Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study.

BACKGROUND: Genomic analysis of circulating tumor DNA (ctDNA) is increasingly incorporated into the clinical management of patients with advanced cancer. Beyond tumor profiling, ctDNA analysis also can enable calculation of circulating tumor fraction (TF), which has previously been found to be prognostic. While most prognostic models in metastatic cancer are tumor type specific and require significant patient-level data, quantification of TF in ctDNA has the potential to serve as a pragmatic, tumor-agnostic prognostic tool. PATIENTS AND METHODS: This study utilized a cohort of patients in a nationwide de-identified clinico-genomic database with metastatic castration-resistant prostate cancer (mCRPC), metastatic breast cancer (mBC), advanced non-small-cell lung cancer (aNSCLC), or metastatic colorectal cancer (mCRC) undergoing liquid biopsy testing as part of routine care. TF was calculated based on single-nucleotide polymorphism aneuploidy across the genome. Clinical, disease, laboratory, and treatment data were captured from the electronic health record. Overall survival (OS) was evaluated by TF level while controlling for relevant covariables. RESULTS: A total of 1725 patients were included: 198 mCRPC, 402 mBC, 902 aNSCLC, and 223 mCRC. TF ≥10% was highly correlated with OS in univariable analyses for all cancer types: mCRPC [hazard ratio (HR) 3.3, 95% confidence interval (CI) 2.04-5.34, P < 0.001], mBC (HR 2.4, 95% CI 1.71-3.37, P < 0.001), aNSCLC (HR 1.68, 95% CI 1.34-2.1, P < 0.001), and mCRC (HR 2.11, 95% CI 1.39-3.2, P < 0.001). Multivariable assessments of TF had similar point estimates and CIs, suggesting a consistent and independent association with survival. Exploratory analysis showed that TF remained consistently prognostic across a wide range of cutpoints. CONCLUSIONS: Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology.

A chemotherapy only therapeutic approach to pediatric Hodgkin lymphoma: AHOPCA LH 1999.

BACKGROUND: AHOPCA is a collaborative group that designs uniform treatment regimens (protocols) for children diagnosed with cancer in Central America. Based on a preliminary report from one of the AHOPCA centers, AHOPCA adopted a treatment regimen to maintain a good event-free survival (EFS) as well as eliminate radiation therapy from the treatment of children with Hodgkin lymphoma. PROCEDURE: Newly diagnosed patients with histologically proven Hodgkin lymphoma were staged according to the Ann Arbor classification and divided into favorable (stage I, stage IIA, and IIIA) and unfavorable (stage IIB, IIIB, and IV) groups. Subjects classified as group 1 (favorable) were treated with six 28-day cycles of chemotherapy (COPP/COPP ± ABV). Subjects classified as group 2 (unfavorable) were treated with eight 28-day cycles of COPP/ABV chemotherapy. RESULTS: Of 269 patients registered, 216 were eligible for evaluation. The mean age at diagnosis was 7.5 years with a male to female ratio of 3.7-1. The predominant histology was nodular sclerosis (44%) but with a relatively high proportion of mixed cellularity (35.2%) The EFS at 5 and 10 years was 71% and 68%, respectively. There was a 14% rate of abandonment of therapy. CONCLUSION: This treatment regimen for children with Hodgkin lymphoma, when applied as a multi-institutional regimen, had poorer outcome than our previously reported preliminary data and was inferior to the EFS reported in high-income countries. The major contributor adversely affecting EFS in this report is abandonment of therapy. Given these results, AHOPCA initiated a concerted effort to decrease abandonment of therapy.

Theranostics - a sure cure for cancer after 100 years?

Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide. Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer. This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects. We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade. From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine. Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine. Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field.

Proposed three-phenylalanine motif involved in magnetoreception signalling of an Actinopterygii protein expressed in mammalian cells.

