Long-term event-free survivors after high-dose therapy and autologous stem-cell transplantation for low-grade follicular lymphoma.

Although follicular lymphoma (FL) is generally responsive to conventional-dose chemotherapy, improved survival in patients with this disease has been difficult to demonstrate. High-dose chemo/radiotherapy followed by autologous stem-cell transplantation (ASCT) can improve response rates, although its effects on survival remain controversial. Between 1990 and 2003, we transplanted 49 patients with low-grade FL at our institution. Twenty-two patients (45%) had undergone histologic transformation at the time of ASCT. In all, 44 patients (90%) had relapsed disease and five patients (10%) were resistant to chemotherapy at the time of transplantation. After ASCT, 30 patients (61%) were in complete remission (CR). The median overall survival (OS) has not been reached, while the median event-free survival (EFS) is 2.4 years. At a median follow-up of 5.5 years (longest 12.4 years), a plateau has been reached with 56% of patients remaining alive, and 35% event-free. ASCT was well tolerated except for two (4%) treatment-related deaths. In multivariable analysis, CR after ASCT and age less than 60 years are the best predictors of EFS and OS. ASCT is thus a safe therapeutic approach in FL, resulting in long-term EFS and OS for some patients, even with transformed disease.

Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes.

Matrix metalloproteinases (MMPs), proteolytic enzymes produced by monocytes, may contribute to atherosclerotic arterial wall remodeling and to plaque rupture. Because estrogen influences the synthesis of MMPs, we examined the effect of raloxifene, a selective estrogen receptor modulator, on monocyte MMP production. Human primary blood monocytes treated with raloxifene (10 micromol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor induced a 2- to 3-fold increase in MMP-1 production by monocytes. The enhancement of MMP-1 production by raloxifene in LPS-activated monocytes occurred through a cyclooxygenase-2- and prostaglandin E(2)-independent mechanism. Additionally, compared with monocytes acquired during the placebo phase, peripheral blood monocytes from 5 of 6 healthy postmenopausal women treated with raloxifene (60 mg daily for 1 month) in a clinical trial produced significantly higher levels of MMP-1 when the monocytes were activated with LPS. Furthermore, serum obtained during the raloxifene phase from 4 of these subjects, when added to control monocytes, significantly enhanced LPS-induced MMP-1 production compared with that from serum obtained during the placebo phase. In summary, raloxifene increases the production of MMP-1 in activated monocytes; this effect may be favorable in atherosclerotic arterial wall remodeling but unfavorable for plaque stability.

Shortened-duration GABA(A) receptor-mediated synaptic potentials underlie enhanced CA1 excitability in a chronic model of temporal lobe epilepsy.

Intracellular recording techniques were used to examine GABA(A) receptor-mediated synaptic inhibition in pyramidal cells of the CA1 region of the rat hippocampus in the post-self sustaining limbic status epilepticus model of temporal lobe epilepsy. Orthodromically evoked, monosynaptic inhibitory postsynaptic potentials were recorded in vitro following pharmacological blockade of ionotropic glutamate and GABA(B) receptors. Inhibitory postsynaptic potentials from epileptic tissue were kinetically altered relative to controls; both the 10-90% rise-time and width (measured at half-maximum amplitude) were reduced by approximately 50% resulting in significant shortening of duration. The degree of pyramidal cell hyperexcitability, assessed before pharmacological treatment as the number of action potentials evoked by maximum intensity afferent stimulation, correlated significantly with the magnitude of synaptic potential duration reduction determined following blockade of glutamatergic neurotransmission. Bath application of the benzodiazepine type 1 receptor agonist zolpidem reduced post-self sustaining limbic status epilepticus CA1 pyramidal cell hyperexcitability substantially (but not completely) via a marked increase in inhibitory postsynaptic potential area. Post-self-sustaining limbic status epilepticus inhibitory postsynaptic potentials which exhibited the most pronounced shortening were augmented by zolpidem to a greater degree than longer duration synaptic potentials. In contrast, zolpidem-induced augmentation of control inhibitor, postsynaptic potential area was much less robust. It is suggested that a deficiency in post-self-sustaining limbic status epilepticus GABA(A) receptor-mediated synaptic inhibition contributes to a state of partial disinhibition which is a major factor in enhanced CA1 excitability in chronic limbic epilepsy. Possible mechanisms underlying post-self-sustaining limbic status epilepticus kinetic abnormalities are discussed.

Aberrant neuronal physiology in the basal nucleus of the amygdala in a model of chronic limbic epilepsy.

