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Background Lithium augmentation of antidepressants for treatment of unipolar major depression was one of the first adjunctive strategies based on a neuropharmacologic rationale. Randomized controlled trials supported its efficacy but most trials added lithium to tricyclic antidepressants (TCAs). Despite its efficacy, use of lithium augmentation remains infrequent. The current systematic review and meta-analysis examines the efficacy of lithium augmentation as an adjunct to second generation antidepressants as well as to TCAs and considers reasons for its infrequent use. Method A systematic search of Medline and the Cochrane Clinical Trials database was performed. Randomized, placebo-controlled trials of lithium augmentation were selected. A fixed-effects meta-analysis was performed. Odds ratios for response were calculated for each treatment-control contrast, for the trials grouped by type of initial antidepressant (TCA or second generation antidepressant), and as a meta-analytic summary for all treatments combined. Results Nine trials that included 237 patients were selected. The odds ratio for response to lithium vs. placebo in all contrasts combined was 2.89 (95% CI 1.65, 5.05, z=3.72, p=0.0002). Heterogeneity was very low, I²=0%. Adjunctive lithium was effective with TCAs (7 contrasts) and with second generation agents (3 contrasts). Discontinuation due to adverse events was infrequent and did not differ between lithium and placebo. Limitations The meta-analysis is limited by the small size and number of trials and limited data for treatment resistant patients. Conclusions Adjunctive lithium appears to be as effective for second generation antidepressants as it was for the tricyclics. [ABSTRACT FROM AUTHOR]

DON (6-diazo-5-oxo-L-norleucine), a glutamine antagonist, has been subjected to limited clinical trials since 1957. Use of the drug in adults has been curtailed due to sparse reports of effectiveness as well as its dose-limiting toxicities, i.e., severe nausea, vomiting and mucositis. In earlier studies, children given DON orally in combination with 6-mercaptopurine had significant prolongation of remission of acute leukemias during maintenance therapy. As DON is acid-labile and relatively unstable in solution, oral administration does not appear to be ideal for DON. In the trial described in this report, i.v. DON therapy was studied, using i.v. chlorpromazine to control vomiting, in 20 children, 17 of whom were evaluable following treatment at DON dose levels ranging from 150 mg/m2 to 520 mg/m2. Nausea and vomiting, the dose-limiting toxicity for adults, was controlled with chlorpromazine. Mucositis, which has also been observed in adults, did not occur in the children given DON i.v. A maximum tolerated dose was not defined; however, the projected maximum tolerated dose appears to be in excess of 450 mg/m2. DON was measured in plasma using a rapid-sampling HPLC procedure. The total body clearance, plasma t1/2, and area under the plasma concentration curve (AUC) were calculated using a noncompartmental method. The drug is rapidly cleared from plasma (t 1/2 = 3 h), and its volume of distribution is approximately twice that of total body water in children. These pharmacokinetic data, differ from that of adults reported by others. Specifically, the plasma t 1/2 for children is longer: total body clearance (Cl), and volume of distribution at steady state (Vss) are greater. In addition, no dose dependency of t 1/2, Cl or Vss was observed in this study, and the DON pharmacokinetics were linear and predictable. Five of nine children with acute leukemia showed improvement, though insufficient for classification as partial response, and five of eight children with solid tumors also showed improvement. Further trials using DON in combination with thiopurines or other agents appear indicated. [ABSTRACT FROM AUTHOR]

Aims Among people with diabetes, 10-25% will experience a foot ulcer. Research has shown that supplementation with arginine, glutamine and β-hydroxy-β-methylbutyrate may improve wound repair. This study tested whether such supplementation would improve healing of foot ulcers in persons with diabetes. Methods Along with standard of care, 270 subjects received, in a double-blinded fashion, (twice per day) either arginine, glutamine and β-hydroxy-β-methylbutyrate or a control drink for 16 weeks. The proportion of subjects with total wound closure and time to complete healing was assessed. In a post-hoc analysis, the interaction of serum albumin or limb perfusion, as measured by ankle-brachial index, and supplementation on healing was investigated. Results Overall, there were no group differences in wound closure or time to wound healing at week 16. However, in subjects with an albumin level of ≤ 40 g/l and/or an ankle-brachial index of < 1.0, a significantly greater proportion of subjects in the arginine, glutamine and β-hydroxy-β-methylbutyrate group healed at week 16 compared with control subjects ( P = 0.03 and 0.008, respectively). Those with low albumin or decreased limb perfusion in the supplementation group were 1.70 (95% CI 1.04-2.79) and 1.66 (95% CI 1.15-2.38) times more likely to heal. Conclusions While no differences in healing were identified with supplementation in non-ischaemic patients or those with normal albumin, addition of arginine, glutamine and β-hydroxy-β-methylbutyrate as an adjunct to standard of care may improve healing of diabetic foot ulcers in patients with risk of poor limb perfusion and/or low albumin levels. Further investigation involving arginine, glutamine and β-hydroxy-β-methylbutyrate in these high-risk subgroups might prove clinically valuable. [ABSTRACT FROM AUTHOR]

