Hazzaa Alzahrani

Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party

Rabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age- and disease severity-matched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P = .009). Transplant-free survival was 52% for rATG and 76% for hATG (P = .002). On multivariate analysis, rATG (hazard ratio = 3.9, P = .003) and age more than 37 years (hazard ratio = 4.7, P = .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848.

Ocular Findings after Allogeneic Hematopoietic Stem Cell Transplantation

OBJECTIVE To study the incidence, causes, and outcome of major ocular complications in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). DESIGN Retrospective, noncomparative, observational clinical study. PARTICIPANTS The study included a total of 620 patients who underwent allogeneic HSCT in the period from 1997 to 2007 at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. INTERVENTION Allogeneic HSCT. MAIN OUTCOME MEASURES Patients with ocular complications were referred to the ophthalmology division for complete ophthalmologic examination, including visual acuity, tonometry, Schirmer test, biomicroscopy, and dilated ophthalmoscopy. Laboratory investigations were performed whenever indicated. The incidence and causes of major ocular complications after allogeneic HSCT were determined. Visual acuity at 1 year after allogeneic HSCT was recorded. RESULTS Major ocular complications occurred in 80 (13%) of 620 patients who underwent allogeneic HSCT. There were 36 male patients (45%) and 44 female patients (55%) with a mean age of 29 years and an age range of 9 to 65 years. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate in 69 patients, and cyclosporine, methotrexate and corticosteroids, or mycophenolate mofetil in 11 patients. The most frequently encountered ocular complications were chronic GVHD, dry eye syndrome without GVHD, corneal ulcers, cataract, glaucoma, cytomegalovirus retinitis, fungal endophthalmitis, and acquisition of allergic conjunctivitis from atopic donors. There was no correlation between the pattern of ocular complications and the transplanted stem cell source. Best-corrected visual acuity (BCVA) at 1 year after transplantation was less than 20/200 in 13 patients (16%), less than 20/50 in 17 patients (21%), and better than 20/50 in 50 patients (63%). CONCLUSIONS Ocular complications are common in patients undergoing allogeneic HSCT. Early recognition and prompt treatment are important. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Standard treatment of acquired SAA in adult patients 18-40 years old with an HLA-identical sibling donor.

Matched related donor allo-SCT is the treatment of choice for patients with severe aplastic anemia (SAA) younger than 40 years of age. The standard conditioning regimen for such patients is cyclophosphamide with antithymocyte globulin. Unmanipulated BM is the best stem cell source for aplastic anemia patients going for SCT. Post-transplant GVHD prophylaxis with cyclosporine should be continued for 1 year. Early graft failure is rare but potentially life-threatening complication of SCT that can be managed with salvage SCT using more intense conditioning regimen.

Fludarabine-Based Conditioning Chemotherapy for Allogeneic Hematopoietic Stem Cell Transplantation in Acquired Severe Aplastic Anemia

Thirty-eight patients who met the diagnostic criteria for severe aplastic anemia underwent allogeneic hematopoietic stem cell transplantation (HSCT). The median patient age was 20 years (range, 14-36 years). Twenty-four patients were treatment-naïve, 11 had failed one or more previous courses of immunosuppressive therapy, and 3 had failed a previous HSCT. The conditioning regimen included fludarabine 30 mg/m(2)/day for 3 days (days -9, -8, and -7) and cyclophosphamide 50 mg/kg/day for 4 days (days -5, -4, -3, and -2). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short-course methotrexate. All patients underwent transplantation with unmanipulated bone marrow as the stem cell source. The median total nucleated cell (TNC) dose was 2.43 × 10(8)/kg (range, 0.60-6.7 × 10(8)/ kg). The conditioning regimen was well tolerated, with minimal treatment-related mortality. Engraftment was observed in all patients after transplantation; the median time to engraftment of neutrophils and platelets was 18 and 23 days, respectively. Twenty-five of the 27 patients with available chimeric studies at day 180 maintained donor chimerism. Acute GVHD grade ≥II was diagnosed in 4 patients (11%). Extensive chronic GVHD was observed in 8 patients (25%) who survived beyond day +100, at a median observation time of 43 months. Graft rejection with relapse of aplais was observed in one patient. The overall survival (OS) for the whole group was 79%. A trend toward improved OS was observed in the treatment-naïve patients (83% vs 71%), but this was statistically insignificant (P = .384). The fludarabine-based conditioning regimen used in this study with relatively young cohort of patients was well tolerated, with a low rate of rejection and treatment outcomes comparable to those seen in other, more intense and potentially more toxic conditioning regimens. Our results await validation in a larger study, optimally in a randomized controlled manner.

