MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

Thymus: the next (re)generation.

As the primary site of T-cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way toward the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the preclinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.

Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation: Time To T Up the Thymus.

The success of allogeneic hematopoietic stem cell transplantation, a key treatment for many disorders, is intertwined with T cell immune reconstitution. The thymus plays a key role post allogeneic hematopoietic stem cell transplantation in the generation of a broad but self-tolerant T cell repertoire, but it is exquisitely sensitive to a range of insults during the transplant period, including conditioning regimens, corticosteroids, infections, and graft-versus-host disease. Although endogenous thymic repair is possible it is often suboptimal, and there is a need to develop exogenous strategies to help regenerate the thymus. Therapies currently in clinical trials in the transplant setting include keratinocyte growth factor, cytokines (IL-7 and IL-22), and hormonal modulation including sex steroid inhibition and growth hormone administration. Such regenerative strategies may ultimately enable the thymus to play as prominent a role after transplant as it once did in early childhood, allowing a more complete restoration of the T cell compartment.

Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762.

The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation.

Role and regulation of CD1d in normal and pathological B cells.

CD1d is a nonpolymorphic, MHC class I-like molecule that presents phospholipid and glycosphingolipid Ags to a subset of CD1d-restricted T cells called invariant NKT (iNKT) cells. This CD1d-iNKT cell axis regulates nearly all aspects of both the innate and adaptive immune responses. Expression of CD1d on B cells is suggestive of the ability of these cells to present Ag to, and form cognate interactions with, iNKT cells. In this article, we summarize key evidence regarding the role and regulation of CD1d in normal B cells and in humoral immunity. We then extend the discussion to B cell disorders, with emphasis on autoimmune disease, viral infection, and neoplastic transformation of B lineage cells, in which CD1d expression can be altered as a mechanism of immune evasion and can have both diagnostic and prognostic importance. Finally, we highlight current and future therapeutic strategies that aim to target the CD1d-iNKT cell axis in B cells.

Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation.

Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade II-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4(-) iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade II-IV aGVHD in patients receiving CD4(-) iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4(-) iNKT-cell dose was associated with a relative risk of grade II-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4(-) iNKT cells effectively suppressed T-cell proliferation and IFN-γ secretion in a contact-dependent manner. In conclusion, higher doses of CD4(-) iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD.

Diffuse large B cell lymphoma complicating total knee arthroplasty: case report and literature review of the association of diffuse large B cell lymphoma with joint replacement.

Primary lymphoma of bone is extremely rare. There are increasing reports of lymphoma arising in bone adjacent to metallic prostheses. Herein, we describe the case of a 76-year-old man who developed diffuse large B cell lymphoma in the tibia 3 years after total knee arthroplasty for osteoarthritis. A review of the literature has identified 11 other cases of lymphoma arising in the context of orthopaedic metallic implants. To our knowledge this is the first reported case of a primary lymphoma arising in bone adjacent to a knee prosthesis. Possible pathogenetic mechanisms may include chronic antigenic stimulation of lymphocytes, proliferation of EBV-infected B lymphocytes, and direct mutagenic effects of metallic ions. Further research is required to investigate this intriguing link between metallic orthopaedic prostheses and localized lymphoma.

Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis.

A 20 year old woman, admitted with acute pancreatitis, subsequently developed microangiopathic haemolytic anaemia, thrombocytopenia and mild neurological compromise. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and she was treated with plasma exchange leading to complete resolution of this condition. TTP is a rare multisystem disorder which may be life threatening if not treated promptly. The increasing recognition of acute pancreatitis as a potential aetiological factor offers new insights into the pathogenesis, diagnosis and treatment of TTP.

Disease risk and GVHD biomarkers can stratify patients for risk of relapse and nonrelapse mortality post hematopoietic cell transplant.

The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-versus-host disease (GVHD) leads to prolonged intensive immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and nonrelapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. In this study we tested whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM. The multicenter study population (n = 1604) was divided into two cohorts: historical (2006-2015, n = 702) and current (2015-2017, n = 902) with similar NRM, relapse, and survival. On day 28 post-HCT, patients who had not developed GVHD (75% of the population) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16 and 9%); this difference was even more pronounced in patients with a high disease risk index (relapse 33%, NRM 9%). Such patients are good candidates to test relapse prevention strategies that might enhance GVL.

Hydroxycarbamide associated platelet count oscillations in a patient with polycythaemia vera. A case report and review of the literature.