Studies at the cellular and molecular level of magnetoreception-sensing and responding to magnetic fields-are a relatively new research area. It appears that different mechanisms of magnetoreception in animals evolved from different origins, and, therefore, many questions about its mechanisms remain left open. Here we present new information regarding the Electromagnetic Perceptive Gene (EPG) from Kryptopterus vitreolus that may serve as part of the foundation to understanding and applying magnetoreception. Using HaloTag coupled with fluorescent ligands and phosphatidylinositol specific phospholipase C we show that EPG is associated with the membrane via glycosylphosphatidylinositol anchor. EPG's function of increasing intracellular calcium was also used to generate an assay using GCaMP6m to observe the function of EPG and to compare its function with that of homologous proteins. It was also revealed that EPG relies on a motif of three phenylalanine residues to function-stably swapping these residues using site directed mutagenesis resulted in a loss of function in EPG. This information not only expands upon our current understanding of magnetoreception but may provide a foundation and template to continue characterizing and discovering more within the emerging field.

Epidemiological investigation of a Mycobacterium avium subsp. hominissuis outbreak in swine.

Mycobacterium avium subsp. hominissuis (MAH) infection in swine may cause granulomatous lesions in lymph nodes that must undergo differential diagnosis with those caused by M. tuberculosis complex members. Moreover, MAH outbreaks can lead to severe economic losses due to condemnation of carcasses. A number of potential sources of infection for animals can usually be identified in contaminated farms. This report describes the application of several molecular characterization techniques in order to identify the possible environmental sources of MAH infection in an outbreak involving four breeding farms and six fattening farms. Molecular profiles obtained from MAH strains suggested a likely epidemiological link between clinical and environmental isolates cultured from sawdust and cooling systems from one breeding farm. These results highlight the potential risk posed by these environmental elements in the spread of infection and the need for implementation of adequate management practices in order to minimize this risk.

Classic Hodgkin lymphoma in Guatemalan children of age less than six years: analysis of immune regulatory pathways and the tumor microenvironment.

Classic Hodgkin lymphoma (cHL) in young children (ages 0-6) is rare in high income countries (HICs) but is more prevalent in low- and middle-income countries (LMICs) like Guatemala. Given that the majority of cHL studies have evaluated adolescent/adults, and the immune system changes with age, we sought to characterize Epstein-Barr virus (EBV) expression, immune regulatory pathway markers and the tumor microenvironment in 42 children ages 0-6 with cHL from Guatemala. We found a very high frequency of EBV expression (97.5%). Hodgkin cells showed increased expression of PD1 ligands and CD137, indicative of shared immune regulatory mechanisms with adult cHL. Pediatric cHL also showed an increase in CD8+ tumor infiltrating lymphocytes and tumor associated macrophages within the tumor microenvironment. Despite 25 having high risk disease, only 4 patients died from progressive disease, relapse or infection.

Development of an Ultra-Low Carbon MgO Refractory Doped with α-Al2O3 Nanoparticles for the Steelmaking Industry: A Microstructural and Thermo-Mechanical Study.

The effect of α-Al2O3 nanoparticles (up to 5 wt.%) on the physical, mechanical, and thermal properties, as well as on the microstructural evolution of a dense magnesia refractory is studied. Sintering temperatures at 1300, 1500, and 1600 °C are used. The physical properties of interest were bulk density and apparent porosity, which were evaluated by the Archimedes method. Thermal properties were examined by differential scanning calorimetry. The mechanical behavior was studied by cold crushing strength and microhardness tests. Finally, the microstructure and mineralogical qualitative characteristics were studied by scanning electron microscopy and X-ray diffraction, respectively. Increasing the sintering temperature resulted in improved density and reduced apparent porosity. However, as the α-Al2O3 nanoparticle content increased, the density and microhardness decreased. Microstructural observations showed that the presence of α-Al2O3 nanoparticles in the magnesia matrix induced the magnesium-aluminate spinel formation (MgAl2O4), which improved the mechanical resistance most significantly at 1500 °C.

Obese adults have visual attention bias for food cue images: evidence for altered reward system function.

