Sleep interventions for osteoarthritis and spinal pain: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To determine if sleep interventions improve pain and sleep in people with osteoarthritis (OA) and/or spinal pain compared to control/placebo. DESIGN: Medline, Embase, AMED, PsycINFO, CENTRAL, CINAHL and PEDro were searched from their inception date to July 2017. Keywords relating to "sleep", "OA", "spinal pain", and "randomized controlled trial (RCT)" were combined. Included RCTs investigated the use of sleep interventions for people with OA and/or spinal pain, and measured at least one sleep and health related outcome. Meta-analyses were performed to pool mean differences for pain and sleep quality. PROSPERO: CRD42016036315. RESULTS: Of 1445 unique records, 24 studies were included. Sixteen studies included participants with spinal pain, seven with OA, and one included a mixed population. Sleep interventions included established sleep interventions (ESI) [cognitive behavioural therapy (CBT) and pharmacological interventions], and a range of others. Intervention periods ranged from 4 to 10 weeks. Thirteen studies were of moderate to high quality (PEDro ≥ 6/10). Due to high heterogeneity between studies we also performed sub-group and sensitivity analyses. ESI decreased Insomnia Severity Index (ISI) for people with low back pain (LBP) (pooled mean difference: -6.78/28, 95% confidence interval (95% CI): [-9.47, -4.09], I2 = 40%) and OA (-2.41, [-4.19, -0.63], 0%). However ESI decreased pain for people with LBP (pooled mean difference: visual analogue scale (VAS) -12.77/100, 95% CI: [-17.57, -7.97], I2 = 0%), but not OA (-2.32, [-7.18, 2.54], 27%). CONCLUSION: ESI appeared to improve sleep and pain for people with LBP, and sleep for people with OA. However more vigorous studies need to be conducted.

Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research.

For adults with high-risk or recurrent ALL who lack a suitable sibling donor, the decision between autologous (Auto) and unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) is difficult due to variable risks of relapse and treatment-related mortality (TRM). We analysed data from two transplant registries to determine outcomes between Auto and URD HSCT for 260 adult ALL patients in first (CR1) or second (CR2) CR. All patients received a myeloablative conditioning regimen. The median follow-up was 77 (range 12-170) months. TRM at 1 year post transplant was significantly higher with URD HSCT; however, there were minimal differences in TRM according to disease status. Relapse was higher with Auto HSCT and was increased in patients transplanted in CR2. Five-year leukemia-free (37 vs 39%) and overall survival (OS) rates (38 vs 39%) were similar for Auto HSCT vs URD HSCT in CR1. There were trends favoring URD HSCT in CR2. The long-term follow-up in this analysis demonstrated that either Auto or URD HSCT could result in long-term leukaemia-free survival and OS for adult ALL patients. The optimal time (CR1 vs CR2) and technique to perform HSCT remains an important clinical question for adult ALL patients.

Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients.

The current study assessed renal function based on medical records in adult hematopoietic stem cell transplant (HSCT) recipients with proven or probable invasive fungal infection (IFI) transplanted between 1995 and 2000. We confirm that amphotericin B deoxycholate (AmB-d) is nephrotoxic in a large percentage of HSCT recipients. Due to nephrotoxicity, defined as serum creatinine (SCr) >2.5 mg/dl or a 100% increase in SCr from baseline, 88% of patients treated with AmB-d were switched to a lipid formulation of amphotericin B (LFAB). In total, 53% of patients initiated on AmB-d were switched within the first week of therapy. Significantly more patients (70.6%) treated with AmB-d experienced a 100% increase in SCr from baseline compared to patients treated with either AmBisome (44.4%) or Abelcet (41.2%). A Cox Proportional Hazards Model revealed that, compared to patients initiated on AmBisome or Abelcet, the risk of nephrotoxicity (RR=1.5 vs AmBisome; RR=1.7 vs Abelcet), dialysis (RR=2.4 vs AmBisome; RR=1.4 vs Abelcet), and death (RR=2.0 vs AmBisome; RR=1.1 vs Abelcet) were all increased for patients initiated on AmB-d. Study results suggest that renal function improves and mortality declines when an LFAB is given to HSCT patients as initial therapy rather than as second-line therapy, the current practice.

Long-term follow-up of intensive ara-C-based chemotherapy followed by bone marrow transplantation for adult acute lymphoblastic leukemia: impact of induction Ara-C dose and post-remission therapy.

