The biology of tumor-derived exosomes (TEX) is only partially understood and much remains to be studied in order to define the effect that the tumor microenvironment or the activation of tumor cells ...exerts on their composition and functions. Increased expression and activity of toll-like receptor 4 (TLR4) in chronic infectious and inflammatory conditions is related with cancer progression: its activation induces an inflammatory signaling that increases the tumorigenic potential of cancer cells promoting their immune evasion. We investigated the immune modulatory properties of TEX released upon cell TLR4 activation, and we found that, although differences were observed depending on the type of the tumor, the treatment influences TEX composition and boosts their immunosuppressive ability. Our results suggest that the activation of TLR4 supports tumor progression by stimulating the release of more effective immunosuppressive exosomes, which allow tumor cells to escape immune surveillance and probably even play a role in the metastatic process.
Summary
Peripheral T‐cell lymphomas (PTCLs) are a heterogeneous group of haematological cancers with generally poor clinical outcomes. However, a subset of patients experience durable disease ...control, and little is known regarding long‐term outcomes. The International T‐cell Lymphoma Project (ITCLP) is the largest prospectively collected cohort of patients with PTCLs, providing insight into clinical outcomes at academic medical centres globally. We performed a long‐term outcome analysis on patients from the ITCLP with available 10‐year follow‐up data (n = 735). The overall response rate to first‐line therapy was 68%, while 5‐ and 10‐year overall survival estimates were 49% and 40% respectively. Most deaths occurred prior to 5 years, and for patients alive at 5 years, the chance of surviving to 10 years was 84%. However, lymphoma remained the leading cause of death in the 5‐ to 10‐year period (67%). Low‐risk International Prognostic Index and Prognostic Index for T‐cell lymphoma scores both identified patients with improved survival, while in multivariate analysis, age >60 years and Eastern Cooperative Oncology Group performance status 2–4 were associated with inferior outcomes. The favourable survival seen in patients achieving durable initial disease control emphasizes the unmet need for optimal front‐line therapeutic approaches in PTCLs.
The International T‐cell Lymphoma Project is the largest prospectively collected cohort of patients with peripheral T‐cell lymphomas (PTCLs). In the long‐term outcome analysis of patients with available 10‐year follow‐up data (n = 735), 5‐ and 10‐year overall survival (OS) estimates were 49% and 40% respectively. For patients alive at 5 years, the chance of surviving to 10 years was 84%, but lymphoma remained the leading cause of death in the 5‐ to 10‐year period (67%). The favourable survival seen in patients achieving durable initial disease control emphasizes the unmet need for optimal front‐line therapeutic approaches in PTCLs.
Combined Antiretroviral therapy (cART) suppresses HIV replication but fails to eradicate the virus, which persists in a small pool of long-lived latently infected cells. Immune activation and ...residual inflammation during cART are considered to contribute to viral persistence. Galectins, a family of β-galactoside-binding proteins, play central roles in host-pathogen interactions and inflammatory responses. Depending on their structure, glycan binding specificities and/or formation of distinct multivalent signaling complexes, different members of this family can complement, synergize, or oppose the function of others. Here, we identify a regulatory circuit, mediated by galectin-1 (Gal-1)–glycan interactions, that promotes reversal of HIV-1 latency in infected T cells. We found elevated levels of circulating Gal-1 in plasma from HIV-1-infected individuals, which correlated both with inflammatory markers and the transcriptional activity of the reservoir, as determined by unspliced-RNA (US-RNA) copy number. Proinflammatory extracellular vesicles (EVs) isolated from the plasma of HIV-infected individuals induced Gal-1 secretion by macrophages. Extracellularly, Gal-1 interacted with latently infected resting primary CD4+ T cells and J-LAT cells in a glycan-dependent manner and reversed HIV latency via activation of the nuclear factor κB (NF-κB). Furthermore, CD4+ T cells isolated from HIV-infected individuals showed increased HIV-1 transcriptional activity when exposed to Gal-1. Thus, by modulating reservoir dynamics, EV-driven Gal-1 secretion by macrophages links inflammation with HIV-1 persistence in cART-treated individuals. IMPORTANCE Antiretroviral therapy has led to a dramatic reduction in HIV-related morbidity and mortality. However, cART does not eradicate the virus, which persists in resting CD4+ T cells as the main viral reservoir, consequently requiring lifelong treatment. A major question is how the functional status of the immune system during antiretroviral therapy determines the activity and size of the viral reservoir. In this study, we identified a central role for galectin-1 (Gal-1), a glycan-binding protein released in response to extracellular vesicles (EVs), in modulating the activity of HIV reservoir, thus shaping chronic immune activation in HIV-infected patients. Our work unveils a central role of Gal-1 in linking chronic immune activation and reservoir dynamics, highlighting new therapeutic opportunities in HIV infection.
Background
Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently ...defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria.
Methods
A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed.
Results
Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC.
Conclusion
Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.
Purpose
The Mobius3D system was validated as a modern secondary check dosimetry system.