Limbic epilepsy is a chronic condition associated with a broad zone of seizure onset and pathology. Studies have focused mainly on the hippocampus, but there are indications that changes occur in other regions of the limbic system. This study used in vitro intracellular recording and histology to examine alterations to the physiology and anatomy of the basal nucleus of the amygdala in a rat model of chronic limbic epilepsy characterized by spontaneously recurring seizures. Epileptic pyramidal neuron responses evoked by stria terminalis stimulation revealed hyperexcitability characterized by multiple action potential bursts and no evident inhibitory potentials. In contrast, no hyperexcitability was observed in amygdalar neurons from kindled (included as a control for seizure activity) or control rats. Blockade of ionotropic glutamate receptors unmasked inhibitory postsynaptic potentials in epileptic pyramidal neurons. Control, kindled and epileptic inhibitory potentials were predominantly biphasic, with fast and slow components, but a few cells exhibited only the fast component (2/12 in controls, 0/3 in kindled, 3/10 in epileptic). Epileptic fast inhibitory potentials had a more rapid onset and shorter duration than control and kindled. Approximately 40% of control neurons exhibited spontaneous inhibitory potentials; no spontaneous inhibitory potentials were observed in neurons from kindled or epileptic rats. A preliminary histological examination revealed no gross alterations in the basal amygdala from epileptic animals. These results extend previous findings from this laboratory that hyperexcitability is found in multiple epileptic limbic regions and may be secondary to multiple alterations in excitatory and inhibitory efficacy. Because there were no differences between control and kindled animals, the changes observed in the epileptic animals are unlikely to be secondary to recurrent seizures.

4-Hydroperoxycyclophosphamide purged autologous bone marrow transplantation in non-Hodgkin's lymphoma patients at high risk of bone marrow involvement.

Between June 1990 and January 1994, 19 patients with non-Hodgkin's lymphoma (NHL) at high risk for bone marrow involvement underwent 4-hydroperoxycyclophosphamide (4-HC) purged bone marrow transplantation. Eleven patients had low grade, seven intermediate grade and one high grade NHL and 7/19 patients had received three or more previous chemotherapeutic regimens. Four patients were transplanted in first partial remission (PR) and the remainder in responsive relapse. Fourteen patients had bone marrow (BM) involvement at diagnosis and/or at relapse. The median times to granulocyte and platelet recovery were 26 and 29 days, respectively. There were two toxic deaths and one complete responder developed secondary AML at 31 months post-BMT. Seventeen of 18 evaluable patients achieved a complete remission (CR) and one patient a PR. Fourteen patients (74%) are progression-free at a median follow-up of survivors of 34 months (range 29-55). The 3 year event-free (EFS) and overall survival (OS) probabilities are both 67%. No statistically significant difference was seen between EFS or OS and BM involvement or histologic grade at diagnosis. At 29 months, 4/7 patients with a morphologically involved BM harvest had relapsed or died compared to 1/12 patients with negative BM (P = 0.03). These results are encouraging and warrant further investigation of 4-HC purging in NHL.

Gemtuzumab ozogamicin (Mylotarg) monotherapy for relapsed AML after hematopoietic stem cell transplant: efficacy and incidence of hepatic veno-occlusive disease.

Gemtuzumab ozogamicin (GO) (Mylotarg, CMA-676) is a novel chemotherapeutic agent consisting of an anti-CD33 monoclonal antibody linked to calicheamicin, and is associated with a 30% response rate in patients with CD33-positive acute myeloid leukemia (AML) in first relapse. GO therapy has a 20% incidence of grade 3 or 4 hepatotoxicity, and has recently been associated with hepatic veno-occlusive disease (VOD). The efficacy and toxicity of GO in patients with AML who have relapsed after hematopoietic stem cell transplant (HSCT) is unknown, as this population was largely excluded from phase II studies. We reviewed the outcomes of eight consecutive patients with AML who received GO following relapse after HSCT. Two (25%) had responses to GO. One patient, who had had two previous HSCT and prior hyperbilirubinemia, developed severe VOD and died 14 days after GO therapy. The other seven patients did not meet diagnostic criteria for VOD. We conclude that GO can be safe and effective in patients who relapse following HSCT, but that caution is warranted in patients with multiple risk factors for VOD.

Ontogeny of altered synaptic function in a rat model of chronic temporal lobe epilepsy.

