FaceBase: A Community-Driven Hub for Data-Intensive Research.

The FaceBase Consortium, funded by the National Institute of Dental and Craniofacial Research of the National Institutes of Health, was established in 2009 with the recognition that dental and craniofacial research are increasingly data-intensive disciplines. Data sharing is critical for the validation and reproducibility of results as well as to enable reuse of data. In service of these goals, data ought to be FAIR: Findable, Accessible, Interoperable, and Reusable. The FaceBase data repository and educational resources exemplify the FAIR principles and support a broad user community including researchers in craniofacial development, molecular genetics, and genomics. FaceBase demonstrates that a model in which researchers "self-curate" their data can be successful and scalable. We present the results of the first 2.5 y of FaceBase's operations as an open community and summarize the data sets published during this period. We then describe a research highlight from work on the identification of regulatory networks and noncoding RNAs involved in cleft lip with/without cleft palate that both used and in turn contributed new findings to publicly available FaceBase resources. Collectively, FaceBase serves as a dynamic and continuously evolving resource to facilitate data-intensive research, enhance data reproducibility, and perform deep phenotyping across multiple species in dental and craniofacial research.

Anabolic agents: what is beyond osteoporosis?

Osteoporosis is a common skeletal disorder characterized by low bone mass, which leads to reduced bone strength and an increased risk of fractures. Anabolic agents have been shown to improve bone mass and decrease fracture risk in osteoporosis patients by directly stimulating osteoblasts to produce new bone. Currently, two anabolic agents are available in the USA: recombinantly produced teriparatide (TPTD), which is the fully active (1-34) amino active sequence of human parathyroid hormone (PTH), and abaloparatide (APTD), a synthetic analog of parathyroid hormone-related peptide (PTHrP). At present, both agents are approved only for treatment of patients with osteoporosis at high risk of fracture. Nonetheless, their anabolic properties have led to off-label application in additional settings which include spine fusion, osteonecrosis of the jaw, arthroplasty, and fracture healing. In this article, we summarize available scientific literature regarding the efficacy, effectiveness, and safety of TPTD in these off-label settings.

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=<0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82 and 51% (P=0.03), and the 3-year PFS estimates were 63% and 27% (P=0.001), respectively. The 2-year treatment-related mortality was 8 and 23% and the incidence of grade 3 or 4 GvHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

Clinical outcomes and safety with trabectedin therapy in patients with advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide expanded access program study.

BACKGROUND: This expanded access program (EAP) was designed to provide trabectedin access for patients with incurable soft tissue sarcoma (STS) following progression of disease with standard therapy. The outcomes of trial participants accrued over approximately 5 years are reported. PATIENTS AND METHODS: Adult patients with advanced STS of multiple histologies, including leiomyosarcoma and liposarcoma (L-sarcomas), following relapse or disease progression following standard-of-care chemotherapy, were enrolled. Trabectedin treatment cycles (1.5 mg/m(2), intravenously over 24 h) were repeated q21 days. Objective response, overall survival (OS), and safety were evaluated. RESULTS: Of 1895 patients enrolled, 807 (43%) had evaluable objective response data, with stable disease reported in 343 (43%) as best response. L-sarcoma patients exhibited longer, OS compared with other histologies [16.2 months (95% confidence interval (CI) 14.1-19.5) versus 8.4 months (95% CI 7.1-10.7)], and a slightly higher objective response rate [6.9% (95% CI 4.8-9.6) versus 4.0% (95% CI 2.1-6.8)]. The median treatment duration was 70 days representing a median of three treatment cycles; 30% of patients received ≥ 6 cycles. Safety and tolerability in this EAP were consistent with prior clinical trial data. CONCLUSION: Results of this EAP are consistent with previous reports of trabectedin, demonstrating disease control despite a low incidence of objective responses in advanced STS patients after failure of standard chemotherapy. CLINICALTRIALS.GOV: NCT00210665.

Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons.