We report single institution outcome of brief, intensive ara-C-based chemotherapy using bone marrow transplantation as primary intensification for untreated adult patients with acute lymphoblastic leukemia (ALL). Overall disease-free and overall survival were inferior to those reported with prolonged chemotherapy modeled on pediatric protocols. Survival and disease-free survival were superior for patients receiving allogeneic BMT compared with chemopurged autologous transplant or maintenance chemotherapy (patients ineligible for or declining BMT). In multivariate analysis, non-L2-FAB, higher ara-C dose, absence of CNS disease, non-Ph1+ karyotype, allogeneic BMT, T cell phenotype, and younger age were associated with improved disease-free survival. Autologous BMT was not superior to chemotherapy, and appears unlikely to provide adequate curative treatment for most adult ALL patients if not followed by maintenance.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

The effect of graft purging with 4-hydroperoxycyclophosphamide in autologous bone marrow transplantation for acute myelogenous leukemia.

BACKGROUND: Autologous bone marrow transplantation is an important therapy for patients with acute myelogenous leukemia (AML). However, leukemia in the graft may contribute to posttransplant relapse. Treatment of the graft with 4-hydroperoxycyclophosphamide (4HC) is sometimes used to decrease numbers of infused leukemia cells (4HC purging). No large controlled trials evaluating efficacy and toxicity of 4HC purging are reported. METHODS: We studied 294 patients reported to the Autologous Blood and Marrow Registry receiving either a 4HC-purged (n = 211) or unpurged (n = 83) autograft for AML in first (n = 209) or second (n = 85) remission. Analyses were restricted to patients transplanted less than 6 months after achieving remission. Using Cox proportional hazards regression, we compared time to treatment failure (death or relapse, inverse of leukemia-free survival) after 4HC-purged vs unpurged transplants while controlling for important prognostic factors. RESULTS: Median duration of posttransplant neutropenia was 40 (range, 10-200) days after 4HC-purged transplants and 29 (9-97) days after unpurged transplants (p < 0.01). Transplant-related mortality was similar in the two groups. In multivariate analysis, patients receiving 4HC-purged transplants had lower risks of treatment failure than those receiving unpurged transplants (relative risk, 0.69, p = 0.12 in the first posttransplant year; relative risk, 0.28, p < 0.0001 thereafter). Adjusted three-year probabilities of leukemia-free survival (95% confidence interval) were 56% (47-64%) and 31% (18-45%) after 4HC-purged and unpurged transplants in first remission, respectively. Corresponding probabilities in second remission were 39% (25-53%) and 10% (1-29%). CONCLUSION: Grafts purged with 4HC are associated with higher leukemia-free survival after autologous bone marrow transplants for AML.

Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia.

Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID(50), 1-2 mM). Higher doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusion repeated every 28 days in a Phase I dose escalation study. The maximum tolerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversible neurocortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; median steady-state plasma concentration at this dose was 0.29 +/- 0.16 mM. Although no patients achieved complete or partial remission, four patients achieved hematological improvement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets and decrements in circulating blasts. Monitoring of the percentage of clonal cells using centromere fluorescence in situ hybridization over the course of PB administration showed that hematopoiesis remained clonal. Hematological response was often associated with increases in both colony-forming units-granulocyte-macrophage and leukemic colony-forming units. PB administration was also associated with increases in fetal erythrocytes. These data document the safety of continuous infusion PB and provide preliminary evidence of clinical activity in patients with myeloid malignancies.

Erythropoietin in stem cell transplantation.

Anemia is universal after allogeneic and autologous stem cell transplantation, with both increased red cell utilization and decreased production playing a role. This anemia sometimes is associated with a relative erythropoietin deficiency. In allogeneic stem cell transplantation, randomized trials have demonstrated improved erythropoiesis and a decrease in red cell transfusions in recombinant human erythropoietin (rHuEPO)-treated patients. Studies of rHuEPO in patients undergoing autologous stem cell transplants, however, have not shown a benefit. The role of rHuEPO in stem cell mobilization and treatment of delayed erythropoiesis has yet to be defined and further studies are needed.

Current treatments for infection in neutropenic patients with hematologic malignancy.

