Cervical musculoskeletal and sensorimotor impairments 4 weeks to 6 months following mild traumatic brain injury: An observational cohort study.

BACKGROUND: Clinically relevant scores of neck disability have been observed in adults post mild traumatic brain injury (mTBI), even in those who initially report to be recovered. Potentially cervical musculoskeletal and/or cervical sensorimotor impairments may underlie these persistent symptoms post mTBI. OBJECTIVE: To determine whether cervical impairments exist beyond expected recovery times following concussion compared to healthy controls (HC). STUDY DESIGN: Observational cohort study. METHODS: Participants aged 18-60 years consisting of 39 HC, and 72 individuals, 4 weeks to 6 months post mTBI of which 35 considered themselves asymptomatic (Asymp), and 37 symptomatic (Symp). Cervical outcome measures included range and velocity of motion, flexor muscle endurance, presence of at least one dysfunctional cervical joint, joint position error -neutral and torsion, movement accuracy, smooth pursuit neck torsion test (SPNT) and balance. RESULTS: Individuals in the Symp mTBI group demonstrated significantly reduced: flexion and rotation range, rotation velocity, flexor endurance and movement accuracy as well as increased postural sway and a higher percentage had positive cervical joint dysfunction (p < 0.01]. The mTBI group who considered themselves recovered (Asymp)demonstrated significantly lower rotation range, flexor endurance, and a higher percentage had positive cervical joint dysfunction and positive SPNT (p < 0.05) compared to HCs. CONCLUSION: Individuals reporting symptoms post mTBI demonstrated cervical spine musculoskeletal and sensorimotor impairments beyond expected recovery times. Those not reporting symptoms had fewer but some cervical impairments. The need for a comprehensive neck assessment should be considered, perhaps even in those not reporting symptoms.

Change in a clinical measure of cervical movement sense following four weeks of kinematic training.

BACKGROUND: Training targeted towards improving cervical movement accuracy is an effective strategy in the management of neck pain. Relatively complex measures have been validated to measure this in research although a simple clinical measure using a head mounted laser tracing a standardised pattern has been shown to be reliable. It is not known if this method demonstrate clinically meaningful change to training. OBJECTIVE: To assess change responsiveness of the clinical cervical movement sense (CCMS) test following home kinematic training (KT). STUDY DESIGN: Pre-post treatment observational study. METHODS: The CCMS measure was assessed in 56 patients with chronic neck pain (41 intervention, 15 control) at baseline and 4 weeks post intervention by blinded assessors. Task completion time and error number were assessed reviewing video of the performances. Change pre-post intervention was compared between groups. RESULTS: There was a significantly greater mean improvement in the intervention (-9.2 ± 9.3) seconds) for completion time and combined time and error (-13.3 ± 16) compared to the control group for time (-2.0 ± 9.8) and combined time and error (-1.8 ± 14) with moderate to high effect sizes (Cohen's d 0.76). There was a non-significant trend for decreased number of errors in the intervention (-4.1 ± 9.0) compared to control group (0.2 ± 8.3). CONCLUSION: Completion time of the CCMS test appears to be able to demonstrate meaningful change following four weeks of KT. This further supports its clinical utility as a measure of cervical movement accuracy and provides direction for future clinical use.

Can a simple clinical test demonstrate head-trunk coordination impairment in neck pain?

BACKGROUND: Sensorimotor impairment in neck pain sufferers is well established. Recent research has identified impairment in head and trunk co-ordination in this population. Presently, no clinically appropriate testing exists to quantify such impairment. OBJECTIVE: To determine if a simple and clinically relevant test of head-trunk co-ordination can identify dysfunction in neck pain subjects when compared to healthy controls. STUDY DESIGN: Cross-sectional observational study. METHODS: Thirty-one neck pain and 29 healthy control subjects were assessed using head- and chest-mounted lasers with a target positioned 90 cm away. Subjects were required to rotate the trunk at least 45° with the head laser to be kept as accurately as possible in the centre of the target while sitting and standing. Maximal deviation of the head to the left and right of the target's centre with each trunk movement was measured. RESULTS: The neck pain group demonstrated significantly greater head deviation from the centre in all but one test direction (p= <0.03). Head deviation to the same side as trunk rotation was larger in the neck pain group for both sitting and standing (p= <0.01). No significant differences existed between testing in sitting and standing. CONCLUSION: Differences in trunk-head control exist in persons suffering from neck pain compared to healthy individuals, which can be demonstrated using simple equipment suggesting clinical utility of the measure. Performing the task in standing would seem most suitable as it can avoid influence by reduced thoracic mobility. Further research is required to establish the clinical suitability of this test.