Disinhibition of neurons in the region of the dorsomedial hypothalamus (DMH) elicits sympathetically mediated tachycardia in rats through activation of the brain stem raphe pallidus (RP), and this same mechanism appears to be largely responsible for the increases in heart rate (HR) seen in air jet stress in this species. Neurons projecting to the RP from the DMH are said to be concentrated in a specific subregion, the dorsal hypothalamic area (DA). Here, we examined the hypothesis that the location of RP-projecting neurons in the DA correspond to the sites at which microinjection of bicuculline methiodide (BMI) evokes the greatest increases in HR. To determine the distribution of RP-projecting neurons in the DA, cholera toxin B was injected in the RP in four rats. A consistent pattern of retrograde labeling was seen in every rat. In the hypothalamus, RP-projecting neurons were most heavily concentrated midway between the mammillothalamic tract and the dorsal tip of the third ventricle dorsal to the dorsomedial hypothalamic nucleus approximately 3.30 mm caudal to bregma. In a second series of experiments, the HR response to microinjections of BMI (2 pmol/5 nl; n = 76) was mapped at sites in the DA and surrounding areas in 22 urethane-anesthetized rats. All injection sites were located from 2.56 to 4.16 mm posterior to bregma, and the microinjections that evoked the largest increase in HR (i.e., >100 beats/min in some instances) were located in a region where RP-projecting neurons were most densely concentrated. Thus RP-projecting neurons in the DA may mediate DMH-induced tachycardia and thus play a role in stress-induced cardiac stimulation.

Trimetrexate in relapsed T-cell lymphoma with skin involvement.

PURPOSE: Methotrexate (MTX) is active against lymphomas, but transport or polyglutamylation mutations confer MTX resistance. Because trimetrexate (TMTX) enters cells by passive diffusion and is not polyglutamylated, its activity in relapsed T-cell lymphoma was investigated. PATIENTS AND METHODS: Eligible patients had histologically confirmed relapsed T-cell lymphoma involving the skin, had received more than one previous regimen, were older than 16 years, had normal organ function, and had no CNS disease or serious infections, including human immunodeficiency virus. TMTX (200 mg/m(2)) was given intravenously every 14 days without topical or systemic corticosteroids. Patients who responded received up to 12 doses. RESULTS: Twenty patients were assessable for response. Median age was 59 years (range, 45 to 87 years); 13 patients were men. Three patients had anaplastic large-cell lymphoma, 15 had mycosis fungoides or Sézary syndrome (14 with large-cell transformation), and two had peripheral T-cell lymphoma. Serum lactate dehydrogenase was high in 35%, and beta-2 microglobulin was more than 3.0 mg/L in 35% of patients. The median number of previous regimens was three (range, two to 15) and included MTX in five patients. Disease was refractory to the regimen immediately preceding TMTX in 85% of patients. Responses were complete in one and partial in eight patients (overall response rate, 45%). Two of five patients previously treated with MTX responded. Grade 3 or 4 mucositis was observed after 4%, infection after 3%, neutropenic fever after 6%, neutrophils less than 100/microL after 4%, and platelets less than 10,000/microL after 3% of TMTX doses. CONCLUSION: TMTX is active with acceptable toxicity in this population and merits further investigation.

Tachycardia evoked by disinhibition of the dorsomedial hypothalamus in rats is mediated through medullary raphe.

Activation of neurons in the region of the dorsomedial hypothalamus (DMH) appears to generate the sympathetically mediated tachycardia seen in experimental stress in rats. The purpose of this study was to assess the role of neurons in the area of the medullary raphe pallidus (RP) in the tachycardia caused by stimulation of the DMH. The cardiovascular response to microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) 10 pmol (100 nl)(-1) into the DMH was assessed before, and after, injection of the GABA(A) receptor agonist muscimol 80 pmol (100 nl)(-1) or saline vehicle 100 nl into the RP in urethane-anaesthetized rats. Tachycardia evoked by microinjection of BMI into the DMH was mimicked by microinjection of BMI 30 pmol (75 nl)(-1) into the RP. This DMH-induced tachycardia was markedly suppressed after injection of muscimol into the RP, but the response was unaffected by injection of saline into the same region. Thus, DMH-induced tachycardia is mediated through activation of neurons in the area of the RP, suggesting that these neurons may play a previously unrecognized role in stress-induced cardiac stimulation.