In particular, our objective has been to assess the suitability of the M3D as pre‐treatment patient‐specific ...Quality Assurance (QA) tool for Stereotactic Radiosurgery (SRS) HyperArc (HA) treatments. We aimed to determine whether Mobius3D could safely replace the measurements‐based patient‐specific QA for this type of treatment.
Methods
30 SRS HA treatment plans for brain were selected. The dose distributions, calculated by Mobius and our routinely used algorithm (AcurosXB v.15.6), were compared using gamma analysis index and DVH parameters based on the patient's CT dataset.
All 30 plans were then delivered across the ionization chamber in a homogeneous phantom and the measured dose was compared with both M3D and TPS calculated one.
The plans were delivered and verified in terms of PSQA using the electronic portal imaging device (EPID) with Portal Dosimetry (PD) and myQA SRS (IBA Dosimetry) detector.
Plans that achieved a global gamma passing rate (GPR) ≥ 97% based on 2%/2 mm criteria, with both Mobius3D and the conventional methods were evaluated acceptable. Finally, we assessed the capability of the M3D system to detect errors related to the position of the Multi‐Leaf Collimator (MLC) in comparison to the analyzed measurement‐based systems.
Results
No relevant differences were observed in the comparison between the dose calculated on the CT‐dataset by M3D and the TPS. Observed discrepancies are imputable to different used algorithms, but no discrepancies related to goodness of plans have been found.
Average differences between calculated (M3D and TPS) vs measured dose with ionization chamber were 2.5% (from 0.41% to 3.2%) and 1.81% (from 0.66% to 2.65%), for M3D and TPS, respectively.
All plans passed with a gamma passing rate > 97% using conventional PSQA methods with a gamma criterion of 2% dose difference and 2 mm distance‐to‐agreement. The average gamma passing rate for the M3D system was determined to be 99.4% (from 97.3% to 100%). Results from this study also demonstrated Mobius has better error detectability than conventional measurement‐based systems.
Conclusion
Our study shows Mobius3D could be a suitable alternative to conventional measured based QA methods for SRS HyperArc treatments.
Assessment of left ventricular (LV) filling pressure is among the important components of a comprehensive echocardiographic report. Previous studies noted wide limits of agreement using 2009 American ...Society of Echocardiography/European Association of Echocardiography guidelines, but reproducibility of 2016 guidelines update in estimating LV filling pressure is unknown.
Echocardiographic and hemodynamic data were obtained from 50 patients undergoing cardiac catheterization for clinical indications. Clinical and echocardiographic findings but not invasive hemodynamics were provided to 4 groups of observers, including experienced echocardiographers and cardiology fellows. Invasively acquired LV filling pressure was the gold standard.
In group I of 8 experienced echocardiographers from the guidelines writing committee, sensitivity for elevated LV filling pressure was 92% for all observers, and specificity was 93±6%. Fleiss κ-value for the agreement in group I was 0.80. In group II of 4 fellows in training, sensitivity was 91±2%, and specificity was 95±2%. Fleiss κ-value for the agreement in group II was 0.94. In group III of 9 experienced echocardiographers who had not participated in drafting the guidelines, sensitivity was 88±5%, and specificity was 91±7%. Fleiss κ-value for the agreement in group III was 0.76. In group IV of 7 other fellows, sensitivity was 91±3%, and specificity was 92±5%. Fleiss κ-value for the agreement in group IV was 0.89.
There is a good level of agreement and accuracy in the estimation of LV filling pressure using the American Society of Echocardiography/European Association of Cardiovascular Imaging 2016 recommendations update, irrespective of the experience level of the observer.
The aim of this work is to describe the clinical manifestations at onset and during follow-up in a monocentric cohort of patients with juvenile systemic lupus erythematosus (jSLE) from the Paediatric ...Rheumatology group of the Milan area (PRAGMA).
Patients were retrospectively included in case of i) SLE diagnosis according to the 1997 American College of Rheumatology or the 2012 SLICC classification criteria and ii) disease onset before 18 years.
Among the 177 recruited patients (155 females), haematologic involvement was the most common disease manifestation (75%), followed by joint and cutaneous involvements (70% and 57%, respectively). Renal disease was observed in 58 patients (32.8%), neurological complications in 26 cases (14.7%). Patients presented most commonly 3 clinical manifestations (32.8%), while 2 organ involvements were identified in 54 patients (30.5%) and 4 in 25 subjects (14.1%). The 49 patients with disease onset <10 years had less commonly articular involvement (p=0.02), while patients aged >14.8 years displayed less neurological manifestations (p=0.02). At a median follow-up of 118 month, the disease progressed in 93 patients, with a median of 2 new manifestations per patient. Low complement at diagnosis predicted new clinical manifestations (p=0.013 for C3 and p=0.0004 for C4). The median SLEDAI at diagnosis was 13; SLEDAI was substantially similar at 6 months, decreased at 12 months to remain stable at 18 months and further reduce at 24 months (p<0.0001).
These data from a large jSLE monocentric cohort allow gaining further insights into a rare disease with a still high morbidity burden.
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