Early disease progression and treatment discontinuation in patients with advanced ovarian cancer receiving immune checkpoint blockade

Objective

Delayed responses observed with immune checkpoint blockade (ICB) present a challenge for patients with peritoneal malignancies, who risk early symptomatic disease progression requiring treatment discontinuation. While efforts are ongoing to define the biomarkers of response, it is equally important to identify patients at risk for early discontinuation. We sought to investigate the timing of disease progression in epithelial ovarian cancer (EOC) patients treated with ICB and to identify pre-treatment clinical parameters associated with early discontinuation.

Impact of adherence and highly active antiretroviral therapy on survival in HIV-infected patients

OBJECTIVES: To assess the effect of antiretroviral therapy (ART) adherence on survival in HIV-infected patients. DESIGN: Cohort study at a single hospital in Barcelona, Spain. METHODS: Data on HIV-infected patients older than 18 years of age who began ART during the period 1990 to 1999 were analyzed. Patients were considered nonadherent if the total dose of antiretroviral drug was less than 90% of that prescribed. Adherence was assessed through self-report and hospital pharmacy appointments. Cox regression with time-dependent variables was used. RESULTS: A total of 1219 patients were included. The first ART was with monotherapy in 23.7% of cases, with two drugs in 30.5%, and with triple therapy in 45.8%. In multivariate analysis, the variables that presented significant differences with respect to mortality were clinical stage at the beginning of treatment (AIDS: relative hazard (RH) = 2.97; 95% confidence interval [CI]: 2.14-4.13), CD4 cell count (<200 cells/microL: RH = 5.89; CI: 3.44-10.10), type of treatment (monotherapy: RH = 9.76; CI: 4.56-20.90; bi-therapy: RH = 9.12; CI: 4.23-19.64), and adherence (nonadherence: RH = 3.87; CI: 1.77-8.46). CONCLUSIONS: The modifiable factors most strongly associated with survival were type of treatment and adherence. It would be desirable to accompany therapy with intervention strategies intended to improve adherence.     

Circulating and thymic CD4 CD25 T regulatory cells in myasthenia gravis: effect of immunosuppressive treatment

Accumulating evidence indicates an immunosuppressive role of the thymus-derived CD4+ T-cell population constitutively expressing high level of CD25, T regulatory (Treg) cells, in autoimmune diseases. Here we show that the number of Treg cells in the blood is significantly lower in untreated myasthenia gravis patients than in age-matched healthy subjects, whereas it is normal or elevated in patients on immunosuppressive therapy (prednisone frequently associated with azathioprine). Therapeutic thymectomy (Tx) for either the thymoma or non-neoplastic thymic alterations that are often associated with myasthenia gravis provided unique material for studying intrathymic Treg cells and correlating them with their peripheral counterparts. We observed that Tx prevents the increase of Treg cells in the circulation that follows immunosuppressive therapy (particularly evident if the thymus is not neoplastic), indicating that the thymus contributes to Treg-cell normalization. However, thymic Treg cells are not modulated by immunosuppressive therapy and even in thymectomized patients Treg-cell numbers in the blood eventually recover. The present findings suggest that a deficiency in Treg cells favours the development of myasthenia gravis and that their normalization is an important clinical benefit of immunosuppressive therapy. Treg normalization appears to be largely thymus independent and possibly reflects the reported capacity of corticosteroids to promote Treg-cell development.     

Interleukin‐21 (IL‐21) synergizes with IL‐2 to enhance T‐cell receptor‐induced human T‐cell proliferation and counteracts IL‐2/transforming growth factor‐β‐induced regulatory T‐cell development