Purpose: Accurate dosimetry is essential when irradiating mice to ensure that functional and molecular endpoints are well understood for the radiation dose delivered. Conventional methods of prescribing dose in mice involve the use of a single dose rate measurement and assume a uniform average dose throughout all organs of the entire mouse. Here, the authors report the individual average organ dose values for the irradiation of a 12, 23, and 33 g mouse on a 320 kVp x-ray irradiator and calculate the resulting error from using conventional dose prescription methods. Methods: Organ doses were simulated in the Geant4 application for tomographic emission toolkit using the MOBY mouse whole-body phantom. Dosimetry was performed for three beams utilizing filters A (1.65 mm Al), B (2.0 mm Al), and C (0.1 mm Cu + 2.5 mm Al), respectively. In addition, simulated x-ray spectra were validated with physical half-value layer measurements. Results: Average doses in soft-tissue organs were found to vary by as much as 23%-32% depending on the filter. Compared to filters A and B, filter C provided the hardest beam and had the lowest variation in soft-tissue average organ doses across all mouse sizes, with a difference of 23% for the median mouse size of 23 g. Conclusions: This work suggests a new dose prescription method in small animal dosimetry: it presents a departure from the conventional approach of assigning a single dose value for irradiation of mice to a more comprehensive approach of characterizing individual organ doses to minimize the error and uncertainty. In human radiation therapy, clinical treatment planning establishes the target dose as well as the dose distribution, however, this has generally not been done in small animal research. These results suggest that organ dose errors will be minimized by calibrating the dose rates for all filters, and using different dose rates for different organs. [ABSTRACT FROM AUTHOR]

Purpose: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma. Experimental Design: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m2 or 1.3 mg/m2 IV bolus on days 1 and 8 of a 21-day cycle). Results: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered. Conclusion: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population. [ABSTRACT FROM AUTHOR]

Background: Uncontrolled antidepressant trials suggest that anxious patients with major depressive disorder (MDD) are less responsive to antidepressant treatment than less anxious patients. The objective of this study is to determine whether specific antidepressant effects, estimated by drug-placebo differences, are reduced in anxious depression during treatment of MDD with duloxetine. Methods: This is a retrospective secondary pooled analysis of all placebo-controlled trials of duloxetine at therapeutic doses conducted by the sponsor in outpatients with nonpsychotic unipolar MDD, using the Hamilton Depression Rating Scale (HAMD). Anxious depression was defined by ≥7 on the anxiety/somatization factor of the HAMD. Response was defined as ≥50% improvement from baseline to endpoint on the HAMD. Remission was defined as an endpoint HAMD≤7. Analyses were performed in the intent-to-treat sample with at least one post-treatment rating. Results: Eleven trials included 2,841 patients of whom 1,326 were classified as anxious and 1,515 as nonanxious. Change on the HAMD was greater with duloxetine than placebo in both anxious (9.91 versus 7.55, P<.001) and nonanxious (6.65 versus 5.23, P<.001) patients. Level of anxiety had no effect on the drug–placebo differences. Response and remission rates were significantly greater in duloxetine than placebo-treated patients and drug–placebo differences were unaffected by anxious status. Use of HAMD items psychic and somatic anxiety to define anxious subgroups had similar outcomes. Conclusions: Duloxetine was more effective than placebo in achieving response and remission in both anxious and nonanxious patients. Anxious status did not affect the magnitude of the drug effect. Depression and Anxiety, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The management of high-risk prostate cancer following radical prostatectomy remains a treatment dilemma. Multimodality approaches incorporating surgery, radiation therapy and systemic agents offer the hope of improved cure rates; however, most randomized studies to date are either immature or negative. The systemic treatment options best studied is androgen deprivation, which has been shown to demonstrate a survival advantage in patients with lymph node-positive disease. Systemic chemotherapy has demonstrated a modest survival advantage in androgen-independent disease. Current studies are exploring its role in the adjuvant and neo-adjuvant setting. Lastly, recent randomized trials have demonstrated a biochemical advantage to adjuvant radiation therapy, but it remains to be seen if this will translate to an improvement is survival end points or if salvage radiation therapy would be just as effective. In this update article, we review the use of external beam radiation therapy and systemic agents in combination with surgery for high-risk prostate cancer patients.Prostate Cancer and Prostatic Diseases (2007) 10, 119–126. doi:10.1038/sj.pcan.4500947; published online 20 February 2007 [ABSTRACT FROM AUTHOR]

