Torbjörn Karlsson

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study

This randomized study assessed if intravenous iron improves hemoglobin (Hb) response and permits decreased epoetin dose in anemic (Hb 9–11 g/dl), transfusion-independent patients with stainable iron in the bone marrow and lymphoproliferative malignancies not receiving chemotherapy. Patients (n=67) were randomized to subcutaneous epoetin beta 30 000 IU once weekly for 16 weeks with or without concomitant intravenous iron supplementation. There was a significantly (P<0.05) greater increase in mean Hb from week 8 onwards in the iron group and the percentage of patients with Hb increase ⩾2 g/dl was significantly higher in the iron group (93%) than in the no-iron group (53%) (per-protocol population; P=0.001). Higher serum ferritin and transferrin saturation in the iron group indicated that iron availability accounted for the Hb response difference. The mean weekly patient epoetin dose was significantly lower after 13 weeks of therapy (P=0.029) and after 15 weeks approximately 10 000 IU (>25%) lower in the iron group, as was the total epoetin dose (P=0.051). In conclusion, the Hb increase and response rate were significantly greater with the addition of intravenous iron to epoetin treatment in iron-replete patients and a lower dose of epoetin was required.

Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins

Shb is a recently described Src homology 2 (SH2) domain-containing adaptor protein. Here we show that Shb is expressed in lymphoid tissues, and is recruited into signaling complexes upon activation of Jurkat T cells. Grb2 binds proline-rich motifs in Shb via its SH3 domains. As a result, a number of proteins detected in anti-Shb and anti-Grb2 immunoprecipitates are shared, including phosphoproteins of 22, 36/38, 55/57 and 70 kDa. Shb-association with p22, which represents the T cell receptor associated ζ chain, occurs through the Shb SH2 domain. The central region of Shb binds p36/38. Since this interaction was inhibited by phosphotyrosine, this region of Shb is likely to contain a non-SH2 PTB (phosphotyrosine binding) domain. The Shb PTB domain was found to preferentially bind the sequence Asp-Asp-X-pTyr when incubated with a phosphopeptide library. A peptide corresponding to a phosphorylation site in 34 kDa Lnk inhibited association between Shb and p36/38. Overexpression of Shb in Jurkat cells led to increased basal phosphorylation of Shb-associated p36/38 and p70 proteins. Inactivation of the Shb SH2 domain by an R522K mutation resulted in a reduced stimulation of tyrosine phosphorylation of several proteins in response to CD3 crosslinking when expressed in Jurkat cells. Together, our results show three distinct domains of Shb all participate in the formulation of multimeric signaling complexes in activated T cells. These results indicate that the Shb protein functions in T cell receptor signaling.

Metabolism and nutrition in patients with moderate and severe traumatic brain injury: A systematic review

Primary objective: To examine the evidence on the metabolic state and nutritional treatment of patients with moderate-to-severe traumatic brain injury (TBI). Research design: A systematic review of the literature. Methods and procedures: From 1547 citations, 232 articles were identified and retrieved for text screening. Thirty-six studies fulfilled the criteria and 30 were accepted for data extraction. Main outcomes and results: Variations in measurement methods and definitions of metabolic abnormalities hampered comparison of studies. However, consistent data demonstrated increased metabolic rate (96–160% of the predicted values), of hypercatabolism (−3 to −16 g N per day) and of upper gastrointestinal intolerance in the majority of the patients during the first 2 weeks after injury. Data also indicated a tendency towards less morbidity and mortality in early fed patients. Conclusions: The impact of timing, content and ways of administration of nutritional support on neurological outcome after TBI remains to be demonstrated.

Central and regional blood flow during hyperventilation

Mechanical hyperventilation not only reduces brain oedema after neurotrauma but also affects the central and systemic circulation. We have, in pigs, measured blood flow in the pulmonary artery, the portal vein and in the femoral artery, as well as estimated the splanchnic blood flow and studied the relative perfusion using the microsphere technique in normo– and hypocarbia during intermittent positive pressure ventilation. A normoventilated control group did not change in cardiac output, portal vein blood flow, splanchnic blood flow and femoral arterial blood flow. Hyperventilation was performed to a Pco2 of 3.0± 0.1 kPa. We found that in pigs ventilated with high tidal volume skeletal muscle blood flow did not change during the first 60 min of hyperventilation but gradually decreased thereafter. Blood flow to the cerebellum decreased soon after the induction of hyperventilation, whereas the cerebral blood flow did not decrease until the second hour of hyperventilation. Cardiac output, splanchnic perfusion and portal vein blood flow all decreased. Myocardial perfusion and arterial blood flow to spleen and kidney decreased while pancreatic and liver arterial blood flows were unaffected. It is concluded that mechanical hyperventilation with low frequency and large tidal volumes reduces the flow to most tissues, where the relative decrease according to microsphere measurements is most pronounced in skeletal muscles, heart muscle and cerebellum. However, the changes in cardiac output and splanchnic blood flow were not observed when hyperventilation was induced by increased frequency, keeping the tidal volume constant.

