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Background Varicella zoster virus central nervous system infections can present as aseptic meningitis, encephalitis, myelitis, and vasculopathy. Diagnosis is based on identification of varicella zoster virus deoxyribonucleic acid (DNA) in the cerebrospinal fluid by polymerase chain reaction. Therapy for these infections is acyclovir or valacyclovir. However, acyclovir can have neurotoxic effects that can mimic the presentation of varicella zoster virus central nervous system disease. We present a rare presentation of a patient who had acyclovir-induced neurotoxicity who also had a false-positive cerebrospinal fluid varicella zoster virus polymerase chain reaction result, creating a management dilemma. We review the clinical characteristics of acyclovir-induced neurotoxicity. In addition, we present the diagnostic characteristics of the cerebrospinal fluid viral polymerase chain reaction and alternative methods to diagnose central nervous system varicella zoster virus disease. Case presentation A 68-year-old Hispanic man with end-stage renal disease was diagnosed with cutaneous zoster at an outside facility and was started on acyclovir 4 days prior to admission. His family noted worsening confusion, agitation, speech difficulty, and hallucinations, leading them to bring him to the emergency department. His cerebrospinal fluid varicella zoster virus polymerase chain reaction result was positive, indicating the presence of varicella zoster virus deoxyribonucleic acid in the cerebrospinal fluid; however, he did not have cerebrospinal fluid pleocytosis typical of varicella zoster virus meningoencephalitis. Pharmacy records from the outside hospital revealed supratherapeutic acyclovir dosing. This led to a diagnostic dilemma over whether this patient had varicella zoster virus encephalitis or acyclovir-induced neurotoxicity. Acyclovir was discontinued, and the patient underwent two sessions of hemodialysis to remove acyclovir, which led to a full neurologic recovery. Conclusions Varicella zoster virus encephalitis and acyclovir-induced neurotoxicity can have similar presentations. Varicella zoster virus deoxyribonucleic acid can be present in the cerebrospinal fluid during active cutaneous zoster in the absence of central nervous system disease. If concern for central nervous system varicella zoster virus disease remains high, additional testing with cerebrospinal fluid serology can be performed. Compared with central nervous system varicella zoster virus disease, acyclovir-induced neurotoxicity has a more predictable clinical resolution once drug therapy is discontinued or the patient undergoes hemodialysis, which can aid in making the diagnosis. Clinicians should be aware of this rare and dangerous complication of acyclovir. In addition, clinicians should have an understanding of the diagnostic limitations of cerebrospinal fluid viral polymerase chain reaction and have alternative approaches available to diagnose central nervous system varicella zoster virus disease when it is suspected.

BACKGROUND: Hospitalized patients are frequently treated with opioids for pain control, and receipt of opioids at hospital discharge may increase the risk of future chronic opioid use. OBJECTIVE: To compare inpatient analgesic prescribing patterns and patients' perception of pain control in the United States and non-US hospitals. DESIGN: Cross-sectional observational study. SETTING: Four hospitals in the US and seven in seven other countries. PARTICIPANTS: Medical inpatients reporting pain. MEASUREMENTS: Opioid analgesics dispensed during the first 24-36 hours of hospitalization and at discharge; assessments and beliefs about pain. RESULTS: We acquired completed surveys for 981 patients, 503 of 719 patients in the US and 478 of 590 patients in other countries. After adjusting for confounding factors, we found that more US patients were given opioids during their hospitalization compared with patients in other countries, regardless of whether they did or did not report taking opioids prior to admission (92% vs 70% and 71% vs 41%, respectively; P

A 22-year-old woman was admitted to the medicine service with generalised abdominal pain and nausea. Medical history included a recent motor vehicle accident resulting in multiple orthopaedic injuries and development of a chronic pain syndrome. The patient denied other pertinent medical, social or family history. Medications included escitalopram, cyclobenzaprine, and oxycodone 10 mg every 6 hours as needed for pain. The patient’s initial vitals were temperature 37.3°C, heart rate 81 beats/min, respiratory rate 16 breaths/min, and blood pressure 89/59 mm Hg. Pertinent physical exam included diffuse tenderness to palpation of the abdomen without peritoneal signs and no skin hyperpigmentation. Laboratory evaluation revealed a normal complete blood count, basic metabolic panel, liver function, urinalysis, and lipase. A CT scan of the abdomen and pelvis showed …

Outcomes for patients with high-risk neuroblastoma (HR-NBL) are significantly improved with the addition of immunotherapy (dinutuximab + cytokines) following autologous hematopoietic stem cell transplantation (auto-HSCT). We hypothesized that the immune system is not fully reconstituted at the initiation of immunotherapy. To test this hypothesis, we evaluated hematologic and immune subsets in 34 patients with HR-NBL before and after auto-HSCT. We found that absolute T, B, and NK cell counts at the time of immunotherapy were below normal in 80% of patients. Patients with residual disease at the time of transplantation had significantly lower absolute lymphocyte counts (ALC; P = .008), lower CD16+ cell counts (P = .009), and an abnormal ratio of cytokine-releasing to cytotoxic NK cells at the time of dinutuximab treatment. In addition, the preparative regimen used for auto-HSCT predicted immune recovery. Finally, higher total white blood cell count (P = .013) and ALC (P = .013) at 3 months after completion of therapy were measured in patients who remained in remission compared with those who relapsed. Our results indicate that most patients with HR-NBL do not have full immune reconstitution at the time of dinutuximab treatment after auto-HSCT, and that immune recovery may correlate with disease-related outcomes in patients with high-risk disease.

Patient: Female, 72-year-old Final Diagnosis: Cefepime-induced neurotoxicity Symptoms: Aphasia Medication:— Clinical Procedure: — Specialty: General and Internal Medicine Objective: Unusual or unexpected effect of treatment Background: Cefepime-induced neurotoxicity has been described in intensive care units (ICUs) and neuro ICU settings, occurring in patients started on ce fepime for management of severe infections and sepsis. Most cases occur within 1 to 10 days after starting the drug. We publish a case that occurred on the general medical ward of a patient who had been on cefepime therapy for 4 weeks prior to admission. The aim of this study was to improve the knowledge of this serious condition to general internists as our patient was being managed on the general medical ward. Case Report: A 72-year-old female on prolonged intravenous antibiotics for sacral and pelvic osteomyelitis presented with acute encephalopathy and aphasia in the setting of an acute kidney injury. Due to the acute focal neurologic deficit, she was initially admitted as a stroke alert. After a negative magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG) was pursued and showed nonconvulsive status epilepticus (NCSE). NCSE was likely a result of cefepime therapy in the setting of an acute kidney injury. Conclusions: Cefepime-induced neurotoxicity should be suspected in any patient on cefepime therapy who develops acute changes in mental status, myoclonus, or evidence of seizures. Risk factors for the disease include older age, renal dysfunction, critical illness, and inappropriate dosing based upon renal function. A high index of suspicion is required and delays in diagnosis are common as there are frequently multiple possible causes for altered mental status in systemically ill patients requiring treatment with broad-spectrum antibiotics.

