ERK1/2 inhibition prevents contraction-induced increase in plasma membrane FAT/CD36 content and FA uptake in rodent muscle.

AIM: The purpose of this experiment was to investigate the role of extracellular signal-regulated kinase 1/2 (ERK1/2) signalling in the contraction-induced increase in muscle FA uptake. METHODS: Male Wistar rats (n = 41) were randomly assigned to either a resting or stimulated group. Within each group, animals were randomly assigned to receive PD-98059, an inhibitor of MAP/ERK kinase 1/2 (MEK1/2), a kinase upstream of ERK1/2 and perfused with 550 microM palmitate, [(14)C]palmitate, 7 mM glucose, and no insulin. In the stimulated group, electrical stimulation (ES) of supramaximal trains of 100 ms was delivered every 2 s for 20 min. RESULTS: ERK1/2 phosphorylation was increased by 50% (P < 0.05) during ES but the contraction-induced increase was prevented by the addition of PD-98059. Glucose uptake increased by 3.6-fold (P < 0.05) from rest to ES in muscle perfused without PD-98059 and was not affected by the addition of PD-98059 either at rest (P > 0.05) or during ES (P > 0.05). For a matched palmitate delivery, ES increased palmitate uptake by 35% (P < 0.05). PD-98059 had no effect on palmitate uptake at rest but completely abolished the increase in palmitate uptake during ES. Plasma membrane FAT/CD36 protein content was increased by 38% during ES (P < 0.05) but the contraction-induced increase was prevented by the addition of PD-98059. AMPK activity was increased by ES (P < 0.05) but was unaffected by PD-98059. CONCLUSION: These results show for the first time that the increase in FA uptake and in plasma membrane FAT/CD36 protein content is mediated, at least in part, by the ERK1/2 signalling pathway during muscle contraction.

A pilot study to assess the use of megesterol acetate to promote weight gain in frail elderly persons residing in long-term care.

OBJECTIVE: The purpose of this pilot study was to determine the effectiveness of megesterol acetate (MA) for increasing body weight of frail older persons residing in long-term care settings. DESIGN: A retrospective study. SETTING: Two long-term care facilities in a large city in the southwestern US. PARTICIPANTS: Six white residents (five female, one male, mean age 87.8 years) of the facilities who had a sustained weight loss of 5% in 1 month or 10% in 6 months or longer. MEASUREMENTS: Weight gain or loss of participants receiving 480 milligrams of megesterol acetate for a minimum of 28 consecutive days. RESULTS: Five of the six subjects gained weight over a 2-month period after taking 480 milligrams of MA for 1 month or more. There was a delayed effect of non-fluid weight gain that was statistically significant 2 months after the end of treatment. One woman with diagnoses of stroke, arthritis, and hypertension lost weight despite taking MA continuously for 84 days. CONCLUSIONS: Results suggest that MA has been underutilized by geriatric health professionals as an intervention to ameliorate or reverse anorexia of aging after other nutritional efforts have failed. Using MA to prevent unintentional weight loss and malnutrition may significantly improve the health status of older patients. A prospective study using a larger sample and based on ideal weight should be carried out to evaluate the benefit of MA, with particular attention to weight gain that persists after 2 months. Future studies should also take into account the high dropout rate of participants and consider earlier intervention with MA.

Late intensification therapy in adult acute lymphoid leukemia. The Southeastern Cancer Study Group Experience.

One hundred ninety-two evaluable patients were treated on a multicenter protocol for adult acute lymphoid leukemia to determine in a prospective randomized fashion if late intensification chemotherapy beginning after about six months of treatment would improve remission duration and survival. The complete remission rate was 60%. The median remission duration was 13.5 versus 25.9 months (P = 0.31) for standard maintenance therapy and late intensification, respectively, and the median survival was 17.5 versus 34.7 months (P = 0.19) respectively. Although there was a suggestion that the late intensification strategy was helpful, relapse proved to be common during the early phases of treatment; thus, insufficient numbers of patients were available at the randomization point to conclusively address the possible value of late intensification. Intensive therapy earlier in remission should be evaluated.

