Pro-inflammatory CD4
T helper (Th) cells drive the pathogenesis of many autoimmune conditions. Recent advances have modified views of the phenotype of pro-inflammatory Th cells in autoimmunity, ...extending the breadth of known Th cell subsets that operate as drivers of these responses. Heterogeneity and plasticity within Th1 and Th17 cells, and the discovery of subsets of Th cells dedicated to production of other pro-inflammatory cytokines such as GM-CSF have led to these advances. Here, we review recent progress in this area and focus specifically upon evidence for chemokine receptors that drive recruitment of these various pro-inflammatory Th cell subsets to sites of autoimmune inflammation in the CNS. We discuss expression of specific chemokine receptors by subsets of pro-inflammatory Th cells and highlight which receptors may be tractable targets of therapeutic interventions to limit pathogenic Th cell recruitment in autoimmunity.
Display omitted
Type I regulatory (Tr1) cells are defined as FOXP3−IL-10-secreting clusters of differentiation (CD4+) T cells that contribute to immune suppression and typically express the markers ...LAG-3 and CD49b and other co-inhibitory receptors. These cells have not been studied in detail in the context of the resolution of acute infection in the lung. Here, we identify FOXP3- interleukin (IL)-10+ CD4+ T cells transiently accumulating in the lung parenchyma during resolution of the response to sublethal influenza A virus (IAV) infection in mice. These cells were dependent on IL-27Rα, which was required for timely recovery from IAV-induced weight loss. LAG-3 and CD49b were not generally co-expressed by FOXP3- IL-10+ CD4+ T cells in this model and four populations of these cells based on LAG-3 and CD49b co-expression were apparent LAG-3−CD49b− (double negative), LAG-3+CD49b+ (double positive), LAG-3+CD49b− (LAG-3+), LAG-3−CD49b+ (CD49b+). However, each population exhibited suppressive potential consistent with the definition of Tr1 cells. Notably, differences between these populations of Tr1 cells were apparent including differential dependence on IL-10 to mediate suppression and expression of markers indicative of different activation states and terminal differentiation. Sort-transfer experiments indicated that LAG-3+ Tr1 cells exhibited the capacity to convert to double negative and double positive Tr1 cells, indicative of plasticity between these populations. Together, these data determine the features and suppressive potential of Tr1 cells in the resolution of IAV infection and identify four populations delineated by LAG-3 and CD49b, which likely correspond to different Tr1 cell activation states.
The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated ...between 1975 and 1990.
Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set.
Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update).
The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with ...seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium.
Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients.
Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH.
PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT).
Using the ...International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method.
Among 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS 54.3% in TER patients versus 55.4% (p = 0.7472) in NTER, nor in 5y-OS 69.4% versus 67.7% (p = 0.3841). NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001).
Teratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.
•Teratoma negatively impacts 5y-OS in IGCCCG good prognosis patients.•Teratoma negatively impacts 5y-PFS in IGCCCG intermediate prognosis patients.•Teratoma does not impact survival in IGCCCG poor prognosis patients.
Background
Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature ...evaluating the role of routine intra‐cranial imaging for the screening of asymptomatic BM in mRCC.
Aims
To evaluate the potential utility of routine intra‐cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM.
Methods and Results
The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi‐square tests, analysis of variance, and Kaplan–Meier method to characterize survival outcomes. A p‐value of <0.05 was considered statistically significant for all analyses. A total of 267 mRCC patients with BM were identified of which 106 (40%) presented with asymptomatic disease. The majority of patients presented with multiple (i.e., >1) BM (75%) with no significant differences noted in number of BM or BM‐directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median 95% confidence interval (CI) overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32–62) for patients with asymptomatic BM, and 39 months (95% CI: 29–48) with symptomatic BM (p = 0.10). OS from time of BM diagnosis was 28 months (95% CI: 18–42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10–21) in the symptomatic BM group (p = 0.04).
