Microenvironmental immune cell alterations across the spectrum of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.

Background: The clinicopathological spectrum of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), also known as nodular lymphocyte predominant B-cell lymphoma, partially overlaps with T-cell/histiocyte-rich large B-cell lymphoma (THRLCBL). NLPHL histology may vary in architecture and B-cell/T-cell composition of the tumour microenvironment. However, the immune cell phenotypes accompanying different histological patterns remain poorly characterised. Methods: We applied a multiplexed immunofluorescence workflow to identify differential expansion/depletion of multiple microenvironmental immune cell phenotypes between cases of NLPHL showing different histological patterns (as described by Fan et al, 2003) and cases of THRLBCL. Results: FOXP3-expressing T-regulatory cells were conspicuously depleted across all NLPHL cases. As histology progressed to variant Fan patterns C and E of NLPHL and to THRLBCL, there were progressive expansions of cytotoxic granzyme-B-expressing natural killer and CD8-positive T-cells, PD1-expressing CD8-positive T-cells, and CD163-positive macrophages including a PDL1-expressing subset. These occurred in parallel to depletion of NKG2A-expressing natural killer and CD8-positive T-cells. Discussion: These findings provide new insights on the immunoregulatory mechanisms involved in NLPHL and THLRBCL pathogenesis, and are supportive of an increasingly proposed biological continuum between these two lymphomas. Additionally, the findings may help establish new biomarkers of high-risk disease, which could support a novel therapeutic program of immune checkpoint interruption targeting the PD1:PDL1 and/or NKG2A:HLA-E axes in the management of high-risk NLPHL and THRLBCL.

Negative mpMRI Rules Out Extra-Prostatic Extension in Prostate Cancer before Robot-Assisted Radical Prostatectomy.

Background: The accuracy of multi-parametric MRI (mpMRI) in the pre-operative staging of prostate cancer (PCa) remains controversial. Objective: The purpose of this study was to evaluate the ability of mpMRI to accurately predict PCa extra-prostatic extension (EPE) on a side-specific basis using a risk-stratified 5-point Likert scale. This study also aimed to assess the influence of mpMRI scan quality on diagnostic accuracy. Patients and Methods: We included 124 men who underwent robot-assisted RP (RARP) as part of the NeuroSAFE PROOF study at our centre. Three radiologists retrospectively reviewed mpMRI blinded to RP pathology and assigned a Likert score (1-5) for EPE on each side of the prostate. Each scan was also ascribed a Prostate Imaging Quality (PI-QUAL) score for assessing the quality of the mpMRI scan, where 1 represents the poorest and 5 represents the best diagnostic quality. Outcome measurements and statistical analyses: Diagnostic performance is presented for the binary classification of EPE, including 95% confidence intervals and the area under the receiver operating characteristic curve (AUC). Results: A total of 231 lobes from 121 men (mean age 56.9 years) were evaluated. Of these, 39 men (32.2%), or 43 lobes (18.6%), had EPE. A Likert score ≥3 had a sensitivity (SE), specificity (SP), NPV, and PPV of 90.4%, 52.3%, 96%, and 29.9%, respectively, and the AUC was 0.82 (95% CI: 0.77-0.86). The AUC was 0.76 (95% CI: 0.64-0.88), 0.78 (0.72-0.84), and 0.92 (0.88-0.96) for biparametric scans, PI-QUAL 1-3, and PI-QUAL 4-5 scans, respectively. Conclusions: MRI can be used effectively by genitourinary radiologists to rule out EPE and help inform surgical planning for men undergoing RARP. EPE prediction was more reliable when the MRI scan was (a) multi-parametric and (b) of a higher image quality according to the PI-QUAL scoring system.

Effects of Glucagon-like Peptide-1 on the Reproductive Axis in Healthy Men.

CONTEXT: Glucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans. OBJECTIVE: To investigate the effects of GLP-1 administration on the reproductive axis in humans. DESIGN: Single-blind, randomized, placebo-controlled crossover study. SETTING: Clinical Research Facility, Imperial College Healthcare NHS Trust. PARTICIPANTS: Eighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2). INTERVENTION: Eight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion. MAIN OUTCOME MEASURES: Number of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels. RESULTS: The number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01). CONCLUSIONS: In contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

Effects of Peptide YY on the Hypothalamic-Pituitary-Gonadal Axis in Healthy Men.

CONTEXT: Central and peripheral administration of peptide YY (PYY) has potent anorectic effects, and PYY analogs are under development as antiobesity treatments. Recent animal data suggest PYY may also influence the reproductive axis; however the effects of PYY on the human reproductive system are unknown. OBJECTIVE: To investigate the effects of PYY administration on the reproductive axis in healthy young men. DESIGN: Single-blind, randomized, placebo-controlled crossover study. SETTING: Clinical Research Facility, Imperial College Healthcare NHS Trust. PARTICIPANTS: Eighteen healthy eugonadal men (mean age 24.1 ± 0.9 years, mean body mass index 22.2 ± 0.4 kg/m2). INTERVENTION: Eight-hour intravenous infusion of 0.4 pmol/kg/min PYY3-36 or rate-matched vehicle infusion. MAIN OUTCOME MEASURES: Number of luteinizing hormone (LH) pulses, LH, follicle stimulating hormone (FSH), and testosterone levels. RESULTS: The number of LH pulses (mean number of LH pulses/8 hours: PYY 4.4 ± 0.3 vs vehicle 4.4 ± 0.4, P > .99), LH area under the curve (AUC) (PYY 1503 ± 79 IU.min/L vs vehicle 1574 ± 86 IU.min/L, P = .36), FSH AUC (PYY 1158 ± 513 IU.min/L vs vehicle 1199 ± 476 IU.min/L, P = .49) and testosterone AUC (PYY 10 485 ± 684 IU.min/L vs vehicle 11 133 ± 803 IU.min/L, P = .24) were similar during PYY and vehicle infusions. CONCLUSIONS: Acute intravenous infusion of 0.4 pmol/kg/min PYY does not affect the reproductive axis in healthy men.

Bulbar dysfunction and aspiration pneumonia due to a brainstem haemangioblastoma: an unusual complication of von Hippel-Lindau disease.

A 44-year-old woman with a history of von Hippel-Lindau (VHL) disease, a rare inherited neoplasia syndrome, presented acutely to hospital with a productive cough, symptoms of respiratory tract infection and odynophagia (painful swallowing). A chest X-ray confirmed right-sided pneumonia. Investigation of the persistent odynophagia using barium swallow revealed aspiration of the contrast into the lungs and suggested a neurological cause for her chest infection. Clinical assessment and speech and language therapy confirmed a pseudobulbar palsy. Subsequent neuroimaging identified a cystic haemangioblastoma, located at the cervicomedullary junction of the brainstem, as the cause of the pseudobulbar palsy. Urgent neurosurgical excision produced symptomatic relief and with continuing medical therapy, and clinical resolution of her pneumonia. In patients with VHL disease and other inherited cancer syndromes, a high index of suspicion should be maintained for new tumours presenting with common medical symptoms and signs.