Background Second allogeneic hematopoietic stem cell transplant (HCT) remains as an option for disease relapse after initial HCT. Methods We analyzed retrospectively the outcomes of 65 consecutive patients who underwent a second HCT for disease relapse at the University of Chicago. Univariate and multivariate analysis were conducted, and a scoring system was generated to select the patients who would benefit second HCT. Results All except four patients received T cell depleted (TCD) first HCT. The majority of patients had AML (n = 47) and high risk MDS (n = 5). The median age at second HCT was 45 years (11–73). 13 patients (20%) achieved CR before second HCT. 98% (n = 64) and 72% (n = 47) patients achieved neutrophil and platelet engraftment at a median interval of 10 and 18 days, respectively, following the second HCT. With a median follow up of 23 (5.5–140) months for survivors after second HCT, the estimated 2 years PFS was 17.5% and the 2 years OS was 22.6%. The day 100 cumulative incidence of non-relapse mortality rate was 23.6%, and the cumulative incidence of aGVHD and cGVHD were 16.9% and 7.7% respectively at 1 year after second HCT. In univariate analysis, patients with remission duration after first HCT of > 12 months and those in CR before second HCT had significantly better PFS and OS. A scoring system using disease status before second HCT (CR = 0 vs. non-CR = 1), and remission duration after first HCT ( 12 months = 0) was generated as an approach to classify patients into different risk categories in the purpose to provide guidance to the transplant physician to inform the outcomes to potential patients undergoing 2nd HCT. A score of 12 months after first HCT with acceptable rates of GVHD and donor engraftment.

Background Acute Chest Syndrome (ACS) is one of the leading causes of death among children with Sickle Cell Disease (SCD). Disruption of microvascular integrity is critical to the pathophysiology of ACS, but the factors governing its phenotypic variability are incompletely understood. Because circulating exosomes have been implicated in vascular dysfunction in various diseases, we hypothesized that exosomes induce endothelial dysfunction in patients who experience ACS. Procedure Cross-sectional cohort study including 33 outpatients with SCD (without new health-related complaints or recent transfusions) and a cohort of control patients. Exosomes were isolated from platelet-free plasma. Results ImageStream showed that exosome counts were greatly increased in patients with SCD compared with controls, but there were few differences in the concentrations of exosomes between patients who had experienced ACS (ACS(+)) and those who had not (ACS(−)). Exosomes were added to human microvascular endothelial cells, and the exosomal effects on monolayer integrity was determined using Electric Cell-substrate Impedance Sensing (ECIS). Exosomes from SCD patients without ACS differed minimally from control patients; however, exosomes from ACS(+) decreased endothelial cell resistance compared to ACS(−), (Relative resistance: ACS(+): 0.981 ± 0.055 vs ACS(−): 1.124 ± 0.042; P = 0.006). Treatment of endothelial cultures with exosomes from ACS(−) patients increased endothelial Nitric Oxide Synthase (eNOS) mRNA expression, while ACS(+)-derived exosomes were not able to increase eNOS expression above that of controls. Conclusions These findings demonstrate that patients with SCD have circulating exosomes that produce differential effects that may contribute to the pathophysiology of ACS and may serve as risk-related biomarkers.

Traditionally, new scientific advances have been applied quickly to the leukemias based on the ease with which relatively pure samples of malignant cells can be obtained. Currently, our arsenal of approaches used to characterize an individual's acute myeloid leukemia (AML) combines hematopathologic evaluation, flow cytometry, cytogenetic analysis, and molecular studies focused on a few key genes. The advent of high-throughput methods capable of full-genome evaluation presents new options for a revolutionary change in the way we diagnose, characterize, and treat AML. Next-generation DNA sequencing techniques allow full sequencing of a cancer genome or transcriptome, with the hope that this will be affordable for routine clinical care within the decade. Microarray-based testing will define gene and miRNA expression, DNA methylation patterns, chromosomal imbalances, and predisposition to disease and chemosensitivity. The vision for the future entails an integrated and automated approach to these analyses, bringing the possibility of formulating an individualized treatment plan within days of a patient's initial presentation. With these expectations comes the hope that such an approach will lead to decreased toxicities and prolonged survival for patients.

The unique historical aspects of Pelger and Huet's discovery of the Pelger-Huet cell highlight the diagnostic challenge that this morphologic finding presents to the physician. Making the diagnosis of the benign autosomal dominant anomaly is complicated by the morphologically similar pseudo-Pelger-Huet cell, which can signify underlying myeloid dsyplasia. This article relates the history of the Pelger-Huet anomaly as well as describes the clinical significance and diagnostic workup for the finding of a Pelger-Huet cell on peripheral smear. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc.

Background Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) carry a poor prognosis. We analyzed the results of allogeneic HSCT in 38 children to determine which factors, if any, affected outcome. Procedure The effects of demographic, donor, and disease-related factors were analyzed to determine their effects on overall and disease-free survival (OS, DFS), relapse, and non-relapse mortality (NRM). Results OS and DFS for t-AML and t-MDS were similar. Three-year OS and EFS were the same (15.4 ± 5.8%) and the 3-year NRM was 59.6 ± 8.4%. The 1-year cumulative risk of grade III–IV acute graft-versus-host disease (GVHD) and relapse were 23.7 ± 7.0% and 18.7 ± 6.5%, respectively. The percentage of pre-transplant bone marrow (BM) blasts was positively associated with relapse (P = 0.05), while the percentage of BM blasts at diagnosis of therapy-related disease tended to associate with NRM (P = 0.07). Alternative donor and matched sibling donor grafts had similar outcomes. NRM was higher among patients who did not develop acute GVHD as compared to those with grade 1–2 acute GVHD (69.2 ± 14.2% vs. ± 12.7%, respectively), while NRM was 100% in patients with grade III–IV acute GVHD (P = 0.007). Conclusions The percentage of BM blasts is associated with relapse in these disorders. High rates of NRM negatively impact the outcome of allogeneic HSCT for children with t-AML and t-MDS. Future studies should focus on reducing NRM. © 2005 Wiley-Liss, Inc.

