Transcriptomic analysis of GITR and GITR ligand reveals cancer immune heterogeneity with implications for GITR targeting.

Glucocorticoid-induced tumor necrosis factor related protein (GITR) is a transmembrane protein expressed mostly on CD25+CD4+ regulatory T-cells (Tregs) and upregulated on all T-cells upon activation. It is a T-cell co-stimulatory receptor and has demonstrated promising anti-tumor activity in pre-clinical studies. To date, however, the efficacy of GITR agonism has been discouraging in clinical trials. This study explores GITR and GITR ligand (GITR-L) ribonucleic acid (RNA) expression in solid tumors in an attempt to delineate causes for variable responses to GITR agonists. RNA expression levels of 514 patients with a variety of cancer types were normalized to internal housekeeping gene profiles and ranked as percentiles. 99/514 patients (19.3%) had high GITR expression (defined as ≥ 75th percentile). Breast and lung cancer had the highest proportion of patients with high GITR expression (39% and 35%, respectively). The expression of concomitant high GITR and low-moderate GITR-L expression (defined as <75th percentile) was present in 31% and 30% of patients with breast and lung cancer respectively. High GITR expression also showed a significant independent association with high RNA expression of other immune modulator proteins, namely, PD-L1 immunohistochemistry (IHC) ≥1 (odds ratio (OR) 2.15, P=0.008), CTLA4 (OR=2.17, P=0.05) and OX40 high RNA expression (OR=2.64, P=0.001). Overall, these results suggest that breast and lung cancer have a high proportion of patients with a GITR and GITR-L RNA expression profile that merits further investigation in GITR agonism studies. The association of high GITR expression with high CTLA4 and OX40 RNA expression, as well as positive PD-L1 IHC, provides a rationale for a combination approach targeting these specific immune modulator proteins in patients whose tumors show such co-expression.

Outcomes With Malignancy-Associated High-Risk Pulmonary Embolism: A Nationwide Analysis.

OBJECTIVE: To examine the characteristics and outcomes among patients with high-risk pulmonary embolism (PE) and malignancy. PATIENTS AND METHODS: The Nationwide Readmissions Database was used to identify hospitalizations with high-risk PE from January 1, 2016, to December 31, 2019. The main outcome was the difference in all-cause in-hospital mortality. RESULTS: Among 28,547 weighted hospitalizations with high-risk PE, 4,825 (16.9%) had malignancy. Admissions with malignancy had a lower prevalence of other comorbid conditions except for anemia and coagulopathy. The use of systemic thrombolysis, catheter-directed interventions, and surgical embolectomy was less common among admissions with malignancy, whereas the use of inferior vena cava filter was more common among those with malignancy. All-cause in-hospital mortality was higher among admissions with malignancy even after adjustment (adjusted odds ratio, 1.91; 95% CI, 1.72 to 2.11; P<.001). Metastatic genitourinary, gastrointestinal (other than colorectal), and lung malignancies were associated with the highest incidence of in-hospital mortality. The incidence of intracranial hemorrhage (3.9% vs 3.1%; P=.056) and the composite of non-intracranial hemorrhage bleeding (21.9% vs 20.6%; P=.185) was not different between admissions with and without malignancy. However, admissions with malignancy had higher incidence of gastrointestinal bleeding. CONCLUSION: In this nationwide analysis of patients admitted with high-risk PE, malignancy was independently associated with an increased risk of in-hospital mortality. The risk was highest among patients with metastatic genitourinary, gastrointestinal, and lung malignancies. Advanced therapies were less frequently used among patients with malignancy.

Survival Disparities of Diffuse Large B-Cell Lymphoma in a Community-Based Inner-City Cancer Center.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) comprises approximately 30% of all non-Hodgkin lymphomas. Multiple studies have demonstrated race-based disparities in survival among patients with DLBCL across all stages of disease, in the era both before and after rituximab. The etiology for the racial disparities in survival among patients with DLBCL is still unknown. Moreover, the Revised International Prognostic Index (R-IPI), a tool that predicts the DLBCL patients' outcome, has not yet been validated in African Americans (AA). PATIENTS AND METHODS: We conducted a cohort study of patients diagnosed with DLBCL from January 1, 2007, to December 31, 2017, from our tumor registry in a single community-based inner-city cancer center. We abstracted demographic, clinical, histopathologic, treatment, and R-IPI variables. A total of 181 patients (47.5%) with biopsy-proven DLBCL were included in the retrospective analysis. The median age was 65 years, 47% were men, 41% were AA, and 44% were white. RESULTS: The AA group had a younger median age, higher lactate dehydrogenase levels, higher frequency of B symptoms, and higher HIV infection than the non-AA group. The AA group had significantly decreased median overall survival than the non-AA group (15.7 months; 95% confidence interval, 10.3 to 23.9, vs. 93.6 months; 95% confidence interval, 61.5 to 142.6, respectively; P < .001). The survival disparities persisted after excluding patients with HIV and who did not receive chemotherapy. In addition, AA race predicts a reduced survival by univariate and multivariate analysis. CONCLUSION: AA with DLBCL may have a poorer prognosis than the non-AA population. Further studies should investigate the biology of DLBCL in the AA population.