Therapy of acute myelogenous leukemia in patients over the age of 50: a randomized Southeastern Cancer Study Group trial.

In a randomized trial, 299 evaluable patients with acute myelogenous leukemia, age greater than or equal to 51, were initially randomized to cytosine arabinoside, 100 mg/m2/day, by continuous intravenous infusion for seven days, plus either daunorubicin 45 mg/m2/day x 3 (DA), or m-AMSA 200 mg/m2/day x 3 days (MA). Complete remission (CR) rates were not significantly different, 47% for DA and 42% for MA. Toxicities were similar except that severe hepatic toxicity, serum bilirubin greater than or equal to 7 mg/dl, was more frequent in patients receiving MA (10%) than in patients receiving DA (4%), p less than 0.05. Deaths during induction were significantly more frequent in patients receiving MA (38%) than in patients receiving DA (25%), p = 0.018. Patients achieving a CR received thioguanine, cytosine arabinoside, and daunorubicin (TAD) for three cycles as consolidation. Among evaluable patients, 82/102 (80%) stayed in CR during these three cycles. Patients were then randomized to either no maintenance or to DA every 13 weeks x 4 cycles, at a dose slightly lower than used for induction. Remission duration was similar for the two maintenance programs, 10.7 months for no maintenance and 8.5 months for DA. The percentage of patients evaluable for maintenance achieving three year relapse-free survival was similar for the two maintenance programs, 28% for no maintenance and 21% for DA. However, overall survival was significantly greater (40 vs 12 months, p = 0.007) for patients receiving no maintenance therapy, due to greater survival after recurrence in these patients. At each phase of the study there were substantial numbers of non-evaluable cases, often due to incomplete evaluation of remission status. Of the 379 patients initially entered into the trial, 35% obtained a complete remission. Of all the patients who achieved a complete remission, 61% were both evaluable and in remission upon completion of the maintenance phase. Of these patients who completed the maintenance phase in remission, 15% were relapse free survivors three years following initiation of maintenance therapy. Overall, only 3.2% of patients who entered the trial (35% x 61% x 15%) were continuous relapse-free survivors three years into the maintenance phase.

Evaluation of ferromagnetism and magnetic resonance imaging artifacts of the Strecker tantalum vascular stent.

A woven tantalum vascular stent (Strecker stent) was tested for ferromagnetism at 4.7 T and underwent magnetic resonance imaging (MRI) in vitro and in vivo at 1.5 T to evaluate the production of magnetic susceptibility artifacts. No ferromagnetism was detected. Spin-echo, phase reconstruction, and gradient echo images revealed a low level of susceptibility artifacts both in vitro and in vivo. Our findings demonstrate the feasibility of using MRI to evaluate blood vessels noninvasively following tantalum stent placement.

Vindesine and mitomycin C in metastatic breast cancer. A Southeastern Cancer Study Group Trial.

64 eligible women with previously treated metastatic breast cancer received mitomycin C plus vindesine chemotherapy. Dosage was based on investigators' estimate of patients' bone marrow reserve. There were 19 evaluable patients in the good marrow reserve category, with two complete and three partial responses (26%). In the poor marrow reserve category there were 29 evaluable patients with four partial responses (14%). The 26% response rate in patients with good marrow reserve is consistent with results obtained with this and similar combinations by other investigators.

A comparison of paramedic versus basic emergency medical care of patients at high and low risk during acute myocardial infarction.

This prospective study compares the outcome of patients with acute myocardial infarction managed by mobile intensive care (paramedic phase) with that of similar patients managed by basic emergency medical care (control phase) in the same community before the introduction of paramedics. All paramedic-transported patients were managed according to a standard chest pain protocol with use of prophylactic lidocaine and, as needed, treatment for sinus bradycardia, hypotension and life-threatening ventricular arrhythmia. There were no specific interventions for supraventricular tachyarrhythmia or hypertension. All patients were treated under similar in-hospital protocols. Percent mortality in patients with hypotension, the highest risk subgroup in the control phase, was significantly lowered with paramedic-level care (69 versus 10%, p = 0.01). Patients with hypertension, a relatively low risk subgroup during the control phase (16% mortality), were also at lower risk during the paramedic phase (10% mortality). In fact, there was no mortality in either study phase for patients with an initial systolic blood pressure greater than 180 mm Hg. During the combined study phases, patients with normotension and tachycardia demonstrated a tendency toward higher percent mortality (33%) than either patients with normotension without tachycardia (10%) or those with hypertension and tachycardia (6%). Although the overall percent mortality was reduced by 24% (from 21 to 16%), this decrease was largely due to the improvement of patients with hypotension. Investigation into the feasibility of prehospital interventions for the high risk patient with acute myocardial infarction normotension and tachycardia appears warranted.