Hemolytic uremic syndrome (HUS) is an uncommon but potentially life-threatening complication of hematopoietic stem cell transplantation. We retrospectively studied the medical records of 293 children who underwent allogeneic bone marrow transplantation at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of and to identify risk factors for transplant-associated HUS. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation for patients with hematologic malignancies (n = 244); patients with nonmalignant diseases (n = 49) received disease-specific regimens. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. HUS developed in 28 (9.6%) patients at a median of 171 days after transplantation. We identified older donor age (P = .029), use of antithymocyte globulin in the conditioning regimen (P = .008), and recipient CMV seronegativity (P = .011) as being associated with an increased risk of HUS. With a multiple regression analysis, the use of antithymocyte globulin (β = .86; P = .04) and recipient cytomegalovirus seronegativity (β = .93; P = .035) remained significant risk factors for the development of HUS.

Transplanted patients experience rapid loss of bone, high fracture rates, and increases in morbidity and mortality as a consequence of a posttransplant scenario that is highly deleterious to the skeleton. Immune suppressive drugs, especially glucocorticoids, are toxic to bone, often acting on a background of preexisting osteodystrophy resulting from long-standing renal, hepatic, cardiac, or pulmonary disease. Cyclosporin and tacrolimus lead to a severe osteopenic state in rats, but the skeletal toxicity of the calcineurin inhibitors in the clinical environment is less clear. Nor is it clear whether cyclosporin and tacrolimus differ in their skeletal actions. Mycophenolate mofetil and sirolimus do not appear to have important skeletal toxicity. Preventative strategies include minimizing glucocorticoid exposure and implementing therapies to counter the increase in bone resorption and decrease in bone formation that follows transplantation. Antiresorptive agents, especially bisphosphonates, appear capable of retarding or halting the early bone loss and possibly reduce fracture rates also. Vitamin D and calcium are ineffective, but calcitriol has utility in some reports. Bone anabolic agents, such as synthetic parathyroid hormone and growth hormone, have potential, but data are lacking.

Summary: Encephalopathy is a poorly characterized complication of hematopoietic stem cell transplantation (HSCT). No comprehensive report of encephalopathy exists for children, and the literature contains only a few for adults. We analyzed a large cohort of 405 pediatric patients who underwent allogeneic HSCT during a 10-year period and identified 26 patients (6.4%) who experienced encephalopathy. Identifiable causes of encephalopathy included infection (n=5), single or multiorgan failure (n=4), medication-related complications (n=3), nonconvulsive seizures (n=4), acute disseminated encephalomyelitis (n=2), thrombotic thrombocytopenic purpura (n=2), and stroke (n=1). We were unable to identify the etiology of encephalopathy in five (19%) patients. The prognosis for pediatric patients with encephalopathy was poor: only four (15%) experienced complete neurologic recovery, and 10 (38%) patients experienced partial recovery with residual neurologic deficits. Nine (35%) patients with complete or partial recovery survive long term. A total of 17 patients died; one died of progressive encephalopathy, and 16 died of either relapse of primary disease or toxicity. MRI, CSF analysis including molecular testing for infectious pathogens, and brain biopsy were helpful in obtaining a diagnosis in most of our patients. However, a standardized approach to accurate and timely diagnosis and treatment is needed to improve outcome in these patients.

Peritransplant toxicity and a delay in effective immune reconstitution have limited the utility of alternate donor transplantation for children with refractory severe aplastic anemia. We have assessed the effectiveness of infusing large numbers of highly purified haploidentical CD34+ cells after immunoablative conditioning in three patients who had failed intensive immunosuppression, lacked unrelated donors, and had active or recent serious infections. One patient rejected the first infusion, but engrafted after a second infusion from the same donor. This patient died 4 months after hematopoietic stem cell transplantation with no evidence of lymphoid reconstitution. Two patients experienced mixed chimerism requiring treatment with antibodies and/or donor lymphocyte infusion. Both currently survive more than 1 year after transplantation with normal blood counts, 100% donor engraftment, effective lymphoid reconstitution, and no chronic graft-versus-host disease. We observed functional thymopoiesis as measured by lymphocyte immunophenotyping, T cell receptor excision circles and T cell receptor Vbeta spectratyping complexity analysis. Further study is required to validate the initial promise of these preliminary observations.

We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor > or =1.5 cm2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34+ cells (> or =8 x 10(6)/kg) were obtained with only one apheresis procedure for each of the 11 patients treated with topotecan-filgrastim, but with a mean of 2.3 apheresis procedures for only six (46%) of the 13 patients treated with filgrastim alone (P = 0.0059). The median peak and median total yield of CD34+ cells were six-fold higher for the topotecan-filgrastim group (328/microl and 21.5 x 10(6)/kg, respectively) than for the filgrastim group (54/microl and 3.7 x 10(6)/kg, respectively). Mean times to neutrophil and platelet engraftment were similar. Myelosuppression was the only grade 4 toxicity associated with topotecan-filgrastim mobilization and lasted a median of 5 days. Compared with filgrastim mobilization, topotecan-filgrastim mobilization resulted in a mean cost saving of $3966 per patient. Topotecan-filgrastim is an efficacious, minimally toxic, and cost-saving combination for PBSC mobilization.