Conclusions
Given a substantial proportion of patients may present with asymptomatic BM, limiting intra‐cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra‐cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.
Ground-based, high-resolution spectrographs are providing us with an unprecedented view of the dynamics and chemistry of the atmospheres of planets outside the Solar System. While there are a large ...number of stable and precise high-resolution spectrographs on modest-size telescopes, it is the spectrographs at observatories with apertures larger than 3.5 m that dominate the atmospheric follow-up of exoplanets. In this work we explore the potential of characterising exoplanetary atmospheres with FIES, a high-resolution spectrograph at the 2.56 m Nordic Optical Telescope. We observed two transits of MASCARA-2 b (also known as KELT-20 b) and one transit of KELT-9 b to search for atomic iron, a species that has recently been discovered in both neutral and ionised forms in the atmospheres of these ultra-hot Jupiters using large telescopes. Using a cross-correlation method, we detect a signal of FeII at the 4.5and 4.0level in the transits of MaSCARA-2 b. We also detect FeII in the transit of KELT-9 b at the 8.5level. Although we do not find any significant Doppler shift in the signal of MASCARA-2 b, we do measure a moderate blueshift (3a-6 km s1) of the feature in KELT-9 b, which might be a manifestation of high-velocity winds transporting FeII from the planetary dayside to the nightside. Our work demonstrates the feasibility of investigating exoplanet atmospheres with FIES, and it potentially unlocks a wealth of additional atmosphere detections with this and other high-resolution spectrographs mounted on similar-size telescopes.
The role of cavities on deformation-induced martensitic phase transformations is studied in a laser-welded and neutron irradiated austenitic stainless steel. Orientation dependent nanoindentation ...experiments are performed in the base metal and the weld heat affected zone (HAZ) at room temperature. Transmission electron microscopy study of deformed microstructures indicates indentation-induced α’-martensite forms in the base metal, whereas α’- and ε-martensite arise in the HAZ. The different pathway of martensite phase transformation is attributed to the laser weld-induced annealing of cavities. Our results suggest that deformation-induced martensitic phase transformation of austenitic stainless steel is correlated to neutron irradiated cavity structures.
Display omitted
Active surveillance (AS) is a commonly used strategy in patients with slow-growing disease. We aimed to assess the outcomes and safety of AS in patients with metastatic renal cell carcinoma (mRCC).
...We used the Canadian Kidney Cancer information system (CKCis) to identify patients with mRCC diagnosed between January 1, 2011, and December 31, 2016. The AS strategy was defined as (1) the start of systemic therapy ≥ 6 months after diagnosis of mRCC, or (2) never receiving systemic therapy for mRCC with an overall survival (OS) of ≥1 year. Patients starting systemic treatment <6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until first-line treatment failure (TTF) were compared between the two cohorts.
A total of 853 patients met the criteria for AS (cohort A). Of these, 364 started treatment >6 months after their initial diagnosis (cohort A1) and 489 never started systemic therapy (cohort A2); 827 patients received immediate systemic treatment (cohort B). The 5-year OS probability was significantly greater for cohort A than for cohort B (70% vs. 33.6%; P < .0001). After adjusting for International Metastatic RCC Database Consortium risk criteria and age, both OS (hazard ratio HR = 0.58; 95% confidence interval CI, 0.47-0.70; P < .0001) and TTF (HR = 0.72; 95% CI, 0.60-0.85; P = .0002) were greater in cohort A1 compared with B. For cohort A1, the median time on AS was 14.2 months (range, 6-71).
Based on the largest analysis of AS in mRCC to date, our data suggest that a subset of patients may be safely observed without immediate initiation of systemic therapy.
We aimed to assess the outcomes and safety of active surveillance (AS) in patients with metastatic renal cell carcinoma (mRCC). We identified 853 patients who met the criteria for AS. We compared them to a cohort of patients who received immediate systemic therapy. Our data demonstrated that a large subset of patients with mRCC can be safely observed without immediate initiation of systemic therapy for a significant period of time.
PDF
