Non-Epstein–Barr virus associated lymphoepithelioma-like carcinoma of the esophagogastric junction with microsatellite instability,K-ras wild type

A 60-year-old male was admitted to our hospital for gastric cancer. Considering his general condition, total gastrectomy and dissection of regional lymph nodes were performed. Macroscopically, a 45 mm × 20 mm × 10 mm-sized, ulcero-infiltrative tumor located in the esophagogastric junction was described. Microscopically, the tumor consisted of a poorly differentiated adenocarcinoma intermingled with dense lymphoid infiltration predominantly composed of T-cell lymphocytes. The tumor cells infiltrated the submucosa, muscularis and subserosal layers of the stomach, respectively the esophageal adventitia. No metastases were noticed in the 58 regional lymph nodes. Based on the histopathological features, the diagnosis was lymphoepithelioma-like carcinoma, pT3N0 stage. In situ hybridization for Epstein–Barr virus showed no nuclear signal in tumor cells. The p53 expression was observed in fewer than 10% of the tumor cells. Real-time PCR analysis showed microsatellite instability without K-ras mutation in codon 12. No recurrences or metastases were reported 6 months after surgical intervention. No adjuvant therapy was performed.     

Long-COVID postural tachycardia syndrome: an American Autonomic Society statement

COVID-19 is a global pandemic that has had a devastating effect on the health and economy of much of human civilization. While the acute impacts of COVID-19 were the initial focus of concern, it is becoming clear that in the wake of COVID-19, many patients are developing chronic symptoms that have been called Long-COVID. Some of the symptoms and signs include those of postural tachycardia syndrome (POTS). Understanding and managing long-COVID POTS will require a significant infusion of health care resources and a significant additional research investment. In this document from the American Autonomic Society, we outline the scope of the problem, and the resources and research needed to properly address the impact of Long-COVID POTS.

     

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19⁺ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19⁺ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.     

A review of recent advances in optical fibre sensors for in vivo dosimetry during radiotherapy