Prognostic significance of blood and marrow findings in acute myelogenous leukemia in remission. A Southeastern Cancer Study Group report.

Bone marrow and peripheral blood findings at the time of complete remission were analyzed in 333 patients with acute myelogenous leukemia to determine if any variables were predictive for remission duration and survival. Patients were categorized as to percentage of blasts, promyelocytes, erythroid precursors and lymphocytes in the marrow and hemoglobin concentration, leukocyte and platelet counts, and percentage of granulocytes and blasts in the blood. Additionally, the degree of cellularity in the marrow aspirate and biopsy were analyzed. Patients with less than 1% blasts in the marrow had significantly longer remission durations than those with blasts greater than or equal to 1% (P less than 0.01). Those with hypercellular marrows had significantly shorter remission (P less than 0.05) and survival (P less than 0.01). The transient presence of more than 3% blasts in the blood also was suggestive of a shorter remission duration and survival. The presence of less than 1% blasts in the marrow, normal or decreased biopsy cellularity, and no anemia at the time of remission defined a "good" prognostic group. The quality of remission should be assessed in evaluating the results of therapy and assigning further treatment.

Phase II evaluation of teniposide (VM-26) in metastatic breast carcinoma. A Southeastern Cancer Study Group trial.

The Southeastern Cancer Study Group performed a Phase II study of teniposide in previously treated patients with metastatic breast cancer. No responses were observed in 11 evaluable patients who received teniposide 60 mg/m2 by IV infusion for five consecutive days every three weeks. Toxicity was primarily gastrointestinal and hematologic and was frequently severe. This study demonstrated no therapeutic activity for teniposide when given in this dose and schedule to patients with heavily pretreated metastatic breast cancer.

Continuous-infusion diaziquone in acute myeloid leukemia: a Southeastern Cancer Study Group trial.

Diaziquone (AZQ) is a synthetic quinone with considerable activity against L1210 leukemia and potent myelosuppressive activity in man. To test the efficacy and toxicity of AZQ administered by continuous infusion, a phase II multi-institutional trial was undertaken by the Southeastern Cancer Study Group. Eligible adults with acute myeloid leukemia (AML) received AZQ at a dose of 28 mg/m2 daily by continuous infusion for 5 days. Patients failing to achieve complete remission received a second course utilizing the same dose and schedule. Of 25 evaluable patients with relapsed or refractory AML, three achieved complete response (12%) and two achieved partial response (8%). All patients experienced marked myelosuppression. Severe or life-threatening infection was observed in 15 (56%) patients. Clinical or postmortem evidence of central nervous system hemorrhage was encountered in three (12%) patients with severe refractory thrombocytopenia. Minimal nonhematologic toxicity was observed, suggesting that further studies of this agent in combination regimens and possibly for marrow transplantation preparation in patients with acute leukemia are warranted.

Alternating sequential combination chemotherapy in the management of advanced Hodgkin's disease. A Southeastern Cancer Study Group trial.

The Southeastern Cancer Study Group has explored the use of alternating sequential combination chemotherapy in advanced Hodgkin's disease. Two hundred twelve evaluable patients were randomly assigned to treatment with the six-drug combination, BCNU, cyclophosphamide, vinblastine, procarbazine, prednisone, and bleomycin (BCVPP-Bleo) or with the same drugs alternating in monthly cycles with doxorubicin, dacarbazine, and bleomycin. Both regimens produced complete response rates of approximately 73%. The duration of remission and survival were similar for the two treatment regimens. Although our sequence of combinations does not rigorously meet the criteria for "non-cross-resistant" our results do not lend support to the hypothesis that alternating sequential non-cross-resistant drug combinations improves the outcome in advanced Hodgkin's disease.