Guidelines on obtaining consent for systemic anti-cancer therapy in adults.

This guideline, initially drawn up for use in the UK, is essentially based on ethical principles and should be applicable across other jurisdictions. The document specifically addresses the issues which surround obtaining consent from adults for the administration of systemic anti-cancer therapy in the haemato-oncology setting. Consenting to a treatment or procedure is a complex medical, ethical, and legal issue. The process of obtaining consent and the general steps that should be taken by the healthcare professional involved in obtaining consent from a patient are discussed, and the potential legal and ethical pitfalls which can be encountered are outlined. Of fundamental importance are the requirements that agreement must be given voluntarily, based on adequate information, and the patient must have the ability to understand and retain the information given and be in a position to use it in order to reach a decision. The consenting process should include an explanation of the expected outcomes and possible side effects of treatment even if these are unlikely to occur, and the nature of the consenting process undertaken should be clearly documented. Obtaining consent in an emergency situation is also discussed, as is the process of consenting in individuals with impaired capacity or special needs. Withdrawal of consent and refusal of treatment are also considered.

Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin.

Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1-3.5 mg/L), whereas five of 11 patients who did not respond had sub-therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥ 31 g/L but sub-therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.

An early CT-diagnosis-based treatment strategy for invasive fungal infection in allogeneic transplant recipients using caspofungin first line: an effective strategy with low mortality.

Empirical antifungal therapy is frequently used in allogeneic transplant patients who have persistent febrile neutropenia and can be associated with high cost, toxicity and breakthrough infections. There are limited reports of strategies for early diagnosis of invasive fungal infection (IFI) and, to our knowledge, no reports of treatment strategies based only on high-resolution computerized tomography (HRCT) scans. We used an early treatment strategy for IFI in 99 consecutive patients undergoing allogeneic transplantation. Patients received caspofungin if they had antibiotic-resistant neutropenic fever for more than 72 h and a positive HRCT scan. Fifty-three of 99 patients (54%) had antibiotic-resistant neutropenic fever at 72 h and would have received parenteral antifungal treatment if an empirical approach had been used. The HRCT-based strategy reduced the use of parenteral antifungal agents to 17/99 patients (17%), a 68% reduction. No subsequent diagnoses of IFI occurred within 100 days in patients with a negative HRCT. Only one patient died from IFI within 100 days. These data suggest that this non-empirical strategy may be feasible and that caspofungin may be effective in this setting. A randomized controlled trial is warranted to further assess these results.

The role of maintenance chemotherapy after autotransplantation for acute lymphoblastic leukemia in first remission: single-center experience of 100 patients.

A total of 100 adults with ALL in first CR received melphalan (110 mg/m(2)) with TBI followed by autologous marrow (n=35) or single-agent melphalan (200 mg/m(2)) followed by autologous blood stem cells (n=65). After adequate hematologic recovery, maintenance chemotherapy with 6-mercaptopurine, methotrexate and vincristine-prednisone was administered for 2 years. Six patients, all TBI recipients (P=0.001), died of toxicity. In total 70 patients received 6-mercaptopurine, 53 received methotrexate and 40 received vincristine-prednisone. The cumulative incidence of relapse at 7 years was 45%. The 7-year probabilities of disease-free survival (DFS) and overall survival were 45 and 48%. Age 30 years, >4 weeks to attain remission, and karyotypes t(4;11) and t(9;22) were associated with adverse outcome. Patients with 0 (standard risk), 1 (intermediate risk), and 2-3 (high risk) adverse features had 7-year cumulative incidences of relapse of 19, 53 and 82% (P<0.0001), and 7-year DFS probabilities of 73, 36 and 7% (P<0.0001). The 7-year probabilities of DFS for patients receiving 0, 1, 2 and 3 maintenance chemotherapy agents were 15, 29, 58 and 61% (P<0.0001). Maintenance chemotherapy intensity was an independent determinant of outcome in Cox analysis. Maintenance chemotherapy after autotransplantation reduces relapse and improves outcome in adult patients with ALL.

An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-alpha2b in patients with multiple myeloma maintained on a steady dose of interferon-alpha2b.

PURPOSE: To compare the effects of pegylated interferon-alpha2b (P-IFN) and interferon-alpha2b (IFN) on quality of life (QoL) and toxicity in patients with multiple myeloma maintained on a steady dose of IFN. PATIENTS AND METHODS: Consenting, eligible myeloma patients on IFN maintenance therapy for at least 6 weeks were randomly (1:1) allocated to receive P-IFN for 3 months followed by IFN for 3 months, or to continue with IFN for 3 months followed by P-IFN for 3 months (cross-over design). Patients were assessed for toxicity and QoL. Dose of P-IFN was equivalent to IFN. RESULTS: The study enrolled 60 patients. At enrollment, 35 patients were in complete remission, 20 in partial remission and 5 were minimal responders. P-IFN was associated with significantly better global QoL score (mean difference 8.4; P = 0.0002). There was a significant improvement in functional scales--physical (P = 0.03), emotional (P = 0.04), social (P = 0.0008) with P-IFN. Fatigue (P = 0.0003), pain (P = 0.02) and appetite loss (P = 0.003) symptom scales were less in patients while on P-IFN. There were no statistically significant differences between treatment arms in QoL as measured by QLQ-MY24. CONCLUSION: These data suggest that patients on P-IFN have a better QoL. Dose escalation studies are warranted to investigate potential impact on survival.

Guidelines on the insertion and management of central venous access devices in adults.

Central venous access devices are used in many branched of medicine where venous access is required for either long-term or a short-term care. These guidelines review the types of access devices available and make a number of major recommendations. Their respective advantages and disadvantages in various clinical settings are outlined. Patient care prior to, and immediately following insertion is discussed in the context of possible complications and how these are best avoided. There is a section addressing long-term care of in-dwelling devices. Techniques of insertion and removal are reviewed and management of the problems which are most likely to occur following insertion including infection, misplacement and thrombosis are discussed. Care of patients with coagulopathies is addressed and there is a section addressing catheter-related problems.

Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from veno-occlusive disease.

Veno-occlusive disease (VOD) is a common and high-risk complication of allogeneic stem cell transplantation (SCT). Defibrotide has recently been used successfully to treat the disorder. We report on 58 patients who received defibrotide prophylaxis without concurrent heparin. No patients fulfilled the Baltimore criteria for VOD or died of the condition within 100 days of SCT. None of this group developed haemorrhagic complications secondary to defibrotide. These observations suggest that prophylaxis with defibrotide alone may reduce the incidence of VOD post-SCT although a randomised controlled trial is warranted to further evaluate its role.

Use of physiological doses of human growth hormone in haematological patients receiving intensive chemotherapy promotes haematopoietic recovery: a double-blind randomized, placebo-controlled study.