Phase II studies of bryostatin-1 in patients with advanced sarcoma and advanced head and neck cancer.

BACKGROUND: Bryostatin 1 is a marine derived macrolactone with antineoplastic activity modulated through protein kinase C, and with good activity in in vitro and in vivo models. There are few drugs that offer palliation for metastatic soft-tissue sarcoma and head and neck cancer, and drugs with new mechanisms of action warrant detailed disease specific study. PATIENTS AND METHODS: Two phase II studies for patients with incurable soft tissue sarcoma (12), or head and neck cancer (12) were conducted. Patients were treated with bryostatin, 120 mg/m2/72 hours every 2 weeks for 3 cycles prior to re-evaluation. Most patients had received prior chemotherapy. RESULTS: No patients had objective responses to therapy. Six patients had brief periods of disease stabilization. Toxicity was generally mild, with myalgia being prominent (n=8). Hyponatremia, not previously described, occurred in 5 patients. The mechanism of this toxicity was unclear. CONCLUSIONS: Bryosytatin 1 given as a single agent for advanced adult soft tissue sarcoma and head and neck cancer is inactive. Myalgia and hyponatremia were the predominant toxicities.

Irinotecan in relapsed or refractory non-Hodgkin's lymphoma.

Irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor with a broad spectrum of antitumor clinical activity. Various schedules and doses have been studied, and major complications were delayed diarrhea and myelosuppression. We explored the activity of irinotecan in patients with relapsed or refractory non-Hodgkin's lymphoma, using a 3-week schedule of administration. Eligible patients had histologically proven relapse, had received no more than two previous regimens, were > or = 15 years and < or = 75 years old, had normal renal function, neutrophil count > 1,500/microL, platelet count > 100,000/microL, and no human immunodeficiency virus infection or central nervous system involvement. Patients were treated with irinotecan 300 mg/m2 i.v. every 21 days with intensive loperamide management of diarrhea. Responders received up to six treatment cycles. Of 25 patients registered so far, 22 are evaluable for response. The median age was 67 years (range: 25 to 74 years) and 11 were male. The median number of previous regimens was 2 (range: 1 to 4 regimens), and 16 patients had disease that was refractory to their last regimen. Serum lactate dehydrogenase level was high in 75%, and beta2-microglobulin was > 3.0 mg/L in 26% of patients. Responses were seen in 8 of 22 (36%) patients with non-Hodgkin's lymphoma. Response rates were 40% for indolent, 0% for mantle cell, 45% for relapsed aggressive, and 33% for refractory aggressive lymphomas. Grade 3/4 toxicities included myelosuppression, neutropenic fever, and delayed diarrhea. Irinotecan appears active and relatively well tolerated in patients with relapsed aggressive non-Hodgkin's lymphoma. Accrual to this study is continuing for better determination of the response rate in all histologic subtypes of non-Hodgkin's lymphoma.

Paclitaxel plus topotecan treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.