Insulin resistance after cardiopulmonary bypass in the elderly patient.

Objectives. Preoperative carbohydrate administration attenuates insulin resistance. We studied effects of preoperative oral carbohydrate loading in elderly patients undergoing coronary artery bypass grafting. Design. Eighteen patients were assigned either to get a carbohydrate drink or to be controls. Perioperatively, glucose was administered. A gastric emptying test was performed. Glucose and insulin concentrations were measured. Levels of glucose, insulin and stress hormones were studied pre-, per- and postoperatively. Results and discussion. Preoperative carbohydrate loading did not affect stress hormones. Gastric residual after the carbohydrate drink was 11±3% (mean±SEM). Glucose concentration was lower before anaesthesia induction in the carbohydrate group, possibly due to increased insulin release. Insulin levels differed at baseline, induction and day six. All patients returned to baseline on day six. Conclusions. The study group was insulin resistant on postoperative day one and two. The effects were explainable by the traumatic stress response. No adverse effect was noted from the carbohydrate drink. If glucose is administered intravenously during surgery, there is no obvious advantage of preoperative carbohydrate loading on insulin resistance or stress hormone response.

Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study

Objectives:  Thalidomide and bortezomib have been frequently used for second‐line therapy in patients with myeloma relapsing after or refractory to initial melphalan‐based treatment, but no randomized trials have been published comparing these two treatment alternatives.

Brain energy metabolism in patients with spontaneous subarachnoid hemorrhage and global cerebral edema

BACKGROUNDPrevious studies of spontaneous subarachnoid hemorrhage (SAH) have shown that global cerebral edema on the first computed tomography scan is associated with a more severe initial injury and is an independent predictor of poor outcome. Effects of secondary ischemic events also influence outcome after SAH. OBJECTIVEThis study demonstrates that early global edema is related to markers of an increased cerebral energy metabolism as measured with intracerebral microdialysis, which could increase vulnerability to adverse events. METHODSFifty-two patients with microdialysis monitoring after spontaneous SAH were stratified according to the occurrence of global cerebral edema on the first computed tomography scan taken a median of 2 hours after the initial bleed. Microdialysis levels of glucose, lactate, and pyruvate were compared between the global edema (n = 31) and no global edema (n = 21) groups. Clinical outcome was assessed with the Glasgow Outcome Scale score at ≥ 6 months. RESULTSPatients with global edema showed significantly elevated lactate and pyruvate levels 70 to 79 hours after SAH and marginally significantly higher levels of lactate 60 to 69 hours and 80 to 89 hours after SAH. There was a trend toward worse outcome in the edema group. CONCLUSIONPatients with global cerebral edema have higher interstitial levels of lactate and pyruvate. The edema group may have developed a cerebral hypermetabolism to meet the increased energy demand in the recovery phase after SAH. This stress would make the brain more vulnerable to secondary insults, increasing the likelihood of energy failure.

Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma

Objectives:  Thalidomide and bortezomib have been frequently used for second‐line therapy in patients with myeloma relapsing after or refractory to initial melphalan‐based treatment, but no randomized trials have been published comparing these two treatment alternatives.

Glutamine concentration and tissue exchange with intravenously administered α-ketoglutaric acid and ammonium: A dose-response study in the pig

OBJECTIVE We investigated the effects of an intravenous load of alpha-ketoglutaric acid, ammonium (NH(4)(+)), and metabolic acidosis on plasma concentration and splanchnic and hindleg tissue exchange of glutamine, glutamate, alanine, and arginine in postabsorptive, anesthetized pigs. METHODS Sixteen anesthetized piglets received a constant infusion of NH(4)Cl for 4 h and alpha-ketoglutaric acid in incremental dosages for 3 h (group 1, n = 8) or a constant infusion of alpha-ketoglutaric acid for 4 h and NH(4)Cl in incremental dosages for 3 h (group 2, n = 8). Plasma amino acids were analyzed and splanchnic blood flow was calculated according to the indocyanine green dye infusion technique. Femoral artery blood flow was measured with ultrasound flowmetry. Statistical evaluation of within-group differences was made with the Wilcoxon signed rank test. RESULTS Plasma glutamine levels increased dose-dependently in group 2 (P < 0.05) but not in group 1. Glutamate concentration increased, mainly in group 2 (P < 0.05), whereas the plasma concentration of alanine decreased in both groups (P < 0.05). Plasma concentration of arginine increased in both groups (P < 0.05). Splanchnic uptake and skeletal muscle release of glutamine did not change in either group compared with baseline values. Splanchnic glutamate release decreased (P < 0.05) in group 1 at 240 min; muscular uptake was unaffected in both groups. Splanchnic uptake and muscular release of alanine were unaffected in both groups. The significance level was set at 0.05. CONCLUSION Our findings indicate that the splanchnic bed or hindleg skeletal muscle was not the source of the increased plasma concentration of glutamine in this study.