In vivo and in vitro studies suggest human growth hormone (hGH) receptors on bone marrow stem cells may be biologically active and could be exploited to promote haemopoetic recovery after intensive chemotherapy. Patients with haematological malignancies receiving intensive chemotherapy and requiring hospitalization were randomized in a double-blind, placebo-controlled single-centre trial. Patients were randomly assigned to receive either hGH 500 microg/day or placebo, for 6 weeks. There was no significant difference in patient characteristics at baseline between the placebo and treatment arms. Patients treated with hGH showed significantly faster recovery of platelets to 25 x 10(9)/l (median of 16 versus 19 days; P = 0.03) compared to the placebo-controlled arm (hazard ratio 1.47 favouring hGH, 95% confidence interval (CI), 1.03-2.08). Time to relapse did not differ significantly between arms. There was no change in the anthropometric parameters at the start and end of hGH/placebo therapy. The study drug was well tolerated. Treatment with hGH in physiological doses improves platelet recovery, but is not associated with a lower relapse rate or improved anthropometric parameters in patients receiving intensive chemotherapy.

Parainfluenza type 3 infection post stem cell transplant: high prevalence but low mortality.

Parainfluenza type 3 (PIV 3) is a well-recognized cause of respiratory illness after stem cell transplantation (SCT), with an estimated incidence of 2-7% and a high mortality rate associated with lower respiratory tract infection (LRTI). A 12-month retrospective study was undertaken in which 23 positive cases of PIV 3 occurred in SCT recipients. The frequency of infection was 36.1% in matched unrelated donor SCT recipients, 23.8% in sibling allogeneic SCT recipients and 2.3% in autologous transplant recipients. Seventeen cases were outpatient or community acquired despite standard infection control measures. Eleven patients only developed upper respiratory tract symptoms. LRTI symptoms developed in 12 patients, of whom eight had a new infiltrate on chest X-ray. Overall mortality at 30 days from PIV 3 diagnosis was 4% (one patient). Four patients died within 100 days of PIV 3 diagnosis, but PIV 3 was not believed to be the primary cause of death in any of these patients. Early ribavirin was used in eight patients and only one patient who received ribavirin died. These results suggest a higher prevalence of PIV 3 but a lower mortality than documented previously, particularly in allogeneic transplant recipients. The authors propose that the high prevalence reflects the unit's policy of active surveillance for respiratory viruses and the difficulty in preventing transmission of PIV 3, especially in the outpatient setting during an outbreak period. Ribavirin treatment may improve outcome in patients with LRTI but is not required in all patients with PIV 3.

A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone.

PURPOSE: We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of (186)Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC). METHODS: Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of (186)Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life. RESULTS: Thirty-eight patients with a median age of 67 years (range 50-77) and a median PSA of 57 ng/ml (range 4-3,628) received a median activity of 4,978 MBq (186)Re-HEDP (range 4,770-5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18-24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66-90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15-49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months. CONCLUSION: We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach.

Cytokine profiles in stem cell transplantation: possible use as a predictor of graft-versus-host disease.

Graft-versus-host disease (GvHD) complicates many allogeneic stem cell transplants (alloSCT), and several factors are known to be associated with the development of GvHD besides human leucocyte antigen (HLA) incompatibility. We investigated whether changes in serum levels of soluble IL-2 receptor (sIL-2Ralpha), tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF) and soluble Fas (sFas) correlated with the development of GvHD in patients undergoing SCT, and might thus be potentially of use to anticipate the development of GvHD, allowing early modification of immunosuppressive therapy.sIL2Ralpha and sFas levels were significantly raised in allograft, autograft (allo and auto) and non-graft groups compared to the normal controls (HC), but there was no statistical difference between the three patient groups. TNF-alpha was raised in the auto and allo groups and the non-graft patients compared to the HC group (median 4.37 pg/ml), but only reached significance in the allo group (median 6.02 pg/ml; p = 0.008) when this was compared with the non-graft patients. There was no significant difference in TGF-ss levels between any of the groups. The median serum VEGF levels were decreased in allo and auto patients compared to HC, (31 and 62 pg/ml versus 90 pg/ml, respectively), with a significant difference in the auto group (p = 0.007). VEGF levels were significantly lower in the auto versus the allo group (p = 0.008) and also in the auto versus the non-graft group (median 104 pg/ml; p = 0.011). When the allo group was divided into patients who developed GvHD and those who did not, serum VEGF levels were significantly higher in those with GvHD (p = 0.028).