The objective of this study is to investigate the outcome of children 24 months of age or younger (infants) at the time of allogeneic bone marrow transplantation (BMT) for acute leukemia or myelodysplasia. We analyzed the survival rate, prognostic factors, incidences of late sequelae, and immune reconstitution in 22 infants who underwent allogeneic BMT. The 5-year event-free survival estimate was 45.5% (95% confidence interval (CI), 24.4% to 63.3%). Six patients died of transplant-related complications and six died of disease relapse. Remission status at the time of BMT was the most important prognostic factor (P = 0.005): no patient who received a transplant while their disease was not in remission survived, whereas the 5-year survival estimate for infants who underwent BMT during remission was 56% (95% CI, 31% to 75%). Long-term outcomes in the 10 infant survivors were compared with those of 10 older controls matched for diagnosis, disease status at the time of BMT, calendar year at the time of BMT, and source of stem cells. Immune function 1 year after transplantation and the incidences and spectra of late sequelae were similar for both groups during a median of 3.5 years (range, 1.5 to 7.2 years) of follow-up.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoiesis due to a mutation in the PIG-A gene. Affected patients may demonstrate hemolysis or venous thrombosis, and may develop MDS or aplastic anemia. Successful results may be obtained after conditioning and transplantation from syngeneic or genotypically matched sibling donors. Experience with transplantation from matched unrelated donors (MUD) is limited to eight patients, with only one survivor. We report three patients who underwent successful MUD BMT for PNH. All three patients had severe aplastic anemia (SAA) and PNH at the time of BMT. Unrelated donors were six-antigen HLA-matched (n = 2) or HLA-A mismatched (n = 1). Conditioning consisted of cytarabine, cyclophosphamide, TBI, and ATG. Grafts were T cell-depleted by anti-CD6/CD8 antibodies + complement. Further GVHD prophylaxis consisted of cyclosporine. Patients received 0.7-1.1 x 10(8) nucleated cells/kg and 1.1-2.1 x 10(6) CD34(+) cells/kg. Neutrophil engraftment occurred at 16-21 days. One patient developed grade 1 acute GVHD. Although all three patients experienced significant transplant-related complications, they ultimately resolved and all patients are alive and well 30-62 months after BMT. T cell-depleted MUD BMT is an effective treatment option for PNH-related MDS and SAA.

Twenty-three children with de novo acute myelogenous leukemia (AML) (n= 20), secondary AML (n = 1), or non-Hodgkin's lymphoma (NHL) (n = 2) underwent allogeneic bone marrow transplantation (alloBMT) for graft failure (n = 1) or recurrent malignancy (n = 22) between February 1992 and August 1999 following autologous BMT (ABMT). Induction chemotherapy was given to 14 patients and nine patients went directly to alloBMT. Five received marrow from matched siblings, 14 from matched unrelated donors and four from mismatched family members. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Nine patients are alive disease-free between 627 and 2433 days (1.7–6.7 years) post BMT resulting in a 4-year DFS of 39%. Eight patients relapsed at a median of 206 days (range, 35–669 days) post alloBMT and all eventually died. Eight patients (two of whom also relapsed) died of RRT. Although RRT and relapse remain significant problems, a significant percentage of pediatric patients failing ABMT may be cured with alloBMT. Bone Marrow Transplantation (2001) 27, 155–162.

To test whether magnetic resonance angiography can document the evolution of vasculopathy in patients with sickle cell disease, we reviewed records to identify all patients who underwent magnetic resonance angiography from 1993 to 1999. Of 512 angiographies performed, 105 were of sickle cell disease patients, and 24 sickle cell disease patients 7 years of age or older underwent baseline and follow-up examinations. Films were paired by patient, blinded as to examination date and treatment, and quantitatively compared. Four patients who received allogeneic bone marrow transplantation were compared to 7 patients who received other therapy and to 13 untreated patients. Quantitative analysis revealed a 10% increase in the measured diameter of 64 vessels (p = 0.001) following any treatment. Patients who had undergone allogeneic bone marrow transplantation exhibited a 12% increase in the lumen of 22 vessels (p = 0.041), whereas patients treated with chronic transfusion or hydroxyurea exhibited an 8% increase in 42 vessels (p = 0.016). In 2 patients with severe stenosis, the artery normalized after transplantation, and the blood flow rate was reduced in all patients who underwent transplantation. In untreated patients, there was a trend for the size of the arterial lumen to decrease, which is consistent with disease progression. Results suggest that treatment can reverse progression of vasculopathy. Bone marrow transplantation may enable stenoses to heal and can substantially reduce cranial blood velocity, suggesting that allogeneic bone marrow transplantation may prevent infarction or brain damage.

Summary Background For most conditions amenable to bone-marrow transplantation, grafts from HLA-matched but unrelated donors have yielded poorer results than those obtained from matched-sibling donors. We assessed this pattern in the light of improvements in donor selection and posttransplant supportive care. Methods We reviewed transplant outcome in 103 consecutive patients with childhood leukaemia who underwent allogeneic bone-marrow transplantation with HLA-matched sibling marrow (n=52) or matched unrelated donor marrow (n=51) between May, 1990, and March, 1996, at St Jude Children's Research Hospital. Findings Analysis of engraftment, frequency of procedurerelated complications, and disease-free survival revealed no advantage from use of matched-sibling marrow. The 2-year disease-free survival estimate for standard-risk recipients of matched-sibling marrow was 81 [8·1]% compared with 73 [12·1]% in the unrelated donor marrow group (p=0·77). In the high-risk category, patients with a matched-sibling donor had a 2-year disease-free survival of 31 [11·6]%, compared with 32 [15·1]% among recipients of matched unrelated donor marrow (p=0·87). Interpretation We believe this improved result with unrelated donor marrow is a consequence of recent innovations in histocompatibility matching, prevention of graft-versus-host disease (GvHD), and antiviral prophylaxis. We suggest that such grafts can now be used in patients at both standard and high risk without compromising treatment outcome.

Prospective magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), neuropsychological testing and neurological examinations were performed to determine the long-term effect of successful haematopoietic stem cell transplantation on the neurological status of nine children with sickle cell disease. A scoring system for severity of brain parenchymal and vascular lesions was developed and applied. Neurological examinations and neuropsychometric tests were stable, but MRI and MRA studies were not. Transient changes occurred early in two patients. Persistent changes occurred in five. Parenchymal lesions occurred in zero of two patients without prior lacunae or infarcts and in all seven with prior lacunae or infarcts (P = 0.0278).

