Modulation of cancer-specific immune responses by amino acid degrading enzymes.

To evade immune destruction, tumours exploit a wide range of immune escape mechanisms, including the induction of an immunosuppressive tumour microenvironment. This is mediated, in part, by amino acid-degrading enzymes indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, arginase 1 and arginase 2, which have emerged as key players in the regulation of tumour-induced immune tolerance. Here we describe how the expression of tryptophan- and arginine-degrading enzymes by tumour and tumour-infiltrating cells can hamper cancer-specific immune responses, and discuss how this knowledge is being exploited to develop new strategies for cancer immunotherapy

Modulation of cancer-specific immune responses by amino acid degrading enzymes.

To evade immune destruction, tumours exploit a wide range of immune escape mechanisms, including the induction of an immunosuppressive tumour microenvironment. This is mediated, in part, by amino acid-degrading enzymes indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, arginase 1 and arginase 2, which have emerged as key players in the regulation of tumour-induced immune tolerance. Here we describe how the expression of tryptophan- and arginine-degrading enzymes by tumour and tumour-infiltrating cells can hamper cancer-specific immune responses, and discuss how this knowledge is being exploited to develop new strategies for cancer immunotherapy

Comparison of a therapeutic‐only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders

Background Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. Objectives To determine whether a therapeutic‐only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. Search Methods We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. Selection criteria We included RCTs, non‐RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders. We excluded uncontrolled studies, cross‐sectional studies, and case‐control studies. We excluded cluster‐RCTs, non‐randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long‐term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. Data collection and analysis We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. Main results We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three‐year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single‐centre, single‐blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes. We identified no completed non-RCTs or CBAs. We identified no ongoing RCTs, non-RCTs, or CBAs. Authors’ conclusions We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.</p

Alternative agents versus prophylactic platelet transfusion for preventing bleeding in patients with thrombocytopenia due to chronic bone marrow failure: a network meta-analysis and systematic review

To compare the relative efficacy of different treatments for thrombocytopenia (artificial platelet substitutes, platelet-poor plasma, fibrinogen, rFVIIa, rFXIII, thrombopoietin mimetics, antifibrinolytic drugs or platelet transfusions) in patients with chronic bone marrow failure and to derive a hierarchy of potential alternate treatments to platelet transfusions

Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review (Russian translation of Cochrane plain language summary)

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Desborough MJR, Hadjinicolaou AV, Chaimani A, Trivella M, Vyas P, Doree C, Hopewell S, Stanworth SJ, Estcourt LJ. Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD012055. DOI: 10.1002/14651858.CD012055.pub

Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review

BACKGROUND: People with thrombocytopenia due to bone marrow failure are vulnerable to bleeding. Platelet transfusions have limited efficacy in this setting and alternative agents that could replace, or reduce platelet transfusion, and are effective at reducing bleeding are needed. OBJECTIVES: To compare the relative efficacy of different interventions for patients with thrombocytopenia due to chronic bone marrow failure and to derive a hierarchy of potential alternative treatments to platelet transfusions. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (the Cochrane Library 2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 27 April 2016. SELECTION CRITERIA: We included randomised controlled trials in people with thrombocytopenia due to chronic bone marrow failure who were allocated to either an alternative to platelet transfusion (artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII (rFVIIa), desmopressin (DDAVP), recombinant factor XIII (rFXIII), recombinant interleukin (rIL)6 or rIL11, or thrombopoietin (TPO) mimetics) or a comparator (placebo, standard of care or platelet transfusion). We excluded people undergoing intensive chemotherapy or stem cell transfusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data and assessed trial quality. We estimated summary risk ratios (RR) for dichotomous outcomes. We planned to use summary mean differences (MD) for continuous outcomes. All summary measures are presented with 95% confidence intervals (CI).We could not perform a network meta-analysis because the included studies had important differences in the baseline severity of disease for the participants and in the number of participants undergoing chemotherapy. This raised important concerns about the plausibility of the transitivity assumption in the final dataset and we could not evaluate transitivity statistically because of the small number of trials per comparison. Therefore, we could only perform direct pairwise meta-analyses of included interventions.We employed a random-effects model for all analyses. We assessed statistical heterogeneity using the I(2) statistic and its 95% CI. The risk of bias of each study included was assessed using the Cochrane 'Risk of bias' tool. The quality of the evidence was assessed using GRADE methods. MAIN RESULTS: We identified seven completed trials (472 participants), and four ongoing trials (recruiting 837 participants) which are due to be completed by December 2020. Of the seven completed trials, five trials (456 participants) compared a TPO mimetic versus placebo (four romiplostim trials, and one eltrombopag trial), one trial (eight participants) compared DDAVP with placebo and one trial (eight participants) compared tranexamic acid with placebo. In the DDAVP trial, the only outcome reported was the bleeding time. In the tranexamic acid trial there were methodological flaws and bleeding definitions were subject to significant bias. Consequently, these trials could not be incorporated into the quantitative synthesis. No randomised trial of artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII, rIL6 or rIL11 was identified.We assessed all five trials of TPO mimetics included in this review to be at high risk of bias because the trials were funded by the manufacturers of the TPO mimetics and the authors had financial stakes in the sponsoring companies.The GRADE quality of the evidence was very low to moderate across the different outcomes.There was insufficient evidence to detect a difference in the number of participants with at least one bleeding episode between TPO mimetics and placebo (RR 0.86, 95% CI 0.56 to 1.31, four trials, 206 participants, low-quality evidence).There was insufficient evidence to detect a difference in the risk of a life-threatening bleed between those treated with a TPO mimetic and placebo (RR 0.31, 95% CI 0.04 to 2.26, one trial, 39 participants, low-quality evidence).There was insufficient evidence to detect a difference in the risk of all-cause mortality between those treated with a TPO mimetic and placebo (RR 0.74, 95%CI 0.52 to 1.05, five trials, 456 participants, very low-quality evidence).There was a significant reduction in the number of participants receiving any platelet transfusion between those treated with TPO mimetics and placebo (RR 0.76, 95% CI 0.61 to 0.95, four trials, 206 participants, moderate-quality evidence).There was no evidence for a difference in the incidence of transfusion reactions between those treated with TPO mimetics and placebo (pOR 0.06, 95% CI 0.00 to 3.44, one trial, 98 participants, very low-quality evidence).There was no evidence for a difference in thromboembolic events between TPO mimetics and placebo (RR 1.41, 95%CI 0.39 to 5.01, five trials, 456 participants, very-low quality evidence).There was no evidence for a difference in drug reactions between TPO mimetics and placebo (RR 1.12, 95% CI 0.83 to 1.51, five trials, 455 participants, low-quality evidence).No trial reported the number of days of bleeding per participant, platelet transfusion episodes, mean red cell transfusions per participant, red cell transfusion episodes, transfusion-transmitted infections, formation of antiplatelet antibodies or platelet refractoriness.In order to demonstrate a reduction in bleeding events from 26 in 100 to 16 in 100 participants, a study would need to recruit 514 participants (80% power, 5% significance). AUTHORS' CONCLUSIONS: There is insufficient evidence at present for thrombopoietin (TPO) mimetics for the prevention of bleeding for people with thrombocytopenia due to chronic bone marrow failure. There is no randomised controlled trial evidence for artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII or rIL6 or rIL11, antifibrinolytics or DDAVP in this setting

Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review (Russian translation of Cochrane plain language summary)

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Desborough MJR, Hadjinicolaou AV, Chaimani A, Trivella M, Vyas P, Doree C, Hopewell S, Stanworth SJ, Estcourt LJ. Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD012055. DOI: 10.1002/14651858.CD012055.pub

Progressive dyspnoea following the treatment of <it>Mycobacterium abscessus</it> infection in an individual with relapsing granulamatosis with polyangitis (Wegener’s), complicated by hearing loss requiring cochlear implantation

<p>Abstract</p> <p>Backgound</p> <p>Granulomatosis with polyangitis (Wegener’s) is a vasculitic disease predominantly affecting the lungs, skin, kidneys, ears, nose and throat. <it>Mycobacterium abscessus</it> is an uncommon rapidly growing mycobacterium causing sporadic lung disease. This is the first report of both GPA and <it>Mycobacterium abscessus</it> pulmonary disease reported in literature.</p> <p>Case Presentation</p> <p>We present a case report of a 33 year old Caucasian man with relapsing disease complicated by pulmonary infection with <it>Mycobacterium abscessus</it>. He subsequently required bilateral cochlear implantation for progressive sensori-neural hearing loss. His <it>M. abscessus</it> was treated successfully with a prolonged course of antimicrobial therapy. His Granulomatosis with polyangitis (Wegener’s) relapsed towards the end of antimicrobial therapy and required treatment. Shortly after completing his antimicrobial therapy and relapse, he developed progressive dyspnea due to pulmonary fibrosis.</p> <p>Conclusion</p> <p>The potential causes of his progressive dyspnoea are discussed including the potential role of his underlying disease and treatment.</p