Randomized comparison of tamoxifen versus diethylstilbestrol in estrogen receptor-positive or -unknown metastatic breast cancer: a Southeastern Cancer Study Group trial.

In a randomized study 115 postmenopausal women with advanced breast cancer who were estrogen receptor-unknown or -positive were treated initially with tamoxifen or diethylstilbestrol (DES). Their pretreatment characteristics showed no significant difference. The frequency of response was identical with tamoxifen and DES, showing a complete response rate of 2% versus 2% and a partial response rate of 4% versus 8%, respectively; stable disease was present in 78% versus 73% of the patients, respectively. The median time to disease progression (5 vs 6 months) and median survival depending on initial hormone therapy (34 vs 35 months) were identical for tamoxifen and DES, respectively. Gastrointestinal toxicity was more frequent and more severe with DES than tamoxifen. Responses were seen with withdrawal of each agent and on crossover to the alternative agent. Our conclusions are that: DES and tamoxifen are equally effective in treating metastatic breast cancer in the postmenopausal patient who is estrogen receptor-positive or -unknown; withdrawal and crossover responses are seen with both agents; side effects are minimal but more frequent with DES; and on the basis of cost-effectiveness DES is the preferable agent.

Treatment of chronic lymphocytic leukemia using chlorambucil and prednisone with or without cycle-active consolidation chemotherapy. A Southeastern Cancer Study Group Trial.

Patients with untreated chronic lymphocytic leukemia (CLL) received protocol treatment with 6 months of chlorambucil (CB) (30 mg/M2) and prednisone (P) (80 mg/d X 5) every 2 weeks. Complete and partial responders (CR, PR) were then randomized to consolidation with six more courses of CB and P or to four courses of cytosine arabinoside (25 mg/M2 every 12 hours X 8, subcutaneously) and cyclophosphamide (25 mg/M2 every 12 hours X 8, orally) every three weeks. Of the 178 eligible patients entered, 138 (78%) were evaluable for induction therapy which produced a 22% hematologic CR and an overall response rate (CR + PR) of 74%. Eighty-two patients received adequate consolidation, at the end of which 43 were in CR. No difference was seen in response or survival between the two consolidation treatments. Responders had longer survival than nonresponders (P = 0.0001) even when a 6-month "guarantee time" was excluded, but there was no survival difference between CR and PR. Thus, intermittent CB and P is a well-tolerated, useful therapy for CLL but the addition of cyclophosphamide and cytosine arabinoside does not improve results.

Ineffectiveness of levamisole in prolonging remission or survival of women treated with cyclophosphamide, doxorubicin, and 5-fluorouracil for good-risk metastatic breast carcinoma: a Southeastern Cancer Study Group Trial.

A total of 97 women with good-risk metastatic breast cancer received therapy with cyclophosphamide, doxorubicin, and 5-FU; half of these patients were randomly allocated to receive levamisole, 2.5 mg/kg, 2 days of each week in addition to chemotherapy, while the other half received an identical placebo. Good-risk patients consisted of those with bone-only metastasis, or local chest wall recurrence with or without bone metastasis. No significant difference in response rate, duration of disease control, or survival was observed between the groups. No major toxicity was associated with levamisole.

Long-term survival in adult acute lymphoblastic leukemia: follow-up of a Southeastern Cancer Study Group trial.

Current observation was obtained for adults treated on a protocol for acute lymphoblastic leukemia, which was open from 1972 to 1978, in order to determine the long-term outcome and to evaluate potential prognostic factors. Long-term survival (five + years) was seen in 32% (25/79) of patients who achieved complete remission; 16/79 remain in first remission and 2/79 are currently in second remission. Young age (less than 40) and female sex were significant prognostic factors for long-term survival, but the basis for this advantage is unclear. Further improvements in chemotherapy are needed.