Introduction: The Dependent Coverage Provision (DCP) of the 2010 Affordable Care Act aims to improve (1) access to medical care among individuals aged 18-25 nationwide and (2) the efficiency of care by increasing appropriate outpatient care and reducing avoidable inpatient care. Individuals became eligible for coverage under their parents' private insurance in late September 2010. Previous studies have demonstrated improvement in access to care among those eligible for DCP, but no studies have examined the experience of young adults with serious disease requiring chronic medical care such as sickle cell disease (SCD). We hypothesized SCD patients aged 18-25 had increased access to commercial insurance, higher use of outpatient and lower use of inpatient care in the years following DCP implementation compared to patients ineligible for DCP. Methods: This national analysis of patients aged 0-30 with qualifying SCD claims was performed using the Truven Health Analytics MarketScan Commercial Claims and Encounters dataset 2003-2013. The dataset contains commercial insurance claims of employees and dependants representing more than 50 million lives annually. We included patients with a continuous 12 month enrollment, and >1 inpatient or outpatient SCD claim in a given year. SCD claims included those with ICD-9 codes for homozygous SCD (HgbSS), sickle cell thalassemias (HgbSC, HgbSbo, HgbSb+) with and without crises, or splenic sequestration and/or acute chest syndrome. We defined 2003-2010 as pre-DCP and 2011-2013 as post-DCP. Inflation adjusted annual average per person spending, defined as reimbursements paid to providers, of SCD related inpatient and outpatient care was calculated. Descriptive statistics of number and share of patients by year and age cohort were calculated. Descriptive statistics of number of outpatient and inpatient claims by year and age cohort were calculated. A segmented regression analysis was performed to test for changes in trend of patient share by age cohort after the DCP. Access is defined as share of individuals having any claim type during the year. A difference-in-differences analysis was performed to study changes in medical care use and spending among individuals aged 18-25 pre and post-DCP, compared to those 26-30 and 12-17. Results: ACCESS: The absolute number of individuals increased in each age cohort during the study years. There was a significant increase in the share of 18-25 aged SCD patients compared to other SCD cohorts after DCP implementation (p = 0.03, Figure 1). USE: SCD patients aged 18-25 experienced a statistically significant increased likelihood of having an outpatient claim after the DCP compared to those 26-30 (p SPENDING: Average per person outpatient spending pre and post DCP were: 18-25 year cohort $132 to $108; 12-17 year cohort $131 to $127; and 26-30 year cohort $134 to $100. Average per person inpatient spending pre- and post-DCP were: 18-25 years- $12064 to $16343; 12-17 years- $12700 to $17017; and 26-30 years- $10967 to $17852. Conclusion: Our analysis is the first to demonstrate early success of the DCP among a young adult population suffering from serious disease requiring chronic medical care. We find 18-25 year old SCD patients accessed private insurance at a greater rate and increased their use of less costly outpatient care after the DCP. Inpatient use did not change significantly among this cohort after DCP implementation. We observe inpatient costs to increase among each age cohort, including those 18-25, after the DCP. This result cannot be attributed to technologic change - no new invasive treatments or procedures have been introduced during the study period. Additional work is needed to better understand this result, including an analysis of frequency and length of stay. Limitations include underestimating the number of SCD patients due to missed ICD9 codes and the lack of clinical correlates within the data. Future analysis should replicate this analysis with other chronic conditions as well as measures of quality of care such as patient reported outcomes. Figure 1 Figure 1. Disclosures Henderson: Seattle Genetics: Research Funding.

Objective: Neuroblastoma (NB) is the most common extra cranial solid tumor in childhood. It accounts for approximately 7% of pediatric cancer diagnoses each year in the United States yet is responsible for 15% of pediatric cancer deaths annually. Occurring overwhelmingly in patients with high-risk (HR) disease. Measurable immune surveillance correlates with improved overall disease-free survival in patients with a myriad of cancer subtypes, including NB. Current therapeutic strategies in HR-NB incorporate manipulation of the host immune response, including autologous stem cell transplantation (autoSCT), cis-retinoic acid, and chimeric antibody targeting the tumor-associated antigen disialoganglioside (GD2). Understanding how such therapies affect the immune system and its relation to clinical response is of critical importance. We speculate that patients with higher proportions of regulatory T cells (Tregs) and slower recovery of other lymphocyte subsets will have higher rates of progressive disease and/or relapse. Methods: We reviewed the records of all University of Chicago patients between 2009 and 2015 who received autoSCT as part of upfront therapy for HR neuroblastoma. Data included complete blood count and peripheral blood lymphocyte flow cytometric (FACS) subset monitoring. Our analysis aimed to determine the association between lymphocyte subset kinetics following autoSCT with pre-transplant treatment, transplant conditioning, and disease-free/overall survival. Patients who had a follow-up of greater than one-year post-transplantation were included in the analysis. Results: Thirty-four patients (59% male, median age 5.6 years) received autoSCT between 2009 and 2015 for HR neuroblastoma. Seventy-six percent (n = 26) received either carboplatin, etoposide, melphalan (CEM) or busulfan/melphalan (BuMel) for conditioning. Among those patients, twenty-seven percent received MIBG prior to their autoSCT. The other patients received BSO/melphalan or tandem transplantations. Sixty-eight percent of these patients went on to receive chimeric antibody after their autoSCT irrespective of their conditioning regimen. Antibody therapy with IL-2 or GM-CSF was initiated at a median of 101 days (mean 98.9) post-autoSCT. All patients had normal neutrophil counts at 100 days post transplant, while the total absolute lymphocyte count (ALC), CD8+ T cells, NK cells and CD19+ B cells, were below normal levels in the majority of patients, (100%, 89%, 79% and 94% of patients respectively). Patients who received MIBG prior to autoSCT had a higher proportion of CD3+CD4+CD25+ T cells, the subset containing Tregs, among their total CD3+ population at 100 days post-transplant, (79.8% versus 32.8% p-value = 0.02). Following single autoSCT, patients with higher ALC and CD4+ cells had increased disease free survival in evaluations after six months post transplant. (Figure 1) CD8+ cells, NK cells and CD19+ cell counts were not significant in this analysis. Conclusions: Patients with HR NB have differential immune cell recovery following autoSCT that is dependent on the type of therapy received prior to autoSCT. Specifically, patients who received MIBG had markedly higher proportion of CD3+CD4+CD25+ T cell recovery compared to patients not receiving pre-autoSCT MIBG. This is the subset containing Tregs, which may indicate suppression of an anti-NB immune response long-term. Immune reconstitution is globally poor in all patients at the time of chimeric antibody immunotherapy that is initiated around day 100-post autoSCT. There are features of immune reconstitution that appear to correlate with improved outcomes, including elevated ALC, CD8+ and CD4+ cell counts when evaluated at least six months post transplantation. Additional characterization of T cell subsets is currently being performed to quantify the number of Treg cells in the CD3+CD4+CD25+ T cell subset population. Prospective evaluation of both immune cell recovery and functional evaluation of cells is required to confirm these findings, which may have a profound impact on how immune modulatory therapy is scheduled for those patients with high-risk neuroblastoma. Figure 1 (Panel A) Patients with higher ALC (panel A) and CD4+ cells (panel B) checked at least 6 months after stem cell transplantation had increased disease-free survival (DFS) compared to those patients with diminished ALC and CD4+ cells recovery. Figure 1. (Panel A) Patients with higher ALC (panel A) and CD4+ cells (panel B) checked at least 6 months after stem cell transplantation had increased disease-free survival (DFS) compared to those patients with diminished ALC and CD4+ cells recovery. Disclosures No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation (HSCT) corrects the Wiskott-Aldrich syndrome (WAS) phenotype. However, the toxicity and mortality frequently associated with this approach warrant the exploration of new therapeutic strategies. Transplantation studies of a murine model of WAS deficiency have been limited by the occurrence of a radiation-induced fatal exacerbation of a pre-existing colitis in the peritransplantation period. Here we demonstrate that when crossed to a C57/B6 background, WAS-deficient males show little if any colitis and reliably survive HSCT. We show that HSCT corrects the hematologic and functional deficiencies of WAS knockout mice. These results strengthen the analogy between murine and human WAS and provide a basis for the use of WAS-deficient mice to explore novel approaches for correction of the disease phenotype.

Background Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. Methods We infused a single dose of a serotype-8–pseudotyped, self-complementary adeno virus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity

We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34+ stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800.

Dispersants have been a controversial oil spill response technique since their introduction during the Torrey Canyon oil spill off the coast of the United Kingdom in 1967. Despite reductions in the toxicity of dispersants and improvements in their application since then, dispersants have not been used extensively in the United States because of logistical difficulties, unfavorable weather conditions, and a lack of demonstrated effectiveness during actual spill conditions. In addition, there is a widely held perception in the United States that dispersant use has been limited by complex authorization procedures. This paper reviews the dispersant policies of several European nations and Canada and compares them with those of the United States. Recent developments in U. S. dispersant policy are outlined, particularly those designed to expedite decision making. The paper concludes by examining some recent U. S. oil spills in which dispersant use was considered.

We present a unique case of Budd-Chiari syndrome caused by Gaucher's disease. The diagnosis was based on Doppler sonography, magnetic resonance imaging, contrast-enhanced three-dimensional magnetic resonance angiography, standard venography, and venous pressure measurements and was confirmed histologically.

Francis James Zacharias (“Jim”) served with the Royal Air Force in the Gold Coast and RAF Halton during the later stages of the second world …

Purpose To determine the incidence, etiology and outcome of graft failure in pediatric allogeneic bone marrow transplant (BMT) recipients. Patients and methods Patients with primary or secondary graft failure were identified by database review. A retrospective chart review was performed. Etiologic factors were identified and assessed for statistical significance. Results 309 children underwent allogeneic BMT during the time interval studied. Four cases of primary graft failure and 7 cases of secondary graft failure occurred. Nonmalignant diagnosis, lower total nucleated cell (TNC) dose, and conditioning without total body irradiation were associated with a higher incidence of graft failure. Donor source, donor/recipient CMV status, CD34+ cell dose, and alloimmunization were not associated with graft failure. Conclusions Graft failure is a relatively uncommon occurrence in pediatric patients. Autologous reinfusion may allow time to prepare the patient for a second transplant and decrease complications associated with aplasia. More immunosuppressive conditioning regimens may decrease the incidence of graft failure, particularly in patients with non-malignant diseases or those with lower stem cell doses. More frequent monitoring of chimerism by VNTR analysis may detect late graft failure earlier and allow for more rapid intervention.

Hemorrhagic cystitis (HC) is a well-documented adverse event experienced by patients undergoing hematopoietic stem cell transplantation. When severe, HC causes significant morbidity, leads to renal complications, prolongs hospitalization, increases health-care costs, and occasionally contributes to death. We retrospectively studied the medical records of 245 children undergoing an initial allogeneic bone marrow transplantation for malignant disease at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of HC in all patients and to identify the risk factors for HC in this cohort. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. Severe HC developed in 27 patients (11.0%). The median duration of HC was 73 days (range, 5–619 days); 12 patients had ongoing HC at the time of death. In univariate analyses, patients were at increased risk of severe HC if they were male (P = .021) or had received T cell-depleted grafts (P = .017), grafts from unrelated donors (P = .021), a lower total nucleated cell dose (P = .032), or antithymocyte globulin (P = .0446). Multiple regression analysis revealed male sex (β = .97; P = .027) and unrelated donor graft recipients (β = .83; P = .039) to be significant factors.

The histiocytoses are rare disorders of antigen-processing phagocytic or antigen-presenting cells. Allogeneic bone marrow transplantation (BMT) can be curative of these disorders. We report a series of five children with Langerhans cell histiocytosis (n=2) or hemophagocytic lymphohistiocytosis (n=3), who received allogeneic BMT with a total body irradiation (TBI)-containing regimen (TBI, cytarabine, and cyclophosphamide) at our institution between 1995 and 2000. One of these patients received busulfan, cyclophosphamide, and etoposide for the first of two BMTs. All grafts except one (a matched sibling-donor graft) were T-cell-depleted grafts from unrelated donors. All received cyclosporine graft-versus-host disease (GvHD) prophylaxis; the recipient of the matched sibling graft also received methotrexate. Three patients engrafted at a median of 24 days after transplantation. The patient who did not receive TBI experienced primary graft failure and recurrent disease. After the TBI-containing conditioning regimen was given, a second transplant engrafted on day +17. One patient with concurrent myelodysplastic syndrome died of toxicity on day +33 without evidence of engraftment. No acute or chronic GvHD was observed. Four patients survive disease-free, a median of 63 months after transplantation, all with Lansky performance scores of 100. We conclude that a conditioning regimen containing TBI but not etoposide is effective in allogeneic BMT for children with histiocytic diseases.

Six young patients with X-linked agammaglobulinemia and proven mutations in Btk were treated with cord blood or bone marrow transplants from HLA-matched siblings. Complete blood counts, serum chemistries, serum immunoglobulin concentrations, lymphocyte cell surface markers, and physical findings were evaluated at 3- to 5-day intervals for the first 2 weeks after transplant and then every 3 to 6 months. The first three patients were not given any preparative regimen or antirejection drugs and at 24 to 42 months posttransplant these patients have shown no benefit or harm related to the transplants. The second three patients were not given a preparative regimen but were treated with cyclosporine A (70 days) and mycophenolate mophetil (28 days) after transplant. Two of these patients have developed normal sized, nontender cervical lymph nodes 3 to 12 months after transplant but none of the three patients have shown an increase in serum IgM or an increase in the number of peripheral blood B cells. It is likely that successful engraftment will require more aggressive immunosupressive medications.

The outcome of umbilical cord blood transplantation is governed by UCB cell dose and matching. But stringent cell dose requirements limit access to well matched units. In haplo –cord transplant, early engraftment is determined by the adult graft. Elsewhere we have shown that excessive doses of haplo-identical cells resulted in failure of the UCB graft. Here we investigated the effect of a lower UCB cell dose threshold on ability to identify well matching units. We also prospectively evaluated the effects of UCB cell dose and matching (combined with a fixed dose haplo-graft ) on cord engraftment, platelet recovery, neutrophil recovery and acute GVHD, PFS and OS. We enrolled three consecutive cohorts with increasingly lower UCB cell dose thresholds (1) UCB cell dose >2x 10^ NC/kg (2)≥1x 10^ NC/kg and (3)≥.5x 10^ NC/kg. Additional selection criteria included (1) best HLA match (initially based on 6 HLA, as of mid 2013 based on 8 HR antigens (2)UCB viability, (3) avoidance of DSA antibodies and (4) NIMA compatibility. We continued enrollment on each cohort until at least 10 patients were evaluable for day 100 chimerism. If more than 7 of ten evaluable patients in a cohort achieved >40% UCB chimerism by d 100, the next cohort was started. This rate of success was achieved in all three cohorts, so we have continued accrual in the lowest cell dose. Sixty patients have been accrued at two institutions over 19 months. 43/60 pts had AML or MDS. The majority had ASBMT advanced and intermediate disease. Nearly half of the pts were of minority descent. Conditioning in all pts consisted of fludarabine-melphalan (three pts also received TBI 400) and GVHD prophylaxis of tacrolimus and mycophenolate. Haplo identical CD34 selected cells were co-administered at a dose of 3-5 x10^6 CD34 cells/kg. Pt characteristics and preliminary outcomes are summarized in the table below. Table Cohort 1 2 3 Minimum TNC x10^5/kg 2 1 0.5 n 15 20 25 Age 48 62 64 ASBMT Low/Int/Adv 4/5/6 7/5/7 8/6/11 Weight (kg) 73 (56-96) 72 (50-136) 85(46-122) Caucasian/Other 7/8 13/7 12/13 Median UCB TNC collected (x10^7/kg) and range 2.7 (2.1-8.3) 2.1 (1.4-2.9) 1.7 (0.9-2.7) UCB TNC/kg >3x10^7/kg 7 (46%) (0 UCB failure) 1 (5%) (0 UCB failure) 2 (8%) (0 UCB failure) 2-3 x10^7/kg 8 (54%) (0 UCB failure) 9 (45%) (2 UCB failure) (32%) (0 UCB failure) 1.5-2 x10^7/kg 0 5 (25%) (0 UCB failure) 8 4 (16%) (0 UCB failure) 1-1.5 x10^7/kg 0 5 (25%) (0 UCB failure) 10 (40%) (4 UCB failure) 500 (range) 14 (10-60) 12 (9-18) 12 (9-51) Median Time to Plt >20 (range) 35 (15-88) 20 (13-NR) 21 (10-NR) % with >40% UCB chimerism @d100 100 83 76 * Analysis of UCB graft characteristics includes all patients. Engraftment and GVHD analysis excludes 10 patients with early fatal complications or relapse. Chimerism analysis excludes two additional patients with missing information. NR= not reached The average HLA matching was significantly better (P6/8 match), than in group 1 (6% with >6/8 match). UCB cell doses were significantly lower in groups 2 and 3 (55% with UCB cell dose Seven of 50 evaluable pts had failure of the UCB graft ( This novel cord blood selection algorithm allows identification of well-matched UCB cells (at least 6/8 HR) in two thirds of patients. In approximately one third of cases the best matching UCB unit has a cell dose Disclosures van Besien: Miltenyi Biotec: Research Funding. Stock:Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mark:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau.

The outcome of disease relapse after allogeneic stem cell transplantation (allo-SCT) remains very poor. Second SCT has achieved long term survival in select pts. We retrospectively analyzed the outcomes of 65 pts who underwent 2rd SCT for disease relapse at University of Chicago between September 2002 and September 2013. All except 4 pts received T cell depleted (TCD) SCT as 1st SCT mainly with fludarabine (flu)/clofarabine-melphalan (mel) -alemtuzumab; flu-busulfan-alemtuzumab for MRD or MUD, and flu-mel-ATG for haplo-cord SCT. The majority of pts had AML (n=46) and high risk MDS (n=5). The median age at 2nd allo-SCT was 47ys (11-73). 33 pts, 21 pts and 11 pts received MRD, MUD and Haplo-Cord SCT respectively for 2nd SCT. 13 pts (20%) achieved CR before 2nd SCT. 71% pts received TCD conditioning for 2nd SCT. 98% (n=64) and 72% (n=47) pts achieved neutrophil and platelet engraftment at a median time of 11 and 18 days, respectively, following the 2nd SCT. With a median fellow up of 23 (5.5-140) months for survivors after 2nd SCT, the estimated 1 year PFS was 29.2% and 1 year OS was 33.8%. The day 100 treatment related mortality (TRM) rate was 28%, and the cumulative incidence of aGVHD and cGVHD were 23% and 8%, respectively. Not surprisingly, the majority of pts died from disease relapse (22/47, 47%), followed by infection (11/47, 23%) and GVHD (6/47, 13%). In the univariate analysis, pts with remission duration after 1st SCT >=12 months or CR status before 2nd SCT had significantly better PFS (P=0.001 and 0.009) and OS (P=0.001 and 0.013). The differences of 1 year PFS and OS stratified by these two variables were very striking. The 1 years PFS for pts in CR was 62% compared to 21% for pts not in CR; and 1 year PFS for pts with remission duration >=12 months after 1st SCT was 57% comparing around 14% for pts 60) had no influence on 1 year PFS (P=0.083), younger pts had better 3 year PFS (P=0.026); Alemtuzumab use (n=37 vs. n=16 without alemtuzumab) in the 2nd SCT conditioning for related donors significantly worsened 3 years PFS (44% vs. 8%; P=0.027) but not 1 year PFS, and it had no effect on OS. A scoring system using age (60), disease status before 2nd SCT (CR vs. non-CR), and remission duration after 1st SCT (=12 months) was generated to attempt to classify the pts into different risk categories. The groups of 0 (n=5), 1-2 (n=34), 3-4 (n=26) could separate the 1 year PFS (80% vs. 32.3% vs. 15.4%) and OS (100% vs. 35.3 vs. 19.2%) nicely. Although the numbers are small, pts with a score of 0 (=12 months remission duration after 1st SCT) had excellent outcomes with 1 year PFS of 80%, and 1 year OS of 100%. In conclusion, 2nd allo-SCT is a viable option for disease relapse after TCD allo-SCT with acceptable GVHD and good engraftment for those entering transplant in remission and/or remission duration >=12 months after 1st SCT. Abstract 2509. TablePatient Outcomes after 2nd SCTAll pts CR not in CR Remission duration >=12 months Remission duration 6-12 monthsRemission duration =3 Pts number (n)651352231527534261 yearPFS29.2%61.5%21.2%56.5%13.3%14.8%80%32.3%15.4%3 year PFS21.5%53.8%13.5%43.5%6.7%11.1%80%20.6%11.5%1 year OS33.8%69.2%25%60.9%20%18.5%100%35.3%19.2%3 year OS23.1%46.2%17.3%43.5%6.7%14.8%80%20.6%15.4% Disclosures Artz: Miltenyi: Research Funding. Stock:Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Breast cancer remains the leading cause of cancer-related mortality in women. Comprehensive genomics, proteomics, and metabolomics studies are emerging that offer an opportunity to model disease biology, prognosis, and response to specific therapies. Although many biomarkers have been identified through advances in data mining techniques, few have been applied broadly to make patient-specific decisions. Here, we review a selection of breast cancer prognostic indicators and their implications. Our goal is to provide clinicians with a general evaluation of emerging computational methodologies for outcome prediction.

