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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.