Interleukin‐2 (IL‐2) is a mainstay for current immunotherapeutic protocols but its usefulness in patients is reduced by severe toxicities and because IL‐2 facilitates regulatory T (Treg) cell development. IL‐21 is a type I cytokine acting as a potent T‐cell co‐mitogen but less efficient than IL‐2 in sustaining T‐cell proliferation. Using various in vitro models for T‐cell receptor (TCR)‐dependent human T‐cell proliferation, we found that IL‐21 synergized with IL‐2 to make CD4⁺ and CD8⁺ T cells attain a level of expansion that was impossible to obtain with IL‐2 alone. Synergy was mostly evident in naive CD4⁺ cells. IL‐2 and tumour‐released transforming growth factor‐β (TGF‐β) are the main environmental cues that cooperate in Treg cell induction in tumour patients. Interleukin‐21 hampered Treg cell expansion induced by IL‐2/TGF‐β combination in naive CD4⁺ cells by facilitating non‐Treg over Treg cell proliferation from the early phases of cell activation. Conversely, IL‐21 did not modulate the conversion of naive activated CD4⁺ cells into Treg cells in the absence of cell division. Treg cell reduction was related to persistent activation of Stat3, a negative regulator of Treg cells associated with down‐modulation of IL‐2/TGF‐β‐induced phosphorylation of Smad2/3, a positive regulator of Treg cells. In contrast to previous studies, IL‐21 was completely ineffective in counteracting the suppressive activity of Treg cells on naive and memory, CD4⁺ and CD8⁺ T cells. Present data provide proof‐of‐concept for evaluating a combinatorial approach that would reduce the IL‐2 needed to sustain T‐cell proliferation efficiently, thereby reducing toxicity and controlling a tolerizing mechanism responsible for the contraction of the T‐cell response.     

A comparison of client and therapist goals for people with aphasia: A qualitative exploratory study

Background: A considerable body of literature attests to the efficacy of client and therapist collaborative goal setting to achieving optimal rehabilitation outcomes. Collaborative goal setting and shared decision making relies on good communication, thus potentially disadvantaging people with aphasia.

Aims: This study aims to identify the similarities and differences between client goals and therapist goals in rehabilitation for people with aphasia and to explore reasons why any differences occur.

Methods & Procedures: Three speech-language pathologists and four people with aphasia participated in in-depth semi-structured interviews to identify rehabilitation goals. All the interviews were transcribed and analysed using qualitative content analysis.

Outcomes & Results: Results indicated both matching and mismatching of goals between the clients and the speech-language pathologists. Matched goals tended to focus on communication outcomes. Mismatched goals were those associated with the client's desire to return to previously valued activities. Reasons for the mismatching included: impaired communication made collaboration on goal setting difficult, the service-delivery approach, the goal was perceived to be outside the speech-language pathologist's scope of practice, and the goal was not considered to be appropriate within the confines of the rehabilitative situation.

Conclusions: This study highlights the need for speech-language pathologists to understand their clients' goals and how these can be incorporated into rehabilitation. A re-examination of some professional beliefs was highlighted. Future research may lead to educational resources that enable better collaborative goal setting between therapist and client so that outcomes of rehabilitation are optimised.     

Survival After Thoracoscopic Surgery or Open Lobectomy: Systematic Review and Meta-Analysis

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Histone Mark Profiling in Pediatric Astrocytomas Reveals Prognostic Significance of H3K9 Trimethylation and Histone Methyltransferase SUV39H1

Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01090-x.     

Contribution of magnetic resonance cholangiopancreatography to the diagnosis of biliary tract disease

The aim of the study was to assess the role of magnetic resonance cholangiopan-creatography (MRCP) in the diagnosis of biliary tract and pancreatic duct diseases, also in relation to the data reported in the literature. Over the period from Februrary 2002 to July 2004, 252 consecutive patients, with a clinical or instrumental suspicion of biliary disease were submitted to magnetic resonance to investigate the biliary tract. The definitive diagnosis of disease was obtained by surgery and/or endoscopic retrtograde cholangiopancreatography (ERCP) in patients with clinical or diagnostic evidence of disease and by means of follow-up in the remaining cases. MRCP, combined with T2-weighted FSE sequence on the axial plane yielded positive findings in 191/252 patients (75.79%); in 75/191 (39.26%) either ERCP was indispensable (n = 33) or surgery proved necessary (n = 42). MRCP and surgical sample findings proved discordant in 3/42 cases operated on (7.14%); MRCP and ERCP yielded discordant findings in 11/33 cases (33.33%) submitted to ERCP. With the exception of the limitations associated with the difficulty in obtaining dynamic information relating to functional diseases of Oddi's sphincter, for which, moreover, a progressive tecnological updating is underway, MRCP is the diagnostic reference procedure in biliopancreatic disease, reserving a therapeutic role for ERCP.