In the limbic status model of chronic temporal lobe epilepsy, hippocampal stimulation induces acute status epilepticus in rats; recurrent, spontaneous seizures develop following an asymptomatic silent period lasting several weeks. Previous work has shown increased excitability and decreased inhibition in CA1 pyramidal neurons in chronically epileptic animals. To determine the relationship of altered cellular responses to seizure onset, in vitro intracellular recording was used to follow the evolution of changes in synaptic physiology occurring during the seizure-free silent period. Pyramidal cells displayed increasing epileptiform activity throughout the period investigated, 3-14 days following status; the mean number of evoked action potentials from 1.1+/-0.05 in control cells to 2.4+/-0.4 early (3 days after status) and 4. 3+/-0.7 late (14 days) in the silent period. Monosynaptic inhibitory postsynaptic potentials mediated by gamma-aminobutyric acid-A receptors in silent period cells differed markedly from controls. Area, rise time, and duration of these potentials decreased by 40-60% within 3 days following status and to values commensurate with chronically epileptic animals in 7 to 10 days. gamma-Aminobutyric acid-B receptor-mediated IPSPs diminished more gradually in the silent period, reaching a minimum at day 14. In contrast, presynaptic gamma-aminobutyric acid-B receptor function showed maximum impairment 3 days after status. The benzodiazepine type 1 receptor agonist zolpidem reduced hyperexcitability in both silent period and chronically epileptic cells, but was more effective at unmasking the underlying IPSP in silent period neurons. The results indicate that changes in different components of pyramidal cell inhibitory synaptic physiology associated with chronic epilepsy in this model evolve individually at different rates, but are all complete before seizure onset. Although the results do not imply causality, they do suggest that the development of physiological changes in CA1 pyramidal cells may contribute to the lag period preceding the onset of chronic seizures.

Functional anatomy of limbic epilepsy: a proposal for central synchronization of a diffusely hyperexcitable network.

The limbic/mesial temporal lobe epilepsy syndrome has been defined as a focal epilepsy, with the implication that there is a well defined focus of onset, traditionally centered around the hippocampus. The pathology of the hippocampus in this syndrome has been well described and a number of physiological abnormalities have been defined in this structure in animal models and humans with epilepsy. However, anatomical and physiological abnormalities have also been described in other limbic sites in this form of epilepsy. Previous studies have shown broadly synchronized or multifocal seizure onset within the limbic system of the animal models and human patients. We hypothesized that the epileptogenic circuit for the initiation of seizures was distributed throughout the limbic system with a possible central synchronizing process. In vitro studies showed that multiple limbic sites in epileptic animals (hippocampus, entorhinal cortex, piriform cortex and amygdala) have epileptiform changes with prolonged depolarizations and multiple superimposed action potentials. In vivo studies revealed that thalamic stimulation yields short latency excitatory responses in the entorhinal cortex and hippocampus. In addition, in epileptic animals, thalamic stimulation caused epileptiform responses in the hippocampus. Based on the findings of this study and on previous anatomy and physiology reports, we hypothesize that the process of seizure initiation involves broad circuit interactions involving multiple independent limbic structures, and that the midline thalamus may act as a physiological synchronizer. We offer a new proposal for the functional anatomy of limbic epilepsy that takes widespread hyperexcitability in the limbic system and the potential for thalamic synchronization into consideration.

Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 1. Chemical composition of mainstream smoke.

A new-technology cigarette has been developed. While the new cigarette burns some tobacco, it does not use tobacco as the fuel to sustain combustion and provide heat to the cigarette. Rather, the new cigarette primarily heats tobacco thereby reducing products of smoke formation mechanisms such as tobacco combustion, tobacco pyrolysis and pyrosynthesis. The mainstream smoke composition from a cigarette based on the new design (TOB-HT) has been characterized in comparative chemical testing with two reference cigarettes using the FTC puffing regimen. Thermal properties, UV absorption characteristics, elemental composition and materials balance studies all suggest a simplified smoke aerosol. Twenty-five smoke constituents ("target compounds") identified by the scientific community as compounds that may contribute to the diseases statistically associated with smoking have also been measured. Mainstream smoke concentrations of most target compounds are significantly lower with the TOB-HT cigarette when compared with reference cigarettes in the ultra-light "tar" and light "tar" categories. Taken together, chemical analysis results suggest simplified TOB-HT smoke chemistry with marked reductions in specific chemicals reported to be biologically active.

Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 1. Chemical composition of mainstream smoke.

