David Frame

Spontaneous Apoptosis of Endometrial Tissue is Impaired in Women with Endometriosis

OBJECTIVE To evaluate spontaneous apoptosis in single-cell suspensions of eutopic and ectopic endometrium from women with endometriosis and in eutopic endometrium from fertile controls without endometriosis. DESIGN Paired specimens of eutopic and ectopic endometrial tissue from patients with endometriosis and eutopic endometrium from controls were assessed for spontaneous apoptosis. SETTING Institute for the Study and Treatment of Endometriosis and university-based research laboratories. PATIENT(S) Fertile controls (n = 10) and women with untreated endometriosis (n = 16). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Spontaneous apoptosis assessed with an ELISA-based cell death detection kit. RESULT(S) Spontaneous apoptosis (monitored by absorbance) of eutopic endometrium from patients with endometriosis and fertile controls was 0.63 +/- 0.1 and 1.43 +/- 0.11, respectively. Among patients with endometriosis, spontaneous apoptosis of ectopic endometrium was 0.26 +/- 0.06. Decreased apoptosis of ectopic versus eutopic endometrium was observed independent of cycle phase. CONCLUSION(S) The susceptibility of endometrial tissue to spontaneous apoptosis is significantly lower in women with endometriosis than in fertile controls. We suggest that decreased susceptibility of endometrial tissue to apoptosis contributes to the etiology or pathogenesis of endometriosis.

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant

In recipients of hematopoietic stem cell transplants (HSCTs), BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC). In our institution, HSCT recipients with BKV-associated HC are treated with 1 mg/kg of cidofovir weekly. We identified HSCT recipients with BKV-associated HC, treated with weekly cidofovir. Microbiological response was defined as at least a one log reduction in urinary BKV viral load; clinical response was defined as improvement in symptoms and stability or reduction in the grade of cystitis. Nineteen allogeneic HSCT patients received a mean of 4.5 weekly doses of cidofovir. HC occurred at a mean of 68.7 days after transplant. A clinical response was detected in 16/19 (84%) patients, and 9/19 (47%) had a measurable microbiological response (8/10 nonresponders had a BKV viral load above the upper limit of the assay before treatment). Fourteen out of nineteen (74%) patients had no significant increase in serum creatinine. Five patients with renal dysfunction resolved after completion of the therapy and removal of other nephrotoxic agents. We conclude that weekly low-dose cidofovir appears to be a safe treatment option for BKV-associated HC. Although the efficacy of low-dose cidofovir is not proven, a prospective trial is warranted.

Clofarabine and busulfan conditioning facilitates engraftment and provides significant antitumor activity in nonremission hematologic malignancies

Patients with hematologic malignancies not in remission before allogeneic hematopoietic stem cell transplantation (HSCT) have a poor prognosis. To improve the antitumor activity of conditioning, we combined clofarabine with myeloablative doses of busulfan in a phase 1/2 study in nonremission hematologic malignancies. Forty-six patients were enrolled, including 31 patients with nonremission acute myelogenous leukemia (AML). Patients had a median age of 53 years, with a median comorbidity index of 3. Donors were unrelated, HLA mismatched, or both in 59% of patients. Common grade III to IV nonhematologic toxicities included transient transaminitis (50%), mucositis (24%), hand-foot syndrome (13%), transient hypoxia (13%), nausea/vomiting (9%), and diarrhea (9%). All patients engrafted. Complete remission was achieved in 80% of all patients by day +30 and in 100% of AML patients without prior hematopoietic stem cell transplantation. Two-year nonrelapse mortality for all patients was 31%, and overall survival was 28%. In AML, the overall survival was 48% at 1 year and 35% at 2 years. These data suggest that clofarabine combined with myeloablative doses of busulfan is well tolerated, secures engraftment, and possesses significant antitumor activity, particularly in nonremission AML. This study is registered at www.ClinicalTrials.gov under identifier NCT00556452.

Intravesicular instillation of E-aminocaproic acid for patients with adenovirus-induced hemorrhagic cystitis.

Hemorrhagic cystitis (HC) is a known complication of allogenic BMT. We report a case of a 28-year-old female with CML in chronic phase, which was treated with a matched unrelated donor (MUD) transplant, complicated by hemorrhagic cystitis on day +42 after the transplant. Adenovirus was isolated from the urine and she was treated with ribavirin, 1 g twice a day for 8 days. We report the use of Amicar (E-aminocaproic acid), 2.5 g solution as bladder instillation to treat the intractable hematuria.

Systemic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with severe graft-versus-host disease of the gastrointestinal tract

Abstract : Oral vancomycin is often considered the drug of choice for severe Clostridium difficile‐associated disease due to both its efficacy and pharmacokinetics. The potential for absorption is not well described in patients with impaired gastrointestinal (GI) mucosa. We describe a case of significant and potentially toxic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with grade IV graft‐versus‐host disease (GVHD) of the GI tract. In patients with GI GVHD clinicians need to be aware of the potential for oral absorption and, in select cases, monitoring of levels may be appropriate.

Risk factors for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients

Recurrent Clostridium difficile infection (CDI) represents a significant burden on the healthcare system and is associated with poor outcomes in hematopoietic stem cell transplant (HSCT) patients. Data are limited evaluating recurrence rates and risk factors for recurrence in HSCT patients.

Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes

Obesity is an important public health problem that may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic hematopoietic SCTs between 2004 and 2012. Pretransplant body mass index (BMI) was classified as underweight, normal weight, overweight or obese using the WHO classification or age-adjusted BMI percentiles for children. The study population was predominantly Caucasian, and the median age was 51 years (5 months–73 years). The cumulative 3-year incidence of nonrelapse mortality (NRM) in underweight, normal weight, overweight and obese patients was 20%, 19%, 20% and 33%, respectively. Major causes of NRM were acute and chronic GVHD. The corresponding incidence of relapse was 30%, 41%, 37% and 30%, respectively. Three-year OS was 59%, 48%, 47% and 43%, respectively. Multivariate analysis showed that obesity was associated with higher NRM (hazard ratio (HR) 1.43, P=0.04) and lower relapse (HR 0.65, P=0.002). Pretransplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese compared with normal weight patients (P=0.04 and P=0.05, respectively). The increase in NRM observed in obese patients was partially offset by a lower incidence of relapse with no difference in OS.

Treatment of Dyslipidemia in Allogeneic Hematopoietic Stem Cell Transplant Patients

As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, becomes a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. Also, increasing evidence shows that several anti-hyperlipidemia medications, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in particular, may have a role in modulating graft-versus-host disease (GVHD). However, factors such as drug-drug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid-lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published American College of Cardiology/American Heart Association guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agents potential role in modulating GVHD.

Central Nervous System Complications of Hematopoietic Stem Cell Transplant.

Hematopoietic stem cell transplantation (SCT) is now commonly used to treat several hematologic and nonhematologic diseases. Central nervous system (CNS) complications post-transplantation occur commonly in the first year and result in increased mortality from infectious, toxic, metabolic, or vascular causes. Infections secondary to aspergillus, toxoplasma and viruses cause many of the complications. Drug-related toxicities arising from conditioning regimens and graft-versus-host disease prophylaxis, as well as intraparenchymal hemorrhage, are not uncommon and can result in increased morbidity. Secondary CNS cancers have a higher incidence 5 or more years after allogeneic SCT.

Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure

To the Editor, Deficiency of adenosine deaminase 2 (DADA2) was initially described simultaneously in 2014 by two groups [1, 2]. Enzymatic deficiency occurs via autosomal recessive inheritance of CECR1 gene mutations. Early descriptions of the disorder highlighted early-onset stroke, vasculitis presenting as polyarteritis nodosa, livedo reticularis, recurrent fevers, and hypogammaglobulinemia as the predominant clinical manifestations observed in patients [1–5]. The discovery of additional patients with DADA2 has revealed a highly variable clinical presentation with many features responsive to therapy with anti-tumor necrosis factor agents [2, 6–11]. Although not described in the initial cohorts of patients, hematological manifestations now appear to be a significant clinical component of deficiency of adenosine deaminase 2 [6–9, 12]. The pathogenesis underlying the hematologic dysfunction seen in patients has yet to be elucidated, although persistently elevated levels of tumor necrosis factor (TNF)-alpha have been described to be damaging to hematopoiesis within the bone marrow [13, 14]. Here, we describe a case of two adult brothers with DADA2 presenting with cytopenias and bone marrow hypocellularity. We particularly detail the clinical course of one brother with initial partial response to equine anti-thymocyte globulin and cyclosporine with recurrence of cytopenias following withdrawal of immunosuppression. Retreatment was initiated with anti-tumor necrosis factor alpha therapy resulting in clinical symptom improvement and normalization of blood counts. Patient 1 presented at 47 years of age with leukopenia following evaluation for recurrent upper respiratory and allergy symptoms. Complete blood count (CBC) at that time was notable for white blood cell (WBC) count 2.3 K/μL (35% neutrophils, 11% bands, 28% lymphocytes, 25% monocytes, and 1% basophils), hemoglobin 14.3 g/dL, MCV 90.7 fL, and platelets 153,000 K/μL. The patient’s past medical history was notable for Bmyositis^ as a child and right lower extremity cellulitis with associated sepsis as an adult. Family history was significant for a brother with neutropenia. Physical exam was unremarkable other than diffusely dry and vasculitic-appearing darkened skin on his bilateral lower extremities (Fig. 1a). Within 3 years, he progressed to pancytopenia with hemoglobin falling to 6 g/dL requiring frequent red blood cell transfusions and platelet and absolute neutrophil counts ultimately reaching nadirs of 49,000 and 620/uL, respectively. Initial bone marrow biopsy was hypocellular (range 0–15%) with a patchy distribution of hematopoietic precursors, mild reticulin fibrosis, and an increased proportion of CD3-positive T cells distributed interstitially. Flow cytometric immunophenotyping of the bone marrow disclosed no lymphoid antigen aberrancies and no increase in blasts. Cytogenetic analysis of the bone marrow yielded a normal male karyotype (46, XY). Testing for paroxysmal nocturnal hemoglobinuria was negative. Repeat bone marrow examination performed 6 months later, prior to * Thomas F. Michniacki tmich@med.umich.edu