COVID-19 in HIV-infected patients: A case series and literature review.

During the current COVID pandemic, there is growing interest to identify subsets of the population that may be at a higher than average risk of infection. One such group includes people living with HIV.

Non-Operative Rehabilitation of Isolated Popliteus Tendon Rupture in a Rugby Player.

Isolated rupture of the popliteus tendon is uncommon; instead, it is often seen as part of multi-ligamentous posterolateral corner injuries. In this report, we present a case of a 22-year-old professional rugby player who sustained a lateral blow to his semi-flexed knee in a tackle during a competitive game. A complete popliteus tendon rupture at its musculo-tendinous junction was diagnosed on magnetic resonance imaging despite a relatively unremarkable physical examination. The aims of this report are to highlight the diagnostic challenges with this rare injury as physical signs are often subtle and non-specific. Furthermore, we demonstrate the viability of conservative management in the setting of a direct contact mechanism. Indeed, our patient was successfully treated with a specific rehabilitation protocol via isometric quadriceps contractions, gastrocnemius-soleus and hamstring strengthening exercises and graded activity with successful return to full contact activities at 4 weeks and regular season matches shortly after.

Specific dysregulation of IFNγ production by natural killer cells confers susceptibility to viral infection.

Natural Killer (NK) cells contribute to the control of viral infection by directly killing target cells and mediating cytokine release. In C57BL/6 mice, the Ly49H activating NK cell receptor plays a key role in early resistance to mouse cytomegalovirus (MCMV) infection through specific recognition of the MCMV-encoded MHC class I-like molecule m157 expressed on infected cells. Here we show that transgenic expression of Ly49H failed to provide protection against MCMV infection in the naturally susceptible A/J mouse strain. Characterization of Ly49H(+) NK cells from Ly49h-A transgenic animals showed that they were able to mount a robust cytotoxic response and proliferate to high numbers during the course of infection. However, compared to NK cells from C57BL/6 mice, we observed an intrinsic defect in their ability to produce IFNγ when challenged by either m157-expressing target cells, exogenous cytokines or chemical stimulants. This effect was limited to NK cells as T cells from C57BL/6 and Ly49h-A mice produced comparable cytokine levels. Using a panel of recombinant congenic strains derived from A/J and C57BL/6 progenitors, we mapped the genetic basis of defective IFNγ production to a single 6.6 Mb genetic interval overlapping the Ifng gene on chromosome 10. Inspection of the genetic interval failed to reveal molecular differences between A/J and several mouse strains showing normal IFNγ production. The chromosome 10 locus is independent of MAPK signalling or decreased mRNA stability and linked to MCMV susceptibility. This study highlights the existence of a previously uncovered NK cell-specific cis-regulatory mechanism of Ifnγ transcript expression potentially relevant to NK cell function in health and disease.

Genetic dissection of NK cell responses.

The association of Natural Killer (NK) cell deficiencies with disease susceptibility has established a central role for NK cells in host defence. In this context, genetic approaches have been pivotal in elucidating and characterizing the molecular mechanisms underlying NK cell function. To this end, homozygosity mapping and linkage analysis in humans have identified mutations that impact NK cell function and cause life-threatening diseases. However, several critical restrictions accompany genetic studies in humans. Studying NK cell pathophysiology in a mouse model has therefore proven a useful tool. The relevance of the mouse model is underscored by the similarities that exist between cell-structure-sensing receptors and the downstream signaling that leads to NK cell activation. In this review, we provide an overview of how human and mouse quantitative trait locis (QTLs) have facilitated the identification of genes that modulate NK cell development, recognition, and killing of target cells.