This article presents an overview of the recent developments and requirements in radiotherapy dosimetry, with particular emphasis on the development of optical fibre dosemeters for radiotherapy applications, focusing particularly on in vivo applications. Optical fibres offer considerable advantages over conventional techniques for radiotherapy dosimetry, owing to their small size, immunity to electromagnetic interferences, and suitability for remote monitoring and multiplexing. The small dimensions of optical fibre-based dosemeters, together with being lightweight and flexible, mean that they are minimally invasive and thus particularly suited to in vivo dosimetry. This means that the sensor can be placed directly inside a patient, for example, for brachytherapy treatments, the optical fibres could be placed in the tumour itself or into nearby critical tissues requiring monitoring, via the same applicators or needles used for the treatment delivery thereby providing real-time dosimetric information. The article outlines the principal sensor design systems along with some of the main strengths and weaknesses associated with the development of these techniques. The successful demonstration of these sensors in a range of different clinical environments is also presented.Radiation dosimetry deals with methods for quantitative determination of energy deposited in a given medium directly or indirectly by ionizing radiations. A dosemeter can be defined generally as any device that is capable of providing a reading that is a measure of the average absorbed dose deposited in its (dosemeter) sensitive volume by ionizing radiation. There are commonly agreed codes of practice in the UK that define how dosimetric calibration of treatment beams should be performed,^1,2 in addition to defining the types of ionization chambers that may, or may not, be used for these measurements.Radiotherapy is in a period of rapid scientific and clinical development. The introduction of novel treatment techniques, for example, stereotactic ablative radiotherapy and volumetric modulated arc therapy (VMAT), delivered through the use of technologies such as flattening filter free (FFF) beams and dynamic multi-leaf collimation, is driving the requirement for increasing levels of accuracy and precision in dosimetry. These treatment delivery options are causing existing, well-established, dosimetric equipment to be extended to the limits of its capability. Other recent developments in treatment options include the use of protons and heavy ions, and the availability of small animal irradiation platforms provides additional scope for novel dosimetric systems. Furthermore, the increased use of image-guided radiation therapy, including the use of kilovoltage cone beam CT, MR and positron emission tomography, provides a different set of problems to existing technologies employed within traditional radiotherapy dosimetry.There are also recommendations for comprehensive quality assurance (QA) programmes^3,4 to assess the performance of all types of radiotherapy treatment equipment, including the treatment planning system (TPS), against known tolerances and for comparison with baseline measurements. The increasing complexity of modern treatment modalities has also introduced a more comprehensive patient-specific QA programme to verify, pre-treatment, an individual patient delivery. Radiotherapy also includes multiple layers of checking from the simple cross-checking of work, through independent monitor unit calculations, and on to independent audits of treatment centres'' planning and dosimetry performance.In addition to ensuring the correct calibration of treatment beams, and verification of the delivery pre-treatment, it is important to monitor dose delivery during treatment (in vivo), rather than verification of the treatment to a phantom. In an ideal scenario, the dose delivered directly within the tumour volume, and/or dose to specific organs at risk (OARs), would be measured while the patient is receiving their treatment. However, this is currently generally carried out by measuring the dose at a “surrogate” position, usually by placing a radiation detector directly on, or near to, the patient''s skin surface to provide either an entrance or exit dose value, rather than directly within the tumour itself. There is a growing interest in the need to perform such in vivo measurements in part owing to increasing awareness of the potential risks associated with incorrect delivery or planning of radiation treatments, and because of the use of increasing complex delivery techniques such as intensity-modulated radiation therapy (IMRT) and VMAT, and the move towards more hypofractionated treatments delivered with large doses per fraction.The importance of in vivo dosimetry has been further highlighted in recent years as a result of a number of major radiotherapy incidents,^5–7 and whilst the vast majority of radiotherapy sessions are performed without incident, an international review of radiotherapy incidents identified >7000 incidents over three decades (1976–2007). The incidents range from underdosing, leading to a recurrence risk, to overdosing, causing toxicity and even death.⁵ The investigations following major incidents have generally recommended that some form of in vivo dosimetry measurement would be beneficial,⁸ and professional bodies such as the American Association of Physicists in Medicine have recommended that clinics “should have access to TLD or other in vivo systems”.⁹There are a number of different options available for use as an in vivo dosemeter, with the most commonly used being thermoluminescent detectors (TLDs), diodes, metal-oxide semi-conductor field effect transistors (MOSFET), film and electronic portal imaging devices. These options each have relative strengths and weaknesses, and a number of review articles^10–12 have highlighted the merits of each. For a detailed summary of in vivo dosemeters, not restricted to optical fibre sensors, see table 1 from Mijnheer et al¹⁰ for dosemeters in external beam radiotherapy and table 3 from Tanderup et al¹² for dosemeters in brachytherapy. Methods to infer the full three-dimensional dose distribution are also being developed primarily by the use of back-projected electronic portal imaging images to reconstruct the dose within the CT volume used to plan the patient''s treatment^13–15 or through the analysis of the treatment log files to recreate the multileaf collimator (MLC) positions used during the treatment.^16,17In recent years, there has been some interest¹⁰ in investigating alternatives to the established in vivo detectors, such as plastic scintillation detectors (PSDs), optically stimulated luminescent detectors, radiophotoluminescent dosemeters and implantable MOSFETs. Some of the main reasons for the development of these alternatives to the existing options include the increasing interest in combining a MRI scanner with a radiotherapy linear accelerator (linac), the development of heavy ion and particle beams in radiotherapy and the introduction of new small animal irradiation platforms for radiobiological investigations. These new technologies present different problems from the effect of magnetic fields on dosemeters,¹⁸ the response of dosemeters in different types of treatment beams,^19,20 the miniaturization of treatment fields^21,22 and the associated complexity of radiation dosimetry at very small field sizes.^23,24Optical fibres offer a solution for in vivo radiotherapy dosimetry with many advantages over currently employed clinical dosimetry systems. An optical fibre radiation dosemeter is a photonic system based on optical fibre technology, whereby radiation introduces a modification or modulation in some of the characteristics of the optical signal. The optical fibres can be directly affected by the radiation, in which case it is called an intrinsic sensor, or it can be used for the sole purpose of transmitting the optical signal, and is known as an extrinsic sensor. There are a number of different dosimetry techniques that can incorporate optical fibres to further improve the overall system, and these techniques are discussed in turn, together with examples of such optical fibre-based systems.     