BACKGROUND: The major aim of this study was to investigate whether the motivational salience of food cues (as reflected by their attention-grabbing properties) differs between obese and normal-weight subjects in a manner consistent with altered reward system function in obesity. METHODOLOGY/PRINCIPAL FINDINGS: A total of 18 obese and 18 normal-weight, otherwise healthy, adult women between the ages of 18 and 35 participated in an eye-tracking paradigm in combination with a visual probe task. Eye movements and reaction time to food and non-food images were recorded during both fasted and fed conditions in a counterbalanced design. Eating behavior and hunger level were assessed by self-report measures. Obese individuals had higher scores than normal-weight individuals on self-report measures of responsiveness to external food cues and vulnerability to disruptions in control of eating behavior. Both obese and normal-weight individuals demonstrated increased gaze duration for food compared to non-food images in the fasted condition. In the fed condition, however, despite reduced hunger in both groups, obese individuals maintained the increased attention to food images, whereas normal-weight individuals had similar gaze duration for food and non-food images. Additionally, obese individuals had preferential orienting toward food images at the onset of each image. Obese and normal-weight individuals did not differ in reaction time measures in the fasted or fed condition. CONCLUSIONS/SIGNIFICANCE: Food cue incentive salience is elevated equally in normal-weight and obese individuals during fasting. Obese individuals retain incentive salience for food cues despite feeding and decreased self-report of hunger. Sensitization to food cues in the environment and their dysregulation in obese individuals may play a role in the development and/or maintenance of obesity.

The Use of Different Photoinitiator Systems in Photopolymerizing Resin Cements Through Ceramic Veneers.

OBJECTIVE: To evaluate the effect of different photoinitiator systems on photopolymerizing resin cements through ceramic veneers with different thickness on microshear bond strength (µSBS), flexural strength (FS), and ultimate tensile strength (UTS) and verify the light attenuation through these ceramic veneers. METHODS AND MATERIALS: Four photopolymerizing experimental resin cements were produced with the same resin matrix and associated with four different photoinitiator systems: camphorquinone (CQ), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO), Ivocerin, and TPO + Ivocerin. Eighty disc-shaped ceramic veneers (IPS Empress Esthetic, Ivoclar Vivadent) were fabricated (10-mm diameter) in two different thicknesses: 0.7 and 1.5 mm. A previously characterized multiwave LED (Bluephase G2, Ivoclar Vivadent) was standardized for 40 seconds of photoactivation. Light transmittance through each ceramic veneer thickness (n=5) was measured using a spectrometer (USB 2000, Ocean Optics). The µSBS of each resin cement (n=15) to the ceramic veneer was evaluated using 0.5-mm cylinders with 0.7-mm diameters photoactivated through the different ceramic veneer thicknesses. Samples for FS and UTS tests were made either with or without ceramics veneers (0.7 and 1.5 mm) fixed to the light-curing tip. Data were submitted to two-way analysis of variance and the Tukey test (α=0.05). RESULTS: The multiwave LED emitted higher irradiance into the blue wavelength spectra than into the violet wavelength spectra (p=0.0001). Light transmittance through the ceramic veneers was reduced in a systematic manner based on thickness regardless of the wavelength spectra emitted from the multiwave LED (p=0.00037). The µSBS was reduced in a systematic manner based on thickness regardless of the photoinitiator system (p<0.05). However, resin cements with CQ and Ivocerin showed higher bond strength values in comparison to the resin cement with TPO regardless of the ceramic veneer thickness (p<0.05). The FS and UTS means decreased (p<0.05) with the interposition of 0.7- and 1.5-mm ceramic veneers for all resin cements. The resin cement containing only TPO showed the lowest FS and UTS means (p<0.05) for all ceramic veneers. CONCLUSIONS: The thickness of the ceramic veneers reduced the irradiance of the multiwave LED in all wavelength spectra. Ivocerin alone or associated with TPO showed to be an effective alternative photoinitiator to substitute for CQ. The resin cement containing only TPO had lower bond strength values in comparison to resin cements with CQ, Ivocerin, and Ivocerin + TPO.

