Primary cutaneous Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL) in a patient taking fingolimod

A 55-year-old man with relapsing-remitting multiple sclerosis on fingolimod presented to the dermatology clinic with skin lesions on the left temple and cheek. Histopathology showed a diffuse infiltrate of enlarged, atypical lymphocytes throughout the dermis with an overlying grenz zone and a subpopulation of scattered smaller lymphocytes and plasma cells. Epstein-Barr virus-encoded RNA in situ hybridization stain was positive. Based on the morphologic and immunophenotypic findings, a diagnosis of EBV-positive diffuse large B-cell lymphoma was made. This case aims to raise awareness for the dermatologist that patients on fingolimod may be at increased risk of lymphoproliferative disorders

MRI radiomic features are independently associated with overall survival in soft tissue sarcoma

Purpose: Soft tissue sarcomas (STS) represent a heterogeneous group of diseases, and selection of individualized treatments remains a challenge. The goal of this study was to determine whether radiomic features extracted from magnetic resonance (MR) images are independently associated with overall survival (OS) in STS. Methods and Materials: This study analyzed 2 independent cohorts of adult patients with stage II-III STS treated at center 1 (N = 165) and center 2 (N = 61). Thirty radiomic features were extracted from pretreatment T1-weighted contrast-enhanced MR images. Prognostic models for OS were derived on the center 1 cohort and validated on the center 2 cohort. Clinical-only (C), radiomics-only (R), and clinical and radiomics (C+R) penalized Cox models were constructed. Model performance was assessed using Harrell\u27s concordance index. Results: In the R model, tumor volume (hazard ratio [HR], 1.5) and 4 texture features (HR, 1.1-1.5) were selected. In the C+R model, both age (HR, 1.4) and grade (HR, 1.7) were selected along with 5 radiomic features. The adjusted c-indices of the 3 models ranged from 0.68 (C) to 0.74 (C+R) in the derivation cohort and 0.68 (R) to 0.78 (C+R) in the validation cohort. The radiomic features were independently associated with OS in the validation cohort after accounting for age and grade (HR, 2.4; Conclusions: This study found that radiomic features extracted from MR images are independently associated with OS when accounting for age and tumor grade. The overall predictive performance of 3-year OS using a model based on clinical and radiomic features was replicated in an independent cohort. Optimal models using clinical and radiomic features could improve personalized selection of therapy in patients with STS

Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy.

Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy

Intraoperative identification of esophageal sentinel lymph nodes with near-infrared fluorescence imaging

ObjectiveIn esophageal cancer, selective removal of involved lymph nodes could improve survival and limit complications from extended lymphadenectomy. Mapping with vital blue dyes or technetium Tc-99m often fails to identify intrathoracic sentinel lymph nodes. Our purpose was to develop an intraoperative method for identifying sentinel lymph nodes of the esophagus with high-sensitivity near-infrared fluorescence imaging.MethodsSix Yorkshire pigs underwent thoracotomy and received submucosal, esophageal injection of quantum dots, a novel near-infrared fluorescent lymph tracer designed for retention in sentinel lymph nodes. Six additional pigs underwent thoracotomy and received submucosal esophageal injection of CW800 conjugated to human serum albumin, another novel lymph tracer designed for uptake into distant lymph nodes. Finally, 6 pigs received submucosal injection of the fluorophore-conjugated albumin with an endoscopic needle through an esophagascope. These lymph tracers fluoresce in the near-infrared, permitting visualization of migration to sentinel lymph nodes with a custom intraoperative imaging system.ResultsInjection of the near-infrared fluorescent lymph tracers into the esophagus revealed communicating lymph nodes within 5 minutes of injection. In all 6 pigs that received quantum dot injection, only a single sentinel lymph node was identified. Among pigs that received fluorophore-conjugated albumin injection, in 5 of 12 a single sentinel lymph node was revealed, but in 7 of 12 two sentinel lymph nodes were identified. There was no dominant pattern in the appearance of the sentinel lymph nodes either cranial or caudal to the injection site.ConclusionNear-infrared fluorescence imaging of sentinel lymph nodes is a novel and reliable intraoperative technique with the power to assist with identification and resection of esophageal sentinel lymph nodes

Balanced electric-magnetic dihole in Kaluza-Klein theory

We present a four-dimensional double-black-hole (or dihole) solution in Kaluza-Klein theory, describing a superposition of an electrically charged and a magnetically charged black hole. This system can be balanced for appropriately chosen parameters, and the resulting space-time is completely regular on and outside the event horizons. This solution was constructed using the inverse-scattering method in five-dimensional vacuum gravity, in which it describes a rotating black ring surrounding a static black hole on a Taub-NUT background space. Various properties of this solution are studied, from both a four- and five-dimensional perspective.Comment: 33 pages, 6 figures; v2: expanded discussion of phase space, published versio

Yttrium-90 microsphere induced gastrointestinal tract ulceration

© 2008 South et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

IDOL regulates systemic energy balance through control of neuronal VLDLR expression.

Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity