Robert Carr

Neutrophil production and function in newborn infants.

Bacterial infection is a major cause of death and long-term morbidity in preterm neonates. Infection rates among neonates undergoing intensive care range from 25% to 50% (Stoll et al, 1996; Cooke et al, 1997; Fanaroff et al, 1998) and, in spite of effective antibiotic therapy, sepsisrelated mortality has remained constant at 15±20% for nearly two decades (Gladstone et al, 1990). The reason for such high sepsis rates and attendant mortality are largely due to the immaturity of bactericidal mechanisms. Clinical evidence of the preterm neonates immune incompetence is the pattern of bacterial infections which closely parallels that seen in patients with profound neutropenia (Stoll et al, 1996) and the frequent development of neutropenia in response to bacterial sepsis (Engle et al, 1984; Gessler et al, 1995). These two phenomena can be directly related to immaturity of neutrophil function and production.

European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy.

PURPOSE Treatment options for older patients with acute myeloid leukemia (AML) who are not considered suitable for intensive chemotherapy are limited. We assessed the second-generation purine nucleoside analog, clofarabine, in two similar phase II studies in this group of patients. PATIENTS AND METHODS Two consecutive studies, UWCM-001 and BIOV-121, recruited untreated older patients with AML to receive up to four or six 5-day courses of clofarabine. Patients in UWCM-001 were either older than 70 years or 60 to 69 years of age with poor performance status (WHO > 2) or with cardiac comorbidity. Patients in BIOV-121 were >or= 65 years of age and deemed unsuitable for intensive chemotherapy. RESULTS A total of 106 patients were treated in the two monotherapy studies. Median age was 71 years (range, 60 to 84 years), 30% had adverse-risk cytogenetics, and 36% had a WHO performance score >or= 2. Forty-eight percent had a complete response (32% complete remission, 16% complete remission with incomplete peripheral blood count recovery), and 18% died within 30 days. Interestingly, response and overall survival were not inferior in the adverse cytogenetic risk group. The safety profile of clofarabine in these elderly patients with AML who were unsuitable for intensive chemotherapy was manageable and typical of a cytotoxic agent in patients with acute leukemia. Patients had similar prognostic characteristics to matched patients treated with low-dose cytarabine in the United Kingdom AML14 trial, but had significantly superior response and overall survival. CONCLUSION Clofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics.

PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement

We investigated whether positron emission tomography combined with computed tomography (PET-CT) identifies clinically important bone marrow involvement by diffuse large B-cell lymphoma (DLBCL) with sufficient accuracy to replace routine staging bone marrow biopsy. All patients from a single centre diagnosed as DLBCL since 2005 had data extracted from staging PET-CT, marrow biopsy, and treatment records. Of 130 patients, 35 (27%) were judged to have marrow involvement; 33 were identified by PET-CT compared with 14 by marrow histology. PET identified all clinically important marrow lymphoma, while biopsy did not upstage any patient. Sensitivity and specificity were 94% and 100% for PET-CT and 40% and 100% for marrow biopsy. As a secondary aim, we compared the prognosis of marrow involvement, as detected by PET-CT or biopsy. Cases with marrow deposits identified by PET-CT but not biopsy had progression-free survival (PFS) and overall survival similar to stage IV disease without involved marrow. Positive biopsy conferred significantly inferior PFS (P = .003); these cases frequently had other markers of poor-risk disease. These data confirm that in experienced hands PET-CT has a high level of accuracy for identifying marrow disease in DLBCL, and provide new insight into the nature and clinical significance of marrow involvement.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Thrombospondin-1–Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Cancer

PURPOSE ABT-510 is an angiogenesis inhibitor derived from thrombospondin-1, a naturally occurring inhibitor of angiogenesis. We investigated ABT-510, which was administered subcutaneously in patients with advanced solid malignancies, to assess safety, pharmacokinetics, and serum markers of angiogenesis. PATIENTS AND METHODS ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 h) and bolus injections (100, 200, and 260 mg once daily; 50 and 100 mg twice daily) in 28-day cycles. RESULTS Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. Maximum-tolerated dose was not defined, but 260 mg was defined as the maximum clinically practical dose. ABT-510 pharmacokinetics were linear across the dosage ranges tested, and the potential therapeutic threshold (plasma concentrations > 100 ng/mL > 3 h/d) was achieved with all dose regimens. Median serum basic fibroblast growth factor (bFGF) levels decreased from 14.1 pg/mL (range, 0.5 to 77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2 to 29.4 pg/mL) after 56 days of treatment (P = .003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. Stable disease lasting for six cycles or more was seen in six patients. CONCLUSION ABT-510 demonstrated a favorable toxicity profile and linear and time-independent pharmacokinetics with biologically relevant plasma concentrations. The significant number of patients with prolonged stable disease and the convenient method of dosing merit further studies with this angiogenesis inhibitor.