Neutropenic patients with cancer are a heterogeneous group of patients who carry a variable risk for infection. When such patients present with fever, appropriate empiric antibiotic therapy is initiated and continued until clinical improvement or clinical or microbiologic data direct a modification in treatment. As the duration of neutropenia increases, so does the need for antimicrobial modifications. Changes in therapy may include antimicrobials directed against gram-positive bacteria, resistant gram-negative bacteria, or fungi. Because of the high risk for colonization by vancomycin-resistant enterococci, vancomycin use is restricted as first-line empiric therapy unless the patient is at a high risk for serious gram-positive infection. Usually in the setting of neutropenia, gram-positive infections are of low virulence. Prophylactic antibiotic therapy may increase the selection of resistant strains and should be avoided. Antibiotic therapy should always be combined with prudent infection-control measures, such as aseptic practices, barrier isolation, handwashing, removal of infected catheters, and infection monitoring. In the immunocompromised patient with cancer and neutropenia, all infections should be treated, with the extent, duration, and site of treatment being directed by risk stratification and specific pathogen identification. Patients with neutropenia are at risk for severe morbidity and mortality related to infection.

A dose-finding study of liposomal daunorubicin with CVP (COP-X) in advanced NHL.

BACKGROUND: Standard therapy for lymphoma consists of a cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP) combination regimen. Liposomal daunorubicin (DaunoXome) is an alternative to doxorubicin for patients with lymphoma because of its more favorable safety profile and potentially more selective uptake in lymphoma. The objectives of this study were to determine the maximum tolerated dose (MTD) of liposomal daunorubucin with CVP (COP-X) and the tolerability of the regimen in patients with indolent lymphoma. PATIENTS AND METHODS: Patients with low-grade and intermediate-grade lymphoma having adequate cardiac, hepatic, and renal function were enrolled. Patients received C 750 mg/m2, V 1.4 mg/m2 (maximum 2.0 mg), and liposomal daunorubicin 50-100 mg/m2 i.v. on day 1 and P 100 mg p.o. on days 1-5. MTD was the liposomal daunorubicin dose associated with 20% dose-limiting toxicity (ANC < 500/mm3 for > 5 days or febrile neutropenia). RESULTS: Twenty patients, median age 59 years, were treated. The liposomal daunorubicin MTD combined with CVP was 70-80 mg/m2, depending on patient population. No significant non-hematologic toxicity occurred. Response rate was 44% (2 complete and 5 partial responses). CONCLUSIONS: A liposomal daunorubicin dose of 80 mg/m2 in the COP-X regimen was well tolerated with little nonhematologic toxicity.

Growth characteristics of fibroblasts isolated from the trunk and distal aspect of the limb of horses and ponies.

OBJECTIVE: To determine if there is a difference in in vitro growth of fibroblasts isolated from the trunk and distal aspect of the limb of horses and ponies. To determine the effects of a corticosteroid and monokine on in vitro growth of fibroblasts isolated from the trunk and distal aspect of the limb of horses and ponies. STUDY DESIGN: Growth of fibroblasts from tissues harvested from the trunk and limb were compared from horse and pony samples grown in control media and control media with triamcinolone or monokine added. ANIMALS OR SAMPLE POPULATION: Dermal and subcutaneous tissue from 22 horses and 17 ponies of various ages and breeds. METHODS: Fibroblast growth was assessed by tritiated thymidine uptake using standard cell culture techniques. The effect of a monokine or triamcinolone plus control media were compared with control media for fibroblast growth. RESULTS: Fibroblast growth from tissues isolated from the horse limb was significantly less than growth from the horse trunk and the limb and trunk of ponies. Monokine was more effective than triamcinolone in suppressing fibroblast growth from tissues isolated from the trunk and limb in both horses and ponies. CONCLUSIONS: There are growth differences in fibroblasts isolated from the limb of horses compared with those isolated from the trunk and from the limb and trunk of ponies. CLINICAL RELEVANCE: The difference in fibroblast growth from tissues isolated from the trunk and limb of horses and ponies may provide evidence for the difference reported in the healing characteristics of limb wounds in horses and ponies. Influencing fibroblast growth may provide a key to controlling the development of exuberant granulation tissue in horses and ponies.

Refinements of environmental assessment during an outbreak investigation of invasive aspergillosis in a leukemia and bone marrow transplant unit.