We describe an unusual case of oscillating platelet counts in a patient with polycythaemia vera. Following commencement of cytoreductive hydroxycarbamide therapy, episodes of thrombocytopenia were followed regularly by thrombocytosis. Platelet counts fluctuated periodically between approximately 200 and 800 x 109/l, with a 28 day cycle duration. Frequent adjustment of the hydroxycarbamide dose was not successful in preventing the oscillations in platelet count. In contrast, maintenance of a constant dose led to a gradual damping of the cycles and thus termination of the large oscillations. The case further implicates hydroxycarbamide as a potential cause of cyclic variations in platelet counts, and demonstrates that cessation of this drug is not always necessary in order to treat this phenomenon.

GVHD: biology matters.

Acute graft-versus-host disease (GVHD) targets the crypts in the gastrointestinal (GI) tract that are responsible for the self-renewal of the intestinal mucosa. Recent advances in the identification and culture of intestinal stem cells have improved our understanding of the interactions between the microbiome and the immune system (both innate and adaptive) that are key to the pathophysiology of GVHD. The identification of serum biomarkers that best predict long-term GVHD outcomes derive from the GI tract and have focused attention on cellular elements that act as shields against GVHD as well as its targets. These biomarkers have illuminated new mechanisms of crypt biology and provided insights that should prove useful both in the design of clinical trials and as guides to GVHD prevention and treatment.

GVHD: biology matters.

Acute graft-versus-host disease (GVHD) targets the crypts in the gastrointestinal (GI) tract that are responsible for the self-renewal of the intestinal mucosa. Recent advances in the identification and culture of intestinal stem cells have improved our understanding of the interactions between the microbiome and the immune system (both innate and adaptive) that are key to the pathophysiology of GVHD. The identification of serum biomarkers that best predict long-term GVHD outcomes derive from the GI tract and have focused attention on cellular elements that act as shields against GVHD as well as its targets. These biomarkers have illuminated new mechanisms of crypt biology and provided insights that should prove useful both in the design of clinical trials and as guides to GVHD prevention and treatment.

Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting.

Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.

Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease.

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3α (REG3α) is a biomarker specific for GI GVHD. REG3α serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3γ (the mouse homolog of human REG3α), and the absence of REG3γ in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3γ production and prevented apoptosis of both intestinal stem cells (ISCs) and Paneth cells, but this protection was completely abrogated in Reg3g-/- mice. In vitro, addition of REG3α reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3α/γ to promote crypt regeneration may offer a novel, nonimmunosuppressive approach for GVHD and perhaps for other diseases involving the ISC niche, such as inflammatory bowel disease.

Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition.

Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein, we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumors that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition.

Intracranial hypotension caused by dural-pleural fistula.

This report describes a rare complication in a woman who underwent thoracic spinal surgery. One month postoperatively, her rehabilitation was interrupted by the development of a severe headache, nausea, vomiting, and a right-side occulomotor nerve palsy. Imaging of her brain revealed changes typical of intracranial hypotension, and subsequent imaging of the spine revealed a cerebrospinal fluid (CSF) leak at the site of surgery. The CSF was seen to track into the right pleural space via a dural-pleural fistula. Surgical repair of the fistula led to a definitive resolution in symptoms, thus highlighting the importance of early recognition of this highly unusual complication.

Outcome of patients with pulmonary embolism admitted to the intensive care unit.

BACKGROUND: Pulmonary embolism (PE) is an important cause of in-hospital mortality. Many patients are admitted to the intensive care unit (ICU) either due to hemodynamic instability or severe hypoxemia. Few reports have addressed the outcome of patients with PE; however, none were from ICUs in the Middle East. OBJECTIVES: To describe the demographics, clinical presentation, risk factors and outcome of patients with PE admitted to the medical ICU and to identify possible factors associated with poor prognosis. MATERIALS AND METHODS: Data were collected retrospectively by reviewing the records of patients admitted to the medical ICU with primary diagnosis of PE between January 2001 and June 2007. Demographic, clinical, radiological and therapeutic data were collected on admission to ICU. RESULTS: Fifty-six patients (43% females) with PE were admitted to the ICU during the study period. Their mean age was 40.6 ± 10.6 years. Seven patients (12.5%) had massive PE with hemodynamic instability and 15 (26.8%) had submassive PE. The remaining patients were admitted due to severe hypoxemia. Recent surgery followed by obesity were the most common risk factors (55.4 and 28.6%, respectively). Four patients with massive PE received thrombolysis because the remaining three had absolute contraindications. Fatal gastrointestinal bleeding occurred in one patient post thrombolysis. Additionally, two patients with massive PE and five with submassive PE died within 72 h of admission to the ICU, resulting in an overall mortality rate of 14%. Nonsurvivors were older and had a higher prevalence of immobility and cerebrovascular diseases compared with survivors. CONCLUSIONS: The mortality rate of patients with PE admitted to the ICU in our center was comparable to other published studies. Older age, immobility as well as coexistent cerebrovascular diseases were associated with a worse outcome.