From personal survival to public health: Community leadership by men who have sex with men in the response to HIV

Community leadership and participation by gay men and men who have sex with men (MSM) have been central to the response to HIV since the beginning of the epidemic. Through a wide array of actions, engagement of MSM has been important in the protection of communities. The connection between personal and community health as drivers of health advocacy continue to be a powerful element. The passion and urgency brought by MSM communities have led to the targeting and expansion of HIV and AIDS research and programming, and have improved the synergy of health and human rights, sustainability, accountability, and health outcomes for all people affected by HIV. MSM are, however, frequently excluded from the evidence-based services that they helped to develop, despite them generally being the most effective actors in challenging environments. Without MSM community involvement, government-run health programmes might have little chance of effectively reaching communities or scaling up interventions to lessen, and ultimately end, the HIV pandemic.

Neonates harbour highly active γδ T cells with selective impairments in preterm infants

Acknowledgement of the breadth of T‐cell pleiotropy has provoked increasing interest in the degree to which functional responsiveness is elicited by environmental cues versus differentiation. This is particularly relevant for young animals requiring rapid responses to acute environmental exposure. In young mice, γδ T cells are disproportionately important for immuno‐protection. To examine the situation in humans, we compared populations and clones of T cells from term and preterm babies, and adults. By comparison with αβ T cells, neonate‐derived γδ cells show stronger, pleiotropic functional responsiveness, and lack signatory deficits in IFN‐γ production. Emphasising the acquisition of functional competence in utero, IFN‐γ was produced by γδ cells sampled from premature births, and, although one months post‐partum environmental exposure invariably increased their TNF‐α production, it had no consistent effect on IFN‐γ or IL‐2. In sum, γδ cells seem well positioned at birth to contribute to immuno‐protection and immuno‐regulation, possibly compensating for selective immaturity in the αβ compartment. With regard to the susceptibilities of preterm babies to viral infection, γδ cells from preterm neonates were commonly impaired in Toll‐like receptor‐3 and ‐7 expression and compared with cells from term babies failed to optimise cytokine production in response to coincident TCR and TLR agonists.

A randomized, controlled trial of prophylactic granulocyte-macrophage colony-stimulating factor in human newborns less than 32 weeks gestation

Objective. Preterm neonates undergoing intensive care have high morbidity from sepsis. These infants also frequently develop neutropenia, and when this is associated with sepsis, mortality is high. This study investigates the potential for granulocyte-macrophage colony-stimulating factor (GM-CSF) to effect a clinically relevant increase in neutrophil number when used prophylactically in high-risk preterm neonates, and assesses its safety in this population. Design. In an open, randomized, controlled study, 75 neonates (25 small for gestational age) <32 weeks gestation were randomized to receive GM-CSF (10 μg/kg/d) by subcutaneous injection for 5 days from <72 hours after birth, or to a control group. The primary outcome measure was the neutrophil count during 14 days from study entry. The infants were monitored for potential toxicity. Clinical outcomes, sepsis, and mortality, were recorded, but this initial study was not designed to address clinical benefit. Results. Prophylactic GM-CSF therapy completely abolished neutropenia in treated infants, when both well and septic, throughout the period of study. Neutropenia (≤1.7 × 109/L) developed in 16 of 39 control infants. Five control infants experienced an acute decrease in neutrophil count coincident with the onset of sepsis. There was no evidence of hematologic, respiratory, or gastrointestinal toxicity in treated infants. Treated infants had a trend to fewer symptomatic, blood culture positive septic episodes than controls during 2 weeks from study entry (11/36 vs 18/39). Conclusion. Five-day prophylactic GM-CSF completely abolishes postnatal neutropenia and sepsis-induced neutropenia in preterm neonates at high risk of sepsis, and so removes an important risk factor for sepsis and sepsis-related mortality.GM-CSF, preterm neonates, neutropenia, sepsis.

