Use of the anti-idiotype breast cancer vaccine 11D10 in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer

The results of cytotoxic therapy, including dose-intensive therapy requiring autologous stem cell transplantation (ASCT), have been disappointing in patients with metastatic breast cancer, as almost all patients eventually experience disease progression. There has been a renewed interest in immunotherapeutic strategies in this disease, including evaluation of several breast cancer vaccines. In the current study, we describe the results of a program in which the anti-idiotype breast cancer vaccine 11D10 (TriAb) was administered before and after ASCT in patients with metastatic breast cancer chemosensitive to previous conventional therapy. The toxicity of this approach was acceptable, and idiotype-specific humoral and T-cell proliferative responses were observed in the majority of patients within a few weeks post-ASCT. The actuarial 3-year overall survival rate was 48% (95% CI, 32%-64%), while the progression-free survival rate was 32% (95% CI, 19%-45%). Multivariate analysis identified achievement of a strong antibody and cellular immune response to the vaccine as the only significant prognostic factors for outcome. The ability to reliably produce robust immune responses after ASCT is encouraging. Further studies are required to determine if the immune response mediates an antitumor benefit in these patients.     

Behavioral and Molecular Evidence for a Feedback Interaction Between Morphine and HIV-1 Viral Proteins

Morphine use and addiction is common among HIV infected individuals. There is an abundance of research supporting the effects of morphine and other mu opioid receptor (MOR) ligands, on the function of HIV-