The author reflects on a study which demonstrates the successful use of adjunctive L-methylfolate as treatment for patients with major depressive disorder. He says that study involved two trials, the comparison of L-methylfolate and placebo in 148 patients with nonpsychotic unipolar depression and the use of 15 milligrams per day (mg/day) L-methylfolate or placebo in 75 patients. He is interested on the impact of L-methylfolate's long-term administration in depressed individuals.

The article comments the study on the sequential series of treatments for depression. The author stresses the aspects which made this study differs from typical clinical trials. An overview of the reasons behind the decline of remission rates in patients is offered. He asserts that the study provides an interesting information about relapse but it limits in offering comparisons between treatment strategies.

Purpose of the study: This study was designed to provide data on the efficacy, dose response, incidence and duration of adverse effects of flupirtine in the treatment of cancer-related neuropathic pain. Methods: This was an 8-day, open label, dose escalation study of inpatients in a palliative care unit. After ethics committee approval, patients with moderate to severe neuropathic pain in spite of opioid treatment received an initial dose of flupirtine 100 mg four times daily (QID). This dose could be escalated by 100 mg QID every 2 days to a maximum of 300 mg QID. Efficacy measures included: 11 point scales measuring average pain and worst pain; a neuropathic pain discriminant score; 11 point scales for quality of life activities and a score of percentage pain relief (0–100%). Results: Ten Patients were recruited into the study; only one patient was withdrawn because of side effects thought to be due to the flupirtine. There were significant reductions of average pain (p = 0.0008), worst pain (p = 0.0168) and neuropathic pain discriminant scores (p < 0.0001; see figure). There were also significant improvements in the quality of life measures (p = 0.0017), a reduction of adverse symptoms (p = 0.0017) and an increase in percentage pain relief (p = 0.0078). Additionally there occurred a statistically non-significant downward trend in opioid use. Eight patients elected to continue to take flupirtine after the trial, two taking 200 mg QID and the others 100 mg QID. Of these eight, six said that flupirtine was of considerable help and two said that it helped only a little. Conclusions: Flupirtine is effective in the treatment of neuropathic pain caused by cancer when used in combination with opioids. This compound merits further investigation for the treatment of neuropathic pain associated with other etiologies. [ABSTRACT FROM AUTHOR]

The article reports on a clinical trial which showed that mirtazapine orally disintegrating tablets were well tolerated and effective in reducing depression in nursing home residents 85 years of age or older. The study reported a mean increase in weight among treated subjects of 1.1 lbs by day 28 and 1.32 lbs by day 84.

Background Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes. Methods GBM was applied to pooled data from 12 randomised clinical trials of 4987 participants experiencing an acute depressive episode who were treated with duloxetine, an SSRI or placebo to predict treatment remission. Additional analyses were conducted on the same dataset using the logistic regression model for comparison between these two methods. Results With GBM, there were noticeable differences between treatments when identifying which and to what extent variables were associated with remission. A single logistic regression only revealed a decreasing or increasing relationship between predictors and remission while GBM was able to reveal a complex relationship between predictors and remission. Limitations These analyses were conducted post-hoc utilising clinical trials databases. The criteria for constructing the analyses data were based on the characteristics of the clinical trials. Conclusions GBM can be used to identify and quantify patient variables that predict remission with specific treatments and has greater flexibility than the logistic regression model. GBM may provide new insights into inter-individual differences in treatment response that may be useful for selecting individualised treatments. Trial registration IMPACT clinical trial number 3327; IMPACT clinical trial number 4091; IMPACT clinical trial number 4689; IMPACT clinical trial number 4298; NCT00071695; NCT00062673; NCT00036335; NCT00067912; NCT00073411; NCT00489775; NCT00536471; NCT00666757 (note that trials with IMPACT numbers predate mandatory clinical trial registration requirements) [ABSTRACT FROM AUTHOR]