Low soluble FcRIII receptor demonstrates reduced neutrophil reserves in preterm neonates.

Editor—Studies of human neonate granulopoiesis have been hampered by the lack of a marker of overall neutrophil cell mass. Assumptions about neonate granulopoiesis have therefore largely been extrapolated from rat data. Direct measurement of total neutrophil cell mass (in terms of neutrophils per g body weight) in newborn rats has shown that they have about one quarter the neutrophil mass of adult animals and that their neutrophil mass increases to adult levels by the time they are 4 weeks old.1 In addition, newborn rodents do not have the reserve pool of quiescent granulocyte progenitors, as found in adults, to recruit into production during sepsis. Circumstantial evidence for a similar immaturity of neutrophil …

Combined PET and Biopsy Evidence of Marrow Involvement Improves Prognostic Prediction in Diffuse Large B-Cell Lymphoma

Bone marrow is an important extranodal site in diffuse large B-cell lymphoma (DLBCL), and marrow histology has been incorporated into the new National Comprehensive Cancer Network international prognostic index. Marrow involvement demonstrated histologically confers poor prognosis but is identified by staging PET in more cases. How information from staging PET and biopsy should be combined to optimize outcome prediction remains unclear. Methods: The International Atomic Energy Agency sponsored a prospective international cohort study to better define the use of PET in DLBCL. As a planned subsidiary analysis, we examined the interplay of marrow involvement identified by PET and biopsy on clinical outcomes. Results: Eight countries contributed 327 cases with a median follow-up of 35 mo. The 2-y outcomes of cases with no evidence of marrow involvement (n = 231) were 81% (95% confidence interval [CI], 76%–86%) for event-free survival (EFS) and 88% (83%–91%) for overall survival (OS); cases identified only on PET (n = 61), 81% (69%–89%) for EFS and 88% (77%–94%) for OS; cases indentified only on biopsy (n = 10), 80% (41%–95%) for EFS and 100% for OS; or cases identified by both PET and biopsy (n = 25), 45% (25%–64%) for EFS and 55% (32%–73%) for OS. The hazard ratios for PET-negative/biopsy-negative cases versus PET-positive/biopsy-positive cases were 2.67 (95% CI, 1.48–4.79) for EFS and 3.94 (1.93–8.06) for OS. Conclusion: This large study demonstrates that positive iliac crest biopsy histology only confers poor prognosis for patients who also have abnormal marrow 18F-FDG uptake identified on the staging PET scan. Abnormal 18F-FDG uptake in marrow, when iliac crest biopsy histology is normal, has no adverse effect on outcomes.

Haemopoietic colony stimulating factors for preterm neonates

Bacterial and fungal sepsis is a major cause of morbidity and mortality in neonates. Infection rates are high in infants treated in intensive care units, with the highest rates, of around 30%, occurring in extremely immature preterm neonates.1-3 A survey of neonatal infection at Yale University, ongoing since 1928,4 has documented a decline in neonatal septic deaths commensurate with the establishment of neonatal intensive care units and the liberal use of increasingly effective antibiotics. Mortality from sepsis declined steadily until the early 1980s, but since then it has remained constant at near 15%. This plateau of mortality most likely reflects the poor host defences of immature, preterm neonates.5 Neutrophil leucocytes are central to the defences against bacterial infection,6 and in neonates both neutrophil production and function are immature. Neutropenia, defined as a neutrophil count below the normal range for neonates established by Monroe,7occurs in up to 35% of preterm neonates8 9 and in 50% of all infants born to mothers with pregnancy induced hypertension.10 The development of sepsis together with neutropenia carries a high mortality of 39%, and two out of every three septic infants whose neutrophils fall below 0.5 × 109/l will die.9 It is impossible to measure directly the total neutrophil cell mass in a human neonate. There is a good deal of circumstantial evidence to suggest that neonatal bone marrow has a reduced capacity to produce neutrophils in adequate numbers.11 Neutrophils develop from multipotent haemopoietic stem cells through lineage-committed progenitors (granulocyte-macrophage colony forming units, CFU-GM). These give rise to a proliferative pool, identified morphologically in the bone marrow as promyelocytes and myelocytes, and a storage pool comprising metamyelocytes, bands, and segmented neutrophils, before being released into the circulation. Mature neutrophils circulate with a peripheral blood half life …