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design

Heart failure (HF) affects >5 million patients in the United States, and its prevalence is increasing every year. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors and β-blockers reduce hospitalizations and mortality rates in patients with HF, these lifesaving therapies continue to be underused. Several studies in a variety of clinical settings have documented that a significant proportion of eligible patients with HF are not receiving treatment with these guideline-recommended, evidence-based therapies. In patients hospitalized with HF, who are at particularly high risk for re-hospitalization and death, the initiation of β-blockers is often delayed because of concern that early initiation of these agents may exacerbate HF. Recent studies suggest that β-blockers can be safely and effectively initiated in patients with HF before hospital discharge and that clinical outcomes are improved. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial demonstrated that pre-discharge initiation of carvedilol was associated with a higher rate of β-blocker use after hospital discharge, with no increase in hospital length of stay. In addition, there was no increase in the risk of worsening of HF. Studies of hospital-based management systems that rely on early (pre-discharge) initiation of evidence-based therapies for patients with cardiovascular disease have also found increases in post-discharge use of therapy and a reduction in the rates of mortality and hospitalization. On the basis of these pivotal studies, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) program is designed to improve medical care and education of hospitalized patients with HF and accelerate the initiation of evidence-based HF guideline recommended therapies by administering them before hospital discharge. A registry component, planned as the most comprehensive database of the hospitalized HF population focusing on admission to discharge and 60- to 90-day follow-up, is designed to evaluate the demographic, pathophysiologic, clinical, treatment, and outcome characteristics of patients hospitalized with HF. The ultimate aim of this program is to improve the standard of HF care in the hospital and outpatient settings and increase the use of evidence-based therapeutic strategies to save lives.     

CccDNA persistence during natural evolution of chronic VHB infection

HBV infection remains a public health issue. CccDNA-HBV is a unique, intermediate replicative episome, responsible for persistence of infection in hepatocytes. The clearance of cccDNA may be explained by cellular death. CccDNA detection in chronic infected human livers may represent an important marker in monitoring antiviral therapy. Short term therapy is followed by viral rebound in the majority of chronic HBV hepatitis patients. Based on mathematical models, it is considered that the period needed to achieve a complete intrahepatic cccDNA clearance is 14.5 years.     

Interstitial Outburst of Angiogenic Factors During Skeletal Muscle Regeneration After Acute Mechanical Trauma

Angiogenesis is a key event during tissue regeneration, but the intimate mechanisms controlling this process are still largely unclear. Therefore, the cellular and molecular interplay along normal tissue regeneration should be carefully unveiled. To this matter, we investigated by xMAP assay the dynamics of some angiogenic factors known to be involved in tissue repair, such as follistatin (FST), Placental Growth Factor‐2 (PLGF‐2), epidermal growth factor (EGF), betacellulin (BTC), and amphiregulin (AREG) using an animal model that mimics acute muscle contusion injuries. In situ immunofluorescence was used for the evaluation and tissue distribution of their cellular sources. Tissue levels of explored factors increased significantly during degeneration and inflammatory stage of regeneration, peaking first week postinjury. However, except for PLGF‐2 and EGF, their levels remained significantly elevated after the inflammatory process started to fade. Serum levels were significantly increased only after 24 h for AREG and EGF. Though, for all factors except FST, the levels in injured samples did not correlate with serum or contralateral tissue levels, excluding the systemic influence. We found significant correlations between the levels of EGF and AREG, BTC, FST and FST and AREG in injured samples. Interstitial cells expressing these factors were highlighted by in situ immunolabeling and their number correlated with measured levels dynamics. Our study provides evidence of a dynamic level variation along the regeneration process and a potential interplay between selected angiogenic factors. They are synthesized, at least partially, by cell populations residing in skeletal muscle interstitium during regeneration after acute muscle trauma. Anat Rec, 298:1864–1879, 2015. © 2015 Wiley Periodicals, Inc.