An elective single autograft with high-dose melphalan: single-center study of 451 patients.

In all, 451 myeloma patients, 51% previously untreated, underwent elective single autotransplantation after 200 mg/m(2) melphalan between 1985 and 2001 at the Royal Marsden Hospital. The therapy sequence was: Induction (vincristine, doxorubicin, methylprednisolone+/-cyclophosphamide), marrow or filgrastim-mobilized blood stem cell harvest, autograft, and interferon-alpha2b maintenance. A total of 27 (6%) died of transplant-related toxicity, all within 3 months. Complete or near-complete remission was seen in 59% with an overall response rate of 91%. Subsequent disease progression was seen in 285, and 17 died of unrelated causes. In all, 206 patients were alive at the last follow-up, 6 months to 17.7 years post-transplant (median 65 months); 122 without disease progression at 6 months to 17.7 years (median 58 months). The median overall (OS) and event-free (EFS) survivals were 5.9 and 2.4 years, with 10-year OS and EFS probabilities of 31.4 and 16.5%, respectively. In Cox analysis, it was seen that significantly longer OS occurred for patients who had beta-2-microglobulin <3.5 mg/l (P<0.0001), age <60 years (P=0.001) and albumin > or =35 g/l (P=0.009). EFS was also longer if beta-2-microglobulin was <3.5 mg/l (P=0.0056) and patients were <60 years of age (P=0.033). We conclude that with a single planned autograft, patients with myeloma have an excellent outcome.

Reassessing autotransplantation for acute myeloid leukaemia in first remission - a matched pair analysis of autologous marrow vs peripheral blood stem cells.

The role of autologous stem cell transplantation in adult patients with acute myeloid leukaemia (AML) in first remission is unclear, yet it has become standard treatment for myeloma and this paper explores whether the source of transplanted stem cells may explain this paradox. In total, 57 patients from the Royal Marsden Hospital who received an unpurged bone marrow transplant (ABMT) were matched with 114 patients from the EBMT registry who had undergone peripheral blood stem cell transplantation (PBSCT). Patients were matched for karyotype, FAB type, remission-autograft interval and age. In the PBSCT group, haematopoietic recovery was significantly faster and nonrelapse mortality at 4 years was significantly lower (13 vs 1%, P=0.04). The relapse rate and overall survival at 4 years (20 vs 31% and 77 vs 63%) were also better with PBSCT, although the differences were not statistically significant. Autografting should be reassessed in a randomised trial for first remission AML patients using peripheral blood as a source of stem cells rather than bone marrow.

High-dose melphalan and autotransplantation followed by post transplant maintenance chemotherapy for acute lymphoblastic leukemia in first remission.

A total of 65 adults with acute lymphoblastic leukemia (ALL) received 200 mg/m2 melphalan and an autograft in first remission, with a plan to receive 6-mercaptopurine (6MP), methotrexate (MTX), and vincristine-prednisone (VP) for 2 years afterwards. There was no transplant-related mortality. In all, 69% of patients received 6MP, 54% received MTX, and 49% received VP. The cumulative incidence of relapse at 5 years was 52%. The 5-year probabilities of disease-free (DFS) and overall (OS) survival were 48 and 55%. Age >30 years, >4 weeks to attain remission, and t(9;22) or t(4;11) karyotypes were adverse prognostic features. Patients with 0 (standard risk), 1 (intermediate risk), and 2-3 (high risk) adverse features had 5-year cumulative incidences of relapse of 19, 59, and 100% (P<0.0001), and 5-year probabilities of DFS of 80, 41, and 0% (P<0.0001). The 5-year probabilities of DFS for patients receiving 0, 1, 2, and 3 maintenance therapy agents were 19, 40, 51, and 70% (P=0.0097). Maintenance therapy intensity was an independent determinant of outcome in Cox analysis. These data show that a high-dose melphalan-based autograft is safe and could be widely applicable in ALL in first remission, and that maintenance chemotherapy very likely contributes to improved outcome of autografted ALL patients.