OBJECTIVES: To investigate an outbreak of aspergillosis in a leukemia and bone marrow transplant (BMT) unit and to improve environmental assessment strategies to detect Aspergillus. DESIGN: Epidemiological investigation and detailed environmental assessment. SETTING: A tertiary-care university hospital with a 37-bed leukemia and BMT unit PARTICIPANTS: Leukemic or BMT patients with invasive aspergillosis identified through prospective surveillance and confirmed by chart review. INTERVENTIONS: We verified the diagnosis of invasive fungal infection by reviewing medical charts of at-risk patients, performing a case-control study to determine risk factors for infection, instituting wet mopping to clean all floors, providing N95 masks to protect patients outside high-efficiency particulate air (HEPA)-filtered areas, altering traffic patterns into the unit, and performing molecular typing of selected Aspergillus flavus isolates. To assess the environment, we verified pressure relationships between the rooms and hallway and between buildings, and we compared the ability of large-volume (1,200 L) and small-volume (160 L) air samplers to detect Aspergillus spores. RESULTS: Of 29 potential invasive aspergillosis cases, 21 were confirmed by medical chart review. Risk factors for developing invasive aspergillosis included the length of time since malignancy was diagnosed (odds ratio [OR], 1.0; P=.05) and hospitalization in a patient room located near a stairwell door (OR, 3.7; P=.05). Two of five A. flavus patient isolates were identical to one of the environmental isolates. The pressure in most of the rooms was higher than in the corridors, but the pressure in the oncology unit was negative with respect to the physically adjacent hospital; consequently, the unit acted essentially as a vacuum that siphoned non-HEPA-filtered air from the main hospital. Of the 78 samples obtained with a small-volume air sampler, none grew an Aspergillus species, whereas 10 of 40 cultures obtained with a large-volume air sampler did. CONCLUSIONS: During active construction, Aspergillus spores may have entered the oncology unit from the physically adjacent hospital because the air pressure differed. Guidelines that establish the minimum acceptable pressures and specify which pressure relationships to test in healthcare settings are needed. Our data show that large-volume air samples are superior to small-volume samples to assess for Aspergillus in the healthcare environment.

Philadelphia chromosome-negative engraftment after autologous transplantation with granulocyte-macrophage colony-stimulating factor for chronic myeloid leukemia.

Autologous bone marrow transplantation (BMT) has not been curative in chronic myeloid leukemia (CML), because of the inability to purge CML from the autograft and the absence of the allogeneic T cell-mediated antileukemic activity. However, recent advances demonstrate that normal progenitors can be selected from CML marrows by a variety of techniques, including isolation by their small size. Furthermore, we found that myeloid growth factors have a potent antileukemic effect against CML progenitors in vitro by inducing their terminal differentiation. Based on these data, we initiated a trial of autologous BMT in patients with high-risk CML. Autografts were processed in an attempt to enrich for normal progenitors, first by isolating small cells by counterflow centrifugal elutriation and then incubating them in granulocyte-macrophage colony-stimulating factor (GM-CSF) for 72 hours. After a conditioning regimen of busulfan and cyclophosphamide, all patients received GM-CSF daily for 2 months. The median age of the 13 patients in the trial was 45 years (range 17-56 years). The median duration of disease before BMT was 24 months (range 13-72 months). Eight patients were in chronic phase (CP), and five were in accelerated phase (AP). All patients failed to achieve a cytogenetic response to interferon-alpha and were 100% Philadelphia chromosome (Ph)+ before BMT. There were three transplant-related deaths, all AP patients. All of the remaining 10 patients engrafted with some degree of Ph- hematopoiesis; despite high-risk features, nine patients engrafted 100% Ph-. All patients relapsed cytogenetically at a median of 6 months (range 4-22 months). These results demonstrate that autologous BMT can consistently induce complete Ph- engraftment in CP patients. GM-CSF appears to produce a clinical antileukemic effect against CML after autologous BMT.

Vancomycin-resistant enterococci: the clinical effect of a common nosocomial pathogen.