A new-technology cigarette has been developed. While the new cigarette burns some tobacco, it does not use tobacco as the fuel to sustain combustion and provide heat to the cigarette. Rather, the new cigarette primarily heats tobacco thereby reducing products of smoke formation mechanisms such as tobacco combustion, tobacco pyrolysis and pyrosynthesis. The mainstream smoke composition from a cigarette based on the new design (TOB-HT) has been characterized in comparative chemical testing with two reference cigarettes using the FTC puffing regimen. Thermal properties, UV absorption characteristics, elemental composition and materials balance studies all suggest a simplified smoke aerosol. Twenty-five smoke constituents ("target compounds") identified by the scientific community as compounds that may contribute to the diseases statistically associated with smoking have also been measured. Mainstream smoke concentrations of most target compounds are significantly lower with the TOB-HT cigarette when compared with reference cigarettes in the ultra-light "tar" and light "tar" categories. Taken together, chemical analysis results suggest simplified TOB-HT smoke chemistry with marked reductions in specific chemicals reported to be biologically active.

Stem cell transplantation for metastatic breast cancer: analysis of tumor contamination.

The purpose of this study was to determine the efficacy, engraftment kinetics, effect of bone marrow tumor contamination, and safety of high-dose therapy and granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood progenitor cell (PBPC) support for patients with responding metastatic breast cancer. Forty two patients underwent G-CSF (10 microg/kg) stimulated PBPC harvest. PBPC and bone marrow aspirates were analyzed by histologic and immunocytochemical methods for tumor contamination. Thirty-seven patients received high-dose therapy consisting of cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) given as an infusion over 4 d followed by PBPC reinfusion and G-CSF (5 microg/kg) support. No transplant related deaths or grade 4 toxicity was recorded. CD34+ cells/kg infused was predictive of neutrophil and platelet recovery. With a median follow-up of 38 months, three year survival was 44% with relapse-free survival of 19%. Histological bone marrow involvement, found in 10 patients, was a negative prognostic factor and was associated with a median relapse-free survival of 3.5 months. Tumor contamination of PBPC by immunohistochemical staining was present in 22.5% of patients and found not to be correlated with decreased survival. G-CSF stimulated PBPC collection followed by a single course of high dose chemotherapy and stem cell infusion with G-CSF stimulated marrow recovery leads to rapid, reliable engraftment with low toxicity and promising outcome in women with responding metastatic breast cancer.

The right stuff.

It may seem a little out of place to recall a document calling on the nursing profession to grant some basic rights to its student population, considering the momentous bids for freedom and democracy we've recently seen in other parts of the world.

Enrolled role.

I have followed with great interest the debate on the future of the enrolled nurse for sometime.

Complaints can improve care.

Complaints are often seen as being entirely negative. However, they could be turned to the advantage of an organisation by allowing it to rectify its shortcomings. A complaints procedure can form part of a quality improvement cycle. This paper discusses why nurses are often unable to see the benefits of complaints and how they can be used to improve patient care in the future.

Rationales for rationing health care in the NHS.

Rationing of health-care resources has moved from being a theoretical possibility to becoming a practical reality, a move that has been made more explicit since the introduction of a market-oriented approach to the management of the health service. The following two papers provide an introduction to the debate surrounding health-care rationing and make some suggestions on how the subject can be placed under more explicit democratic controls.

The collapse of the conventional career.

The Collapse of the Conventional Career was commissioned by the ENB as 'the first in a number of discussion papers in which important issues were to be explored so that the professional could debate them fully' (Jean Hooper, chairwoman of the ENB, in her foreword). The author Celia Davis' premise was that, conventionally, a career was seen as comprising full-time work carried out without a break in service. Because many female nurses could not fulfil this expectation they were disadvantaged in a number of ways. In order to address the problems faced in practice by those who would not be able, for various reasons, to undertake a conventional career, Professor Davis looked at what changes in thinking and policy would be required.

Stem cell collection in patients with multiple myeloma: impact of induction therapy and mobilization regimen.

Lenalidomide is an active treatment for multiple myeloma (MM) and is increasingly used as part of the initial treatment of this disease. Recent reports have suggested decreases in the number of CD34+ cells collected and increases in the failure rate among patients whose initial therapy contained lenalidomide when mobilized with G-CSF alone. A retrospective data analysis of 364 patients with MM who underwent stem cell mobilization and attempted harvest at the Hospital of the University of Pennsylvania between January 2002 and December 2007 was performed. Forty-three of the patients received lenalidomide in their induction regimen, and were mobilized with either CY and G-CSF or G-CSF alone. The number of apheresis cycles and the failure rate were lower, whereas the mean number of collected stem cells was higher in patients who were mobilized with CY and G-CSF in comparison with G-CSF alone. This suggests that lenalidomide does not prevent the harvest of adequate numbers of CD34 cells for autologous stem cell transplant, but mobilization with G-CSF and CY may be required to obtain adequate numbers of stem cells. Finally, in our study, the number of lenalidomide cycles did not correlate with stem cell yield.