BACKGROUND: Used as single agents, paclitaxel and topotecan have demonstrated promising activity in treating patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase II clinical trial to investigate the activity and tolerability of the combination of both drugs. PATIENTS AND METHODS: Patients with refractory or relapsed aggressive NHL who had previously been treated with a maximum of two prior chemotherapeutic regimens were given intravenous infusions of paclitaxel 200 mg/m2 over three hours on day one and topotecan 1 mg/m2 over 30 minutes daily from days one to five. All patients received daily subcutaneous injections of filgrastim (granulocyte colony-stimulating factor) 5 microg/kg starting 24 hours after the last dose of chemotherapy until neutrophil recovery. Treatments were repeated every three weeks for a maximum of six courses. Patients who achieved partial remission or complete remission (CR) after at least two courses were offered stem cell transplantation, if eligible. RESULTS: Of the 71 patients eligible for this trial, 66 (93%) were evaluable for treatment response. The median age was 53 years (range 23 to 74 years). Thirty-six percent of the patients had previously been treated with ara-C/platinum-based regimens, and 48% failed to achieve CR after primary induction therapy. Sixty-seven percent of the patients had elevated lactate dehydrogenase levels at the time of treatment initiation. The overall response rate was 48% (95% confidence interval (95% CI): 36%-61%). Patients who had primary refractory disease had a response rate of 31%, compared with 65% for patients who did not. Similarly, the response rate of patients who failed to achieve CR after their most recent previous therapy was 37%, compared with a 65% response rate in patients who relapsed from a first or second CR. The median duration of response was six months. A total of 199 courses were given, with a median of three courses per patient. Neutropenia at levels < or = 500 leukocytes per microliter was observed after 32% of the courses, and thrombocytopenia at levels < or = 20,000 platelets per microliter was observed after 17% of the courses. Grade 3-4 neutropenic fever occurred after 6% of the courses. Non-hematologic toxic effects were predominantly grade 1-2. CONCLUSION: The combination of paclitaxel and topotecan is an effective first or second line salvage therapy for patients with relapsed or refractory aggressive NHL who had prior anthracycline- or platinum-based chemotherapy.

Leptin and its role in pregnancy and fetal development--an overview.

Leptin is a hormone that is secreted by adipose cells in proportion to adipose mass, and therefore a low leptin level signifies depletion of energy stores. It has been proposed that leptin is one of the signals controlling sexual maturation. For example, humans and rodents lacking leptin fail to undergo complete puberty, while overexpression of leptin in mice causes early puberty. The placenta also produces leptin in human pregnancy, increasing the amount in the maternal circulation. The effects of the increased leptin levels during pregnancy are not clear. In contrast, the mouse placenta does not produce endocrinologically significant amounts of leptin. The mouse placenta does secrete a leptin-binding protein, the production of which correlates with a large increase in maternal leptin levels. The physiology of leptin during pregnancy and fetal development differs significantly between species, and is not well understood in any.

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

Stimulation of beta3-adrenergic receptors increases metabolic rate via lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Other acute effects include decreased gastrointestinal motility and food intake and increased insulin secretion. Chronic treatment with a beta3 agonist ameliorates diabetes and obesity in rodents. We studied the effects of beta3 stimulation in A-ZIP/F-1 mice, which have virtually no WAT, a reduced amount of BAT, severe insulin resistance, and diabetes. In contrast with wild-type mice, treatment of A-ZIP/F-1 mice with CL316243, a beta3-adrenergic agonist, did not increase O2 consumption. A single dose of CL316243 produced a 2-fold increase in serum free fatty acids, a 53-fold increase in insulin, and a 2.4-fold decrease in glucose levels in wild-type mice but no change in A-ZIP/F-1 animals. The A-ZIP/F-1 mice also did not show reduced gastrointestinal motility or 24-h food intake during beta3 stimulation. Chronic administration of CL316243 to the A-ZIP/F-1 mice did not improve their thermogenesis, hyperglycemia, or hyperinsulinemia. Thus, all of the beta3 effects studied were absent in the lipoatrophic A-ZIP/F-1 mice, including the effects on nonadipose tissues. From these results, we suggest that all of the effects of beta3 agonists are initiated at the adipocyte with the nonadipose effects being secondary events presumably mediated by signals from adipose tissue.

Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones.