Allogeneic bone marrow transplantation (BMT) is an effective therapy for a variety of malignancies and blood disorders, but rarely serves as a frontline treatment because of numerous, potential complications. Important and frequent complications relate to the profound immunosuppression that inevitably occurs during the first several months following treatment. To better elucidate and subsequently improve immune reconstitution, we examined T and B cell subsets among 43 pediatric BMT recipients in a retrospective study. We found that the relative numbers of T cells and B cells (T:B ratios) were discordant and highly variable among patients at day approximately 100 after BMT. Further investigation of BMT parameters identified a strong correlation between T:B ratios and immunosuppressive drug treatments, providing an explanation for variable lymphocyte reconstitution profiles. Results suggest that: (1) immunosuppressive therapy inhibits B cell expansion more strongly than T cell expansion following BMT; (2) WBC and absolute lymphocyte counts fail to reveal profound B cell immunodeficiencies in some BMT patients; and (3) routine analyses of T:B ratios serve to identify patients warranting close follow-up and extended supportive immunotherapy.

EDITOR—Many of the comments of David, Esmonde, McMillan, and Murray et al are incorrect and overlap.1 Owing to space constraints we have addressed points of fact below and opinion based comments in bmj.com (bmj.com/cgi/eletters/320/7245/1337#EL1) or in the printed 2 and longer web versions of our paper (bmj.com/cgi/content/full/319/7213/807/DC1). Few normative data are published on large series of flash or pattern stimulated visual evoked potentials or the difference in timing between them. In a given subject the flash-pattern difference might be large because of a quicker (shorter) pattern latency than normal, but, to our knowledge, pathologically short pattern evoked responses have not been reported in …

Objective: To establish whether people exposed to drinking water contaminated with 20 tonnes of aluminium sulphate in the Camelford area of Cornwall in the south west of England in July 1988 had suffered organic brain damage as opposed to psychological trauma only. Design: Retrospective study of affected people. Participants: 55 affected people and 15 siblings nearest in age to one of the group but who had not been exposed to the contaminated water were studied. Main outcome measures: Various clinical and psychological tests to determine medical condition and anxiety levels in affected people. Assessment of premorbid IQ (pFSIQ) with the national adult reading test, a computerised battery of psychomotor testing, and measurement of the difference in latencies between the flash and pattern visual evoked potentials in all participants. Results: The mean (SE) pFSIQ was above average at 114.4 (1.1). The most sensitive of the psychomotor tests for organic brain disease was the symbol digit coding (SDC) test (normal score 100, abnormal less than 85). Participants performed less well on this test (54.5 (6.0)) than expected from their pFSIQ (Pless than 0.0001) and a little less poorly on the averaged less discriminating tests within the battery (86.1 (2.5), Pless than 0.0001). In a comparison with the 15 sibling pairs (affected people's age 41.0 (3.3) years vsibling age of 42.7 (3.1) years (P=0.36) the exposed people had similar pFSIQ (114.7 (2.1)) to their siblings (116.3 (2.1), (P=0.59) but performed badly on the symbol digit coding test (51.8 (16.6)) v(87.5 (4.9) for siblings, P=0.03). The flash-pattern differences in exposed people were greater than in 42 unrelated control subjects of similar age (27.33 (1.64) ms v18.57 (1.47) ms, P=0.0002). The 15 unexposed siblings had significantly better flash-pattern differences than their affected siblings (13.4 (2.4) ms v29.6 (2.9) ms, P=0.0002). No effect of anxiety could be shown on these measurements from the analysis of the anxiety scores of exposed people. Conclusion: People who were exposed to the contaminated water at Camelford suffered considerable damage to cerebral function, which was not related to anxiety. Follow up studies would be required to determine the longer term prognosis for affected individuals.

Gene therapy has been proposed for a wide variety of human conditions including monogenic disorders, such as the haemoglobinopathies and immunodeficiency syndromes, cancer and many other diseases. Prerequisites for the success of this approach include the ability to deliver the therapeutic gene intact to the target cell, persistent levels of transgene expression sufficient to correct the disease phenotype, lack of unwanted side-effects associated with vector exposure or gene transfer and relative simplicity allowing the widespread use of this methodology. Although substantial progress has been made in animal models since the inception of genetic therapy in the early 1980s, significant obstacles remain for human therapy, most notably in the area of vector development. The first generation of gene therapy vectors has failed to overcome many of the biological hurdles cited above necessitating the development of alternate means of gene delivery and expression.

Francis Patrick Marsh (“Frank”) was born in Birmingham in 1936 and moved to Leeds with his family in early childhood. The son of Horatio and Violet Marsh, he completed his schooling at Leeds Grammar School, from where he gained admission to Caius College, Cambridge, to read medicine, graduating with a first class honours degree in 1957 . He then moved to the London Hospital Medical College as a clinical student, and his medical life thereafter revolved largely around the London Hospital and its associated medical college with sojourns at the Kent and Canterbury Hospital and the Royal Free Hospital along the way. At the age of 34 years he was appointed as a senior lecturer on the medical unit at the London Hospital Medical College under Professor Clifford Wilson (of “Kimmelstiel-Wilson Kidney”) and later as a consultant physician to the London Hospital, a post …