High treatment-related mortality (TRM) and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total-body irradiation (TBI; 1350 cGy) and fludarabine (Flu) (160 mg/m2). Twenty-seven patients (median age, 33 years; range: 20-58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 107/kg (range: 3.2-7.7 × 107/kg). The cumulative incidences of neutrophil (≥500/μL) and platelet (≥50,000/μL) engraftment were 80% (95% confidence interval [CI], 58%-91%) and 68% (95% CI, 46%-83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days posttransplantation. A higher cryopreserved and infused TNC dose and infused CD3+ cell dose were significant factors associated with the predominant UCB unit (P = .032, .020, and .042, respectively). TRM and relapse rates at 2 years were 28% (95% CI, 12%-47%) and 20% (95% CI, 7%-37%), respectively. Cumulative incidences of grades II–IV and grades III–IV acute graft-versus-host disease (aGVHD) were 37% (95% CI, 20%-55%) and 11% (95% CI, 3%-26%), respectively, and that of chronic GVHD was 31% (95% CI, 15%-49%). With a median follow-up of 23 months, overall survival and disease-free survival rates at 2 years were 58% (95% CI, 34%-75%) and 52% (95% CI, 29%-70%), respectively. This study supports the use of TBI 1350 cGy/Flu as an alternative to conventional myeloablative conditioning for dual UCB transplantation. [ABSTRACT FROM AUTHOR]

Currently, no agents are approved by the United States Food and Drug Administration (FDA) for either prevention or treatment of acute graft-versus-host disease (aGVHD). Formal precedents establishing a comparative basis for assessing the efficacy and safety of new investigational agents are still lacking. As a step toward addressing this problem, a panel of experts met on 2 occasions to reach consensus on recommendations for terminology describing a clinically meaningful primary endpoint in studies assessing treatment for aGVHD. The panel recommended terminology for “very good partial response” (VGPR) that includes both diagnostic and functional criteria. The central hypothesis leading to this proposal is that the potential harm of giving more treatment than needed to produce or maintain complete response exceeds the harm of slight undertreatment that may be associated with less than complete response. VGPR clearly cannot be used as the sole outcome measure in GVHD treatment trials, and must be considered in the context of survival and safety. The proposed use of VGPR as the primary endpoint in GVHD treatment trials will remain provisional until its use has been validated through experience. [Copyright &y& Elsevier]

Background Several professional societies have established nutrition guidelines for patients undergoing HSCT. We surveyed HSCT programs to understand how these compare with clinical practice. Methods Qualitative surveys were emailed to HSCT dietitians. Surveys addressed malnutrition screening; dietary recommendations including nutrition support, graft-versus-host disease (GVHD), immune enhancing nutrients, and prebiotics/probiotics; and nutrition-related preventive care screening. Results Twenty adult programs (19 United States (US), 1 Australia) and 3 pediatric programs (3 US) responded. Annual volume across the 22 US programs was 5405 patients, representing 25% of all transplants in the US. Nineteen programs (83%) follow guidelines for nutrition screening and fourteen for nutrition therapy in the inpatient setting (Table 1); six (26%) follow guidelines for screening and therapy in the outpatient setting. All programs adhere to food safety recommendations and 5 (22%) have additional institutional precautions. However, only 2 programs (9%) report frequent adherence to guidelines for use of enteral nutrition. While there are no guidelines for GVHD diet and uncertainty over alternative nutrition practices, 8 programs (35%) follow a stepwise GVHD diet; 4 (17%) allow immunonutrition supplements; 2 (9%) allow prebiotics, and 7 (30%) allow probiotics after the resolution of neutropenia. With regard to adherence to preventive screening recommendations, only 4 programs (17%) screen for diabetes, 6 (26%) screen for hyperlipidemia, and none screen for abdominal obesity. There are no guidelines for vitamin D deficiency screening, but 10 programs (43%) screen for this. Discussion Wide variations in nutrition practices exist across HSCT programs. Similarly, with the exception of food safety recommendations, there are also wide variations in adherence to established nutrition guidelines. The use of enteral nutrition and preventive screening is particularly varied. Efforts are needed to understand barriers to guideline implementation and their correlation to patient outcomes. Further research is needed regarding new interventions such as immunonutrition, prebiotics, and probiotics. [ABSTRACT FROM AUTHOR]