The Role of Occlusal Factors in the Presence of Noncarious Cervical Lesions in Young People: A Case-Control Study.

OBJECTIVE:: The aim of this retrospective case-control study was to evaluate the influence of different occlusal characteristics and self-referred bruxism in the presence of noncarious cervical lesions (NCCLs). METHODS AND MATERIALS:: The participants were 280 students (140 cases and 140 controls), with an average age of 24.5 years, from six schools of dentistry in Spain. Clinical examination was carried out to record the NCCLs and the static and dynamic occlusal characteristics. The side of mastication and bruxism was collected by questionnaire. Data variables were analyzed by means of univariate and multivariate logistic regression. Odds ratios and the respective 95% confidence intervals were calculated ( p<0.05). RESULTS:: The presence of NCCLs was significantly more likely in subjects with protrusive interferences (odds ratio [OR]=1.82); with lateral interferences, especially on the nonworking side (OR= 1.77); or who were self-reported bruxists (OR=1.72). In the multivariate analysis, protrusive interferences, bruxism, age, and the presence of attrition were risk factors for the development of NCCLs. These factors resulted in a model with an area under the receiver-operating characteristic curve of 0.667 and a positive predictive value of 61.43%. CONCLUSIONS:: There was no significant relationship between most occlusal factors and the presence of NCCLs. Only bruxism, protrusive interferences, age, and occlusal wear were risk factors. The predictive model was not sufficiently explanatory. Occlusal factors alone do not appear to be sufficient to explain the presence of NCCLs.

Prevención de ictus en pacientes con diabetes mellitus tipo 2 o prediabetes. Recomendaciones del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología / Stroke prevention in patients with type 2 diabetes or prediabetes. Recommendations from the Cerebrovascular Diseases Study Group, Spanish Society of Neurology

Objetivo: Actualizar las recomendaciones de la Sociedad Española de Neurología para la prevención del ictus en pacientes con DM-2 o prediabetes, analizando las evidencias disponibles sobre el efecto del control metabólico y el posible beneficio de los antidiabéticos con beneficio vascular añadidos al tratamiento antidiabético estándar en la prevención de ictus.DesarrolloSe han elaborado preguntas tipo PICO (Patient, Intervention, Comparison, Outcome) para identificar cuestiones prácticas para el manejo de pacientes con ictus y poder realizar recomendaciones específicas en cada una de ellas. Posteriormente se han realizado revisiones sistemáticas en Pubmed y se han seleccionado los ensayos clínicos aleatorizados que han evaluado ictus como variable independiente (principal o secundaria). Finalmente se ha elaborado metaanálisis para cada una de las preguntas PICO y se han redactado unas recomendaciones en respuesta a cada una de ellas.ConclusionesAunque no hay evidencia de que un mejor control metabólico reduzca el riesgo de ictus, algunas familias de antidiabéticos con beneficio vascular han mostrado reducción en el riesgo de ictus cuando se añaden al tratamiento convencional, tanto en el ámbito de prevención primaria en pacientes con DM-2 de alto riesgo vascular o con enfermedad vascular aterosclerosa establecida (agonistas GLP-1) como en prevención secundaria de ictus en pacientes con DM-2 y prediabetes (pioglitazona). (AU)

Objective: To update the Spanish Society of Neurology's guidelines for stroke prevention in patients with type 2 diabetes or prediabetes, analysing the available evidence on the effect of metabolic control and the potential benefit of antidiabetic drugs with known vascular benefits in addition to conventional antidiabetic treatments in stroke prevention.DevelopmentPICO-type questions (Patient, Intervention, Comparison, Outcome) were developed to identify practical issues in the management of stroke patients and to establish specific recommendations for each of them. Subsequently, we conducted systematic reviews of the PubMed database and selected those randomised clinical trials evaluating stroke as an independent variable (primary or secondary). Finally, for each of the PICO questions we developed a meta-analysis to support the final recommendations.ConclusionsWhile there is no evidence that metabolic control reduces the risk of stroke, some families of antidiabetic drugs with vascular benefits have been shown to reduce these effects when added to conventional treatments, both in the field of primary prevention in patients presenting type 2 diabetes and high vascular risk or established atherosclerosis (GLP-1 agonists) and in secondary stroke prevention in patients with type 2 diabetes or prediabetes (pioglitazone). (AU)

The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix.