Evaluation of the usefulness of a D dimer test in combination with clinical pretest probability score in the prediction and exclusion of Venous Thromboembolism by medical residents

IntroductionVenous thromboembolism (VTE) requires urgent diagnosis and treatment to avoid related complications. Clinical presentations of VTE are nonspecific and require definitive confirmation by imaging techniques. A clinical pretest probability (PTP) score system helps predict VTE and reduces the need for costly imaging studies. d-dimer (DD) assay has been used to screen patients for VTE and has shown to be specific for VTE. The combined use of PTP and DD assay may improve exclusion of VTE and safely avoid imaging studies.Materials and methodsWe prospectively used the Wells PTP score and a DD test to evaluate 230 consecutive patients who presented with VTE symptoms. The receiver operating characteristic curve was used to identify a new DD cutoff value, which was applied to VTE diagnosis and compared with the upper limit of locally established reference range for prediction of thrombosis alone and in combination with the clinical PTP score.ResultsWe evaluated 118 patients with VTE symptoms fulfilling the inclusion criteria, 64 (54.2%) with clinically suspected deep vein thrombosis (DVT) and 54 (45.8%) with symptoms of pulmonary embolism (PE). The PTP was low in 28 (43.8%) and moderate/high in 36 (56.25%) of the suspected DVT patients, and low in 29 (53.7%) and moderate/high in 25 (46.3%) of the suspected PE patients. Eighteen cases were confirmed by imaging studies: 9 DVT and 9 PE. The agreement between confirmed cases and PTP was significant with PE but not DVT. The negative predictive value for both DVT and PE with current DD cutoff value of <250 μg/L DDU was 100%, whereas with the calculated cutoff the NPV was 88%.ConclusionsWe confirm that PTP score is valuable tool for medical residents to improve the detection accuracy of VTE, especially for PE. The DD cutoff value of 250 μg/L FEU is ideal for excluding most cases of low PTP; however, the calculated cutoff was less specific for the exclusion of VTE.

Mitochondrial Neurogastrointestinal Encephalomyopathy Treated with Stem Cell Transplantation: A Case Report and Review of Literature.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder. The mutation in the ECGF1 gene causes severe deficiency of thymidine phosphorylase (TP), which in turn increases thymidine and deoxyuridine in the blood, serum, and tissue. The toxic levels of these products cause malfunction of the mitochondrial respiratory chain and mitochondrial DNA. Commonly, patients become symptomatic between 15 and 20 years of age (range 5 months to 35 years). The most commonly affected systems are gastrointestinal, followed by ocular, and nervous system. The disease is often fatal; high mortality rate is reported between 20 and 40 years of age. Treatment modalities that can increase thymidine phosphorylase activity and decrease thymidine and deoxy-uridine have shown symptomatic improvements in patients with MNGIE. Platelet transfusion, hemodialysis, peritoneal dialysis or allogeneic hematopoietic stem cell transplantation (HSCT) have been tried. The survival and long-term benefits of these measures are still not clear. Engrafted patients after stem cell transplantation have showed improvements in serum thymidine and deoxyuridine. We are reporting a case of MNGIE from Saudi Arabia, who underwent allogeneic hematopoietic stem cell transplantation. No MNGIE case has been previously reported from Saudi Arabia or the Gulf Arab countries. From the available literature, so far only 11 patients with MNGIE have undergone stem cell transplantation.

Hematidrosis: A Fascinating Phenomenon—Case Study and Overview of the Literature

As previously explored in this journal, the investigation of bleeding symptoms involves a systematic investigative approach that includes investigation of patient and family history, physical examination, and laboratory testing.1 Although this is also true of an investigation into pediatric bleeding, there are special considerations required, including the reduced period of capture for personal history, and fewer hemostatic challenges.2 Sometimes, such investigations prove fruitless and do not uncover a true bleeding diathesis. Hematidrosis is one such example. Hematidrosis is a fascinating disorder characterized by blood oozing from the intact skin and mucous membranes in the absence of a bleeding problem. It frequently affects young girls (i.e., typically between 9 and 13 years) under stressful situations, and probably suffering from an underlying anxiety disorder. These patients usually undergo a thorough and expensive hematology evaluation aimed to identify a possible underlying bleeding disorder, but which fails to provide the answer. Here, we report a case of a 9-year-old girl exposed to bullying at school, which leads to recurrent bleeding episodes. The young patient had no prior medical or psychological illness and presented to our clinic following a 5-month history of recurrent spontaneous blood loss from skin, scalp, ear, mouth, and eyes (►Fig. 1). Her parents claimed that the episodes happen twice weekly on average, mostly in the evening, and with no clear precipitating factors. Each episode lasted for 1 or 2 minutes and was usually self-limited. Family history was negative for any bleeding disorders. She was evaluated by her family physician and a local hematologist, and aworkup for commonbleeding disorderswas unrevealing (►Table 1). The patient also underwent upper gastrointestinal endoscopy because some of these episodeswere accompanied by bleeding from her mouth. The endoscopy and biopsy were consistent with celiac disease, which was later confirmed by serological testing. Nevertheless, no clinical signs of celiac disease could be recorded. Upon her evaluation in our clinic, her vital signs and growth chart were within normal limits, and physical examination was unrevealing; specifically, there were no signs of self or secondary-inflicted injuries (scars, fresh cuts, scratches, or wounds). On further questioning, the parents reported that these episodes did not occur on holidays and usually happened on the days she attended school. The patient admitted that she always felt intimidated and emotionally abused by her school colleagues. A sampling of the fluid discharge confirmed the presence of red andwhite blood cells along with epithelial cells. Hematohidrosis or hematidrosis is a rare and largely mysterious phenomenon, with only a few case reports having been published.3–14 Reported patients are usually young girls,3,5 and present with blood oozing from intact skin or mucous membranes in the setting of stress and anxiety.11 The episodes last for few minutes,3 and resolve almost spontaneously.5 Theworkup for bleeding disorders is usually normal, and the examination of the bloody fluid demonstrates the presence of blood elements. It is important to carefully examine the skin to rule out self-inflicted or secondary injuries (e.g., potentially pointing to Munchausen’s syndrome or Munchausen’s by proxy) and to also differentiate this entity from chromhidrosis (color pigment in sweat), vasculitis, scurvy, or other connective tissue disorders (where vascular fragility can lead to easy bleeding). Some of the reported cases underwent biopsy of the oozing areas with active bleeding and did not show any histopathological findings.4,5 Although the frightening presentation of hematidrosis leads to immediate medical evaluation in most of the cases, the diagnosis is often delayed because the condition is a rare and frequently overlooked phenomenon. Frequently, patients will have extensive evaluations including hematology consultation before reaching a correct diagnosis. The etiology remainsmostly unknown. Stress-induced vasoconstriction (through adrenergic stimulation) in the small blood vessels around the sweat glands and eventually leading to vascular rupture and blood extravasationwith the sweat is the proposed cause.10,11 The fact that most cases

The Saudi Clinical Practice Guideline for the treatment of venous thromboembolism: Outpatient versus inpatient management

Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is commonly encountered in daily clinical practice. After diagnosis, its management frequently carries significant challenges to the clinical practitioner. Treatment of VTE with the inappropriate modality and/or in the inappropriate setting may lead to serious complications and have life-threatening consequences. As a result of an initiative of the Ministry of Health of the Kingdom of Saudi Arabia, an expert panel led by the Saudi Association for Venous Thrombo-Embolism (a subsidiary of the Saudi Thoracic Society) and the Saudi Scientific Hematology Society with the methodological support of the McMaster University Guideline working group, this clinical practice guideline was produced to assist health care providers in VTE management. Two questions were identified and were related to the inpatient versus outpatient treatment of acute DVT, and the early versus standard discharge from hospital for patients with acute PE. The corresponding recommendations were made following the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

