC from chronic hepatitis, dysplastic, and hyperplasia nodules.

Survival Outcome in True Carcinoma of Unknown Primary (tCUP) with p16 + Cervical Metastasis.

Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP). Objective The purpose of this study was to analyze the prognostic value of p16 overexpression for CUP in the absence of true primary (TP). Methods The study involved 43 patients who underwent therapeutic lymph node dissection (LND) from 2000 to 2015 after all the diagnostic work up for CUP. Immunohistochemistry for p16 overexpression was performed. Cox proportional hazard regression analysis was used to analyze the prognostic impact on 5-year overall survival (OS) and recurrence-free survival (RFS). Results The male-to-female ratio was 5.1:1, with a median age of 62 years. The clinicopathological data, except for p16 overexpression, did not differ significantly in terms of 5-year OS and RFS. The Cox regression analysis proposed p16 positivity to be an independent prognosticator of regional recurrence-free survival (RRFS) (hazard ratio [HR] 6.180, p = 0.21). The median time to recurrence and death were 10 and 25 months, respectively. Conclusion Cervical metastasis with p16 overexpression is a significant prognostic factor of improved RFS after surgery in CUP. The prognostic significance of lymph node p16 positivity should be further studied.

Relationships of BRAF V600E Gene Mutation With Some Immunohistochemical Markers and Recurrence Rate in Patients With Thyroid Carcinoma.

Background: The B-type rafkinase (BRAF) V600E gene mutation plays an important role in the pathogenesis, diagnosis, and prognosis of thyroid carcinoma. This study was conducted to investigate the rate of the BRAF V600E mutation, the relationships between the BRAF V600E gene mutation and some immunohistochemical markers, and recurrence rate in patients with differentiated thyroid cancer. Method: The study was conducted by a descriptive and longitudinal follow-up method on 102 thyroid carcinoma patients at 103 Military Hospital, Hanoi, Vietnam. All patients were identified with the BRAF V600E gene mutation by real-time polymerase chain reaction. Results: The rate of BRAF V600E gene mutation in patients with thyroid cancer was 60.8%. Patients with BRAF V600E gene mutation had a significantly higher rate of positive cyclooxygenase 2 (COX-2) and Ki67 markers than those without the mutation (COX-2: odds ratio [OR] = 2.93; 95% confidence interval [CI] = 1.27-6.74, P = .011; Ki67: OR = 3.41; 95% CI = 1.31-8.88, P = .01). A statistically significant relationship was identified between the rate of BRAF V600E mutation and the rate of positive Hector Battifora mesothelial 1 (HBME-1) (B = -1.040; P = .037) and COX-2 (B = -1.123; P = .023) markers. The recurrence rate in patients with BRAF V600E gene mutation was significantly higher than that in those without the mutation (P = .007). The mean of the recurrence time of patients with BRAF V600E mutation was significantly lower than that in those without the mutation (P = .011). Conclusions: A high prevalence of BRAF V600E gene mutation was found in thyroid carcinoma patients. The rates of positive HBME-1, COX-2, and Ki67 markers were significantly correlated to BRAF V600E gene mutation. Patients with BRAF V600E gene mutation showed a significantly higher relapse rate and earlier relapse time than those without the mutation.

Nuclear speckles regulate HIF-2α programs and correlate with patient survival in kidney cancer.

Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on RNA expression of speckle-resident proteins, across >20 cancer types. Of these, clear cell renal cell carcinoma (ccRCC) exhibited a clear correlation between the presence of this speckle expression signature, imaging-based speckle phenotype, and clinical outcomes. ccRCC is typified by hyperactivation of the HIF-2α transcription factor, and we demonstrate here that HIF-2α drives physical association of a select subset of its target genes with nuclear speckles. Disruption of HIF-2α-driven speckle association via deletion of its speckle targeting motifs (STMs)-defined in this study-led to defective induction of speckle-associating HIF-2α target genes without impacting non-speckle-associating HIF-2α target genes. We further identify the RNA export complex, TREX, as being specifically altered in speckle signature, and knockdown of key TREX component, ALYREF, also compromises speckle-associated gene expression. By integrating tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2α gene regulatory programs are impacted by specific manipulation of speckle phenotype and by abrogation of speckle targeting abilities of HIF-2α. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2α-regulated target genes that, in turn, influence patient outcomes. We also identify STMs in other transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation.

Secondary Mediastinal Bleeding Caused by Parathyroid Adenocarcinoma: A Case Report.

Introduction: The clinical picture of parathyroid tumors is mainly related to hypercalcemia such as kidney stones and bone and muscle pain. However, spontaneous cervical hemorrhage due to parathyroidoma bleeding is rare with clinical manifestations of the painful swelling and bruising of the neck accompanied by dysphagia and dyspnea. Case presentation: We report a case of a 71-year-old female patient who presented with acute cervical swelling and extensive bleeding spreading from the neck to the abdomen and 2 flanks. Investigation of patients revealed increased parathyroid hormone levels and hypercalcemia. The neck ultrasound showed the thyroid nodules in 2 lobes, and goiter plongeant on the right. Computed tomography scan images showed a hematoma spreading from the right side of the neck to the mediastinum. Result: The patient required emergency surgery due to dyspnea and hemodynamic instability. The preoperative diagnosis was cervical bleeding with the likely cause being thyroid nodule rupture. However, during the surgery, the bleeding source was determined to be the right parathyroid tumor located deeply below the superior mediastinum. The patient's histopathological result of the tumor is parathyroid adenocarcinoma. Conclusion: From our experience, the hemorrhage from parathyroid tumor should be considered as a cause of acute neck bleeding when no history of trauma or surgery is identified. Post-surgery histopathological analyses of the tumor are very important to detect parathyroid adenocarcinoma.