Enterococcus spp. is now the third most common pathogen among hospitalized patients, accounting for nearly 12% of nosocomial infections. Enterococcus faecalis is the most prevalent enterococcal species (85%-89%), whereas Enterococcus faecium accounts for 10%-15% of enterococcal isolates. Only 5% of E. faecalis isolates are resistant to glycopeptides. E. faecium has also been shown to be resistant to nonglycopeptide compounds, such as penicillins (97%), high-level gentamicin (52.1%), and high-level streptomycin (58.3%). Numerous risk factors for vancomycin-resistant enterococci (VRE) have been identified, including as length of hospital- or ICU-stay, proximity to a hospitalized, colonized VRE, patient severity of illness, renal failure, recent surgery, immunosuppression, and organ recipient status. An important risk factor is prior exposure to antibiotics such as vancomycin, ceftazidime, ciprofloxacin, and metronidazole, as well as the number and duration of recent antibiotics. Interventions to reduce nosocomial VRE cross-transmission have also been studied. Using gowns in addition to gloves diminished the incidence of VRE in one study, but had a negligible effect in a second study. Studies have shown that in many cases (> 60%) vancomycin usage is inappropriate. While controlling the use of vancomycin alone has only variably diminished VRE colonization, other efforts such as narrowing the spectrum of antibiotics, antiseptics, and reducing immunosuppression may be salutary. Attempts to eradicate VRE intestinal carriage with enteral agents (bacitracin, tetracycline + rifampin, novobiocin) have been reported but seem to have only a transient effect. Non-antimicrobial interventions such as removal of intravenous or bladder catheters and/or surgical or percutaneous drainage may be beneficial. In addition, the development of new antimicrobial agents such as streptogramins, glycopeptides, everninomicins, and oxazalididones will hopefully play an important role in reducing morbidity from these pathogens.

Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: Hodgkin's disease patients who never achieve complete remission with conventional chemotherapy (i.e., those with primary induction failure) have a poor prognosis. Some subjects who receive high-dose therapy with autologous hematopoietic progenitor-cell infusion experience prolonged progression-free survival. PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 122 Hodgkin's disease patients who failed to achieve complete remission after one or more conventional therapy regimens and subsequently received an autotransplant between 1989 and 1995 were reviewed. RESULTS: Median age was 27 years (range, 7 to 57 years). Median time from diagnosis to transplantation was 14 months (range, 5 to 38 months). Most patients received high-dose chemotherapy without radiation for pretransplantation conditioning (n = 107). The regimen most frequently used was cyclophosphamide, carmustine, and etoposide (n = 47). Fifteen patients received total-body irradiation (n = 15). The graft consisted of bone marrow (n = 86), blood stem cells (n = 25), or both (n = 11). The 100-day mortality was 12% (95% confidence interval, 7% to 19%). Sixty patients (50%) were considered to have achieved complete remission after autotransplantation; 37 of these had negative imaging studies, whereas scan abnormalities of unknown significance persisted in 23 patients. Twenty-seven patients (22%) had no response or progressive disease after transplantation. Probabilities of progression-free and overall survival at 3 years were 38% (95% confidence interval, 28% to 48%) and 50% (95% confidence interval, 39% to 60%), respectively. In multivariate analysis, "B" symptoms at diagnosis and poor performance score at transplantation were adverse prognostic factors for outcome. CONCLUSION: Autotransplants should be considered for patients with Hodgkin's disease who do not achieve complete remission with conventional therapy.

A phase II "window" study of topotecan in untreated patients with high risk adult acute lymphoblastic leukemia.

To further evaluate the activity of topotecan (TPT) in acute leukemia, TPT was administered (2.1 mg/m2/day for 5 days by continuous i.v. infusion) to adult patients with previously untreated acute lymphoblastic leukemia (ALL) with high-risk features (13 patients) or relapsed ALL (1 patient). Patients achieving a partial response or significant hematological improvement received a second course. All patients subsequently received standard treatment for ALL. Because complete response was achieved in only 1 of 14 patients, the study was terminated prematurely. An additional patient achieved minimal response, and a third patient normalized her hemogram despite ongoing leukemia in the marrow. Overall, six patients had significant hematological improvement (normalization of platelet and/or absolute neutrophil count). Two patients expired due to infections during induction chemotherapy. The primary nonhematological toxicities were mucositis and diarrhea. Exposure to TPT did not appear to influence the response to subsequent standard chemotherapy. The mean steady-state TPT plasma concentration, 16.1+/-1 nM, overlapped the range of LD90 values of primary human leukemia specimens. Cellular topo I content varied over a 3-fold range, encompassing levels found previously in relapsed patients. No relationship was found between topo I expression and markers of cellular proliferation or response to therapy. In contrast, low expression of the apoptosis inhibitor Bcl-2 was associated with response to TPT therapy. TPT has significant, albeit modest, single-agent activity against high-risk adult ALL. This study demonstrates the feasibility of evaluating promising new therapeutic agents in untreated patients with acute leukemia at high risk for failure with conventional therapy.