Plasma cell leukemia: Clinicopathologic, immunophenotypic and cytogenetic characteristics of 4 cases

Plasma cell leukemia (PCL) is a rare hematologic malignancy with very poor outcome. It is defined by the presence of >2 × 10(9)/L plasma cells or >20% plasmacytosis of the differential white cell count in the peripheral blood. Primary PCL is first diagnosed in the leukemic phase, while secondary PCL corresponds to the leukemic transformation of a previously diagnosed multiple myeloma (MM). The incidence of PCL ranges between 2-4% of patients with MM and 0.9% of patients with acute leukemia. In this case series, we describe the clinicopathologic, immunophenotypic, and cytogenetic findings of four patients diagnosed with PCL within a ten-year period (2002-2012) at King Faisal Specialist Hospital and Research Centre (General Organization), Riyadh, Saudi Arabia.

Prophylaxis and treatment of venous thromboembolism in patients with cancer: the Saudi clinical practice guideline.

BACKGROUND AND OBJECTIVES Venous thromboembolism (VTE) is commonly encountered in the daily clinical practice. Cancer is an important VTE risk factor. Proper thromboprophylaxis is key to prevent VTE in patients with cancer, and proper treatment is essential to reduce VTE complications and adverse events associated with the therapy. DESIGN AND SETTINGS As a result of an initiative of the Ministry of Health of Saudi Arabia, an expert panel led by the Saudi Association for Venous Thrombo-Embolism (a subsidiary of the Saudi Thoracic Society) and the Saudi Scientific Hematology Society with the methodological support of the McMaster University working group produced this clinical practice guideline to assist health care providers in evidence-based clinical decision-making for VTE prophylaxis and treatment in patients with cancer. METHODS Six questions related to thromboprophylaxis and antithrombotic therapy were identified and the corresponding recommendations were made following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. RESULTS Question 1 Should heparin versus no heparin be used in outpatients with cancer who have no other therapeutic or prophylactic indication for anticoagulation? Recommendation For outpatients with cancer, the Saudi Expert Panel suggests against routine thromboprophylaxis with heparin (weak recommendation; moderate quality evidence). Question 2 Should oral anticoagulation versus no oral anticoagulation be used in outpatients with cancer who have no other therapeutic or prophylactic indication for anticoagulation? Recommendation For outpatients with cancer, the Saudi Expert Panel recommends against thromboprophylaxis with oral anticoagulation (strong recommendation; moderate quality evidence). Question 3 Should parenteral anticoagulation versus no anticoagulation be used in patients with cancer and central venous catheters? Recommendation For outpatients with cancer and central venous catheters, the Saudi Expert Panel suggests thromboprophylaxis with parenteral anticoagulation (weak recommendation; moderate quality evidence). Question 4 Should oral anticoagulation versus no anticoagulation be used in patients with cancer and central venous catheters? Recommendation For outpatients with cancer and central venous catheters, the Saudi Expert Panel suggests against thromboprophylaxis with oral anticoagulation (weak recommendation; low quality evidence). Question 5 Should low-molecular-weight heparin versus unfractionated heparin be used in patients with cancer being initiated on treatment for venous thromboembolism? Recommendation In patients with cancer being initiated on treatment for venous thromboembolism, the Saudi Expert Panel suggests low-molecular-weight heparin over intravenous unfractionated heparin (weak; very low quality evidence). Question 6 Should heparin versus oral anticoagulation be used in patients with cancer requiring long-term treatment of VTE? Recommendation In patients with metastatic cancer requiring long-term treatment of VTE, the Saudi Expert Panel recommends low-molecular-weight heparin (LMWH) over vitamin K antagonists (VKAs) (strong recommendation; moderate quality evidence). In patients with non-metastatic cancer requiring long-term treatment of venous thromboembolism, the Saudi Expert Panel suggests LMWH over VKA (weak recommendation; moderate quality evidence).