There is uncertainty about the site(s) of action of the antidiabetic thiazolidinediones (TZDs). These drugs are agonist ligands of the transcription factor PPAR gamma, which is abundant in adipose tissue but is normally present at very low levels in liver and muscle. We have studied the effects of TZDs in A-ZIP/F-1 mice, which lack white adipose tissue. The A-ZIP/F-1 phenotype strikingly resembles that of humans with severe lipoatrophic diabetes, including the lack of fat, marked insulin resistance and hyperglycemia, hyperlipidemia, and fatty liver. Rosiglitazone or troglitazone treatment did not reduce glucose or insulin levels, suggesting that white adipose tissue is required for the antidiabetic effects of TZDs. However, TZD treatment was effective in lowering circulating triglycerides and increasing whole body fatty acid oxidation in the A-ZIP/F-1 mice, indicating that this effect occurs via targets other than white adipose tissue. A-ZIP/F-1 mice have markedly increased liver PPAR gamma mRNA levels, which may be a general property of fatty livers. Rosiglitazone treatment increased the triglyceride content of the steatotic livers of A-ZIP/F-1 and ob/ob mice, but not the "lean" livers of fat-transplanted A-ZIP/F-1 mice. In light of this evidence that rosiglitazone acts differently in steatotic livers, the effects of rosiglitazone, particularly on hepatic triglyceride levels, should be examined in humans with hepatic steatosis.

Hepatosplenic candidiasis. A manifestation of chronic disseminated candidiasis.

Much progress has been made over the last decade in diagnosing and treating CDC, a chronic and debilitating infection that interferes with the delivery of intensive cytotoxic chemotherapy in patients with leukemia. The use of fluconazole prophylaxis in these patients has decreased the incidence of CDC dramatically. The greatest future challenges are gaining a better understanding of its pathophysiology, and the continued development of effective diagnostic and therapeutic strategies to treat this unusual manifestation of systemic candidiasis.

Intensity of antianginal therapy in patients referred for coronary angiography: a comparison of fee-for-service and health maintenance organization therapeutic strategies.

BACKGROUND: No formal criteria have been developed to guide medical therapy for angina prior to revascularization, and no comparisons have been made between health maintenance organization (HMO) and fee-for-service (FFS) hospitals with respect to angina treatment. HYPOTHESIS: Using a literature-based measure of medical intensity, we tested the hypothesis that there is no difference in anginal medical therapeutic intensity between HMO and FFS systems. METHODS: For each antianginal drug, we developed a model from which an intensity score between 0 and 100 could be calculated. Average and maximal daily doses of drug were fit to a sigmoid curve such that they represented scores of 50 and 99, respectively. Overall intensity scores were obtained by weighted and unweighted averaging of three scores from nitrates, calcium-channel blockers, and beta blockers. This model was applied to 199 patients undergoing angiography at an FFS and an HMO hospital. RESULTS: HMO patients were taking more classes of antianginal drug (1.9 vs. 1.0, p < 0.001). Overall unweighted (17.7 vs. 11.7, p = 0.02) and weighted (27.3 vs. 16.9, p = 0.003) intensity scores for both HMO and FFS patients were low. HMO intensity scores for the use of beta blockers were greater than FFS scores (19.2 vs. 9.6, p = 0.002). The intensity scores for the use of nitrates and calcium blockers were similar. CONCLUSIONS: Models for the measurement of anginal medical therapy intensity can provide important information regarding medical therapy prior to revascularization. The overall intensity of medical therapy was low in both health care systems. These findings have important implications for patient management, guideline development, and national healthcare policy.

Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3.

Uncoupling protein-3 (UCP3) is a mitochondrial protein that can diminish the mitochondrial membrane potential. Levels of muscle Ucp3 mRNA are increased by thyroid hormone and fasting. Ucp3 has been proposed to influence metabolic efficiency and is a candidate obesity gene. We have produced a Ucp3 knockout mouse to test these hypotheses. The Ucp3 (-/-) mice had no detectable immunoreactive UCP3 by Western blotting. In mitochondria from the knockout mice, proton leak was greatly reduced in muscle, minimally reduced in brown fat, and not reduced at all in liver. These data suggest that UCP3 accounts for much of the proton leak in skeletal muscle. Despite the lack of UCP3, no consistent phenotypic abnormality was observed. The knockout mice were not obese and had normal serum insulin, triglyceride, and leptin levels, with a tendency toward reduced free fatty acids and glucose. Knockout mice showed a normal circadian rhythm in body temperature and motor activity and had normal body temperature responses to fasting, stress, thyroid hormone, and cold exposure. The base-line metabolic rate and respiratory exchange ratio were the same in knockout and control mice, as were the effects of fasting, a beta3-adrenergic agonist (CL316243), and thyroid hormone on these parameters. The phenotype of Ucp1/Ucp3 double knockout mice was indistinguishable from Ucp1 single knockout mice. These data suggest that Ucp3 is not a major determinant of metabolic rate but, rather, has other functions.

Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice.

In lipoatrophic diabetes, a lack of fat is associated with insulin resistance and hyperglycemia. This is in striking contrast to the usual association of diabetes with obesity. To understand the underlying mechanisms, we transplanted adipose tissue into A-ZIP/F-1 mice, which have a severe form of lipoatrophic diabetes. Transplantation of wild-type fat reversed the hyperglycemia, dramatically lowered insulin levels, and improved muscle insulin sensitivity, demonstrating that the diabetes in A-ZIP/F-1 mice is caused by the lack of adipose tissue. All aspects of the A-ZIP/F-1 phenotype including hyperphagia, hepatic steatosis, and somatomegaly were either partially or completely reversed. However, the improvement in triglyceride and FFA levels was modest. Donor fat taken from parametrial and subcutaneous sites was equally effective in reversing the phenotype. The beneficial effects of transplantation were dose dependent and required near-physiological amounts of transplanted fat. Transplantation of genetically modified fat into A-ZIP/F-1 mice is a new and powerful technique for studying adipose physiology and the metabolic and endocrine communication between adipose tissue and the rest of the body.

Liposomal vincristine in relapsed non-Hodgkin's lymphomas: early results of an ongoing phase II trial.

OBJECTIVE: Vincristine is an active agent in lymphomas, but is often neurotoxic, and the resulting dose reductions have been associated with lower remission and survival rates in Hodgkin's disease. Liposomal vincristine (Onco-TCS) has prolonged half-life, reaches higher concentration in tumors and lymph nodes than in nerves, and administered at full doses appears to be less neurotoxic, and more active then free vincristine in mice bearing L-1210 and P-388 leukemias. We therefore explored its activity in relapsed non-Hodgkin's lymphomas (NHL) and acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Eligible patients had histologically proven relapse, age > or = 16 years, normal renal function, neutrophils > 500/microliter, platelets > 50,000/microliter, and no HIV infection, central nervous system disease, or serious neuropathy. Patients were treated with 2.0 mg/m2 of liposomal vincristine i.v. over 60 minutes q 14 days. Responders received up to 12 injections. RESULTS: Of the 51 registered patients, 35 are currently evaluable for response. Median age was 62 years (range 19-86), and 21 were male. The median number of prior regimens was 3 (range 1-10) and had included vincristine in all patients, of whom 51% were refractory to their last regimen. Serum LDH was high in 46%, and beta 2-microglobulin > 3.0 mg/l in 63% of patients. Of the 155 administered injections, 138 (89%) were at the 2.0 mg/m2 level. The median injected dose was 3.8 mg (range 2.6-4.8 mg), and median number of injections was 4 (range 1-12). Responses were seen in 14 of 34 (41%) patients with NHL (95% confidence intervals (95% CI) 25%-59%). Response rates were 10% for indolent, 71% for transformed, and 47% for aggressive NHL, but the 95% confidence intervals overlapped. Median progression-free survival was 5.5 months for responders. Grade 3-4 motor or sensory neuropathy was seen in 11, and caused termination of therapy in five patients. All five had prior neuropathy, two had previously received paclitaxel, one platinum, and two paclitaxel and platinum. Fever was detected in three patients, but there were no toxic deaths. CONCLUSIONS: Liposomal vincristine is active and well tolerated in this heavily pretreated population with relapsed NHL, but can be neurotoxic in a fraction of patients heavily exposed to prior neurotoxic agents. These data, if confirmed, would suggest a potential role for liposomal vincristine in the combination therapy of previously untreated patients with NHL.