Recently, mast cell tryptase has been identified as another potent proangiogenic factor in tumors, along with fibroblast and vascular endothelial growth factors. Its role has been studied in a number of cancers, including carcinoma of the uterine cervix, with discordant results. Our aim was to study the expression of tryptase and bFGF in mast cells (MCs) during development of neoangiogenesis in premalignant and malignant lesions of the cervix. Biopsy specimens from 21 patients without cancer and from 63 patients with dysplasias and squamous cell carcinomas were used. They were stained with Alcian blue-safranin O (ABSO) and immunostained with specific antibodies against factor VIII, CD105, tryptase, and bFGF. Tryptase-positive mast cells increased with tumor progression and were close to newly formed blood vessels. Vascularization showed a linear increase from dysplasia to invasive cancer. We suggest that MC tryptase may upregulate neoangiogenesis in carcinogenesis of the uterine cervix.

Analysis of 16 cystic fibrosis mutations in Mexican patients.

We carried out molecular analysis of 80 chromosomes from 40 unrelated Mexican patients with a diagnosis of cystic fibrosis. The study was performed in two PCR steps: a preliminary one to identify mutation delta F508, the most frequent cause of cystic fibrosis worldwide, and the second a reverse dot-blot with allele-specific oligonucleotide probes to detect 15 additional common mutations in the Caucasian population. A frequency of 45% for delta F508 was found, making it the most common in our sample of Mexican patients. Another five mutations (G542X, 3,849 + 10 kb C-->T, N1303K, SN549N, and 621 + 1 G-->T) were detected, and those accounted for 11.25%. The remaining mutations (43.75%) were undetectable with the methodology used.

Sustained arterial injury and progression of atherosclerosis.

In this paper the following findings were described: 1) Murine arteriosclerosis induced by immune challenge was ultrastructurally characterized by intimal monocyte-macrophage recruitment and minor endothelial alterations; 2) Atherosclerotic lesions of human coronary arteries exhibited frequently segmental or patchy neovascularization, probably representing a response to intimal injury as an example of repair process. Newly formed blood vessels in the intima were derived from both adventitial and luminal endothelial growth; 3) Angiogenesis in vitro was related to the activation of fibrinolytic system especially via the autocrine production of u-PA from endothelial cells, and this process was modulated by cytokines and TGF beta. These findings add more evidence for the hypothesis that the chronic inflammation-repair process plays an essential role in the initiation and progression of atherosclerosis.

Mediastinal paraganglioma irrigated by coronary vessels in a patient with an atypical chest pain.

We present a case of non-functioning anterior mediastinal paraganglioma in a 61-year-old woman. The tumour was accidentally discovered on a coronary angiography performed in an atypical precordial pain and dyspnea. The coronary angiography showed a vascular tumour in the paraaortic localization irrigated from two branches of coronary arteries. Diagnosis was confirmed by a thoracic tomographic scan which revealed an anterior mediastinal tumour. Complete tumour resection was done through a sternotomy with extracorporeal circulation without cardiac arrest. The histological examination of the operative specimen was characteristic of paraganglioma.

Human immunodeficiency virus infection in pregnant women, transmission and zidovudine therapy.

OBJECTIVE: To determine the rate of mother to child transmission of HIV infection in women treated with zidovudine (ZDV). PATIENTS AND METHODS: A consecutive series of 52 HIV-positive pregnant women who either received antenatal care or delivered at our institution. Forty-three women were known to be HIV positive before delivery. Forty were treated with ZDV, 36 intravenously. Twelve had no antenatal care and one refused antenatal treatment. All neonates were treated with ZDV. RESULTS: The HIV transmission rate in children born to mothers treated with ZDV was 6.6%. This compares with a transmission rate of 14% before we used ZDV. All three mothers who transmitted infection had low compliance, initiated therapy late in pregnancy or had advanced disease. CONCLUSION: Our experience supports the idea that ZDV treatment has reduced HIV transmission rate.

Anomalous origin of the left coronary artery from the pulmonary artery. Surgical alternatives depending of the age of the patient.

Four cases of anomalous origin of the left coronary artery from the pulmonary artery, three of which were operated upon in our Centre, are presented. An aortocoronary bypass with reversed autologous saphenous vein was carried out in both of the children; and in the adult, the anomalous ostium was closed from the interior of the pulmonary artery. After 84, 72, and 4 months of evolution, respectively, they were found to be asymptomatic, the mitral insufficiency had disappeared and the venous graft remained patent. In this paper, the clinical form of presentation, diagnostic possibilities and surgical treatment are analysed.

A comparative study of the St. Jude Medical and Björk-Shiley convexo-concave prostheses in isolated valve replacement.

This is a study of 199 consecutive patients who survived isolated mitral or aortic valve replacement with a Björk-Shiley (B-S) or St. Jude Medical (SJM) prostheses. Mean follow-up was 36 months. Preoperative status was similar for both groups (B-S or SMJ). Five year survival rates for mitral valve replacement (MVR) were 91% for B-S and SJM, and for aortic valve replacement (AVR) 96% vs 91% for SJM (p less than 0.06). Linearized incidence of thromboembolism in MVR was 5.62% patient year for BS and 5.23% patient year for SJM (p = NS). Classical risk factors for thromboembolism were evaluated on a univariate analysis: no single risk factor was identified. Only the association of two or more was possibly significant. The presence of inadequate anticoagulation (prothrombin index greater than 50%) was the main risk factor for thromboembolism, as the incidence rate was 19% per patient year when poorly anticoagulated versus 4.6% per patient year incidence in the whole series (p less than 0.01).

Intermittent aortic regurgitation following aortic valve replacement.

Intermittent aortic regurgitation is an unusual complication following a mechanical prosthesis replacement in the early postoperative period. Arterial pressure recording and echocardiographic assessment were enough to diagnose the prosthetic dysfunction. Reexploration of the valve confirmed the dysfunction, which was caused by a pannus of previous aortic valve replacement with the pulmonary valve. The pannus impeded normal closure of the leaflet in an intermittent way during diastole. Reorientation of the valve corrected the aortic insufficiency. Doppler ultrasound was a very useful noninvasive technique in order to evaluate the suspected prosthetic valve dysfunction in the immediate postoperative period.

Cytologic atypia. Clinical significance and follow-up recommendations.

OBJECTIVE: To assess the evolution of cytologic atypia on cervical cytologic smears as an attempt to better understand the natural history of these lesions and to establish a follow-up protocol. STUDY DESIGN: The study group consisted of 76 patients with a diagnosis of cytologic atypia on cervical cytologic smears performed at the gynecology Outpatient Clinic, Hospital del Mar, between December 1989 and June 1993. Patients with inflammatory atypia, a reparative process or findings consistent with human papillomavirus infection had been excluded. Follow-up smears were reviewed. Compliance with follow-up recommendations was also evaluated. RESULTS: Thirty-nine patients returned to the clinic for follow-up after a diagnosis of atypia (51.3%). Progression from atypia to dysplasia was found in 38.5% of patients with at least a follow-up smear. Changes consistent with intraepithelial neoplasia were found in 17 patients: low grade dysplasia was found in 10 patients (mild dysplasia in 8 and atypia in 2) and high grade dysplasia in 7 (moderate in 4 and severe in 3). This progression was most commonly found at the first follow-up visit and within the first year. CONCLUSION: Patients with cytologic atypia were at higher risk of developing dysplasia than those with reparative atypia. Our results support the theory of progression from atypia to dysplasia in a considerable percentage of patients. Follow-up compliance in our patient population was low. One should emphasize the importance of this diagnosis and encourage close cytologic follow-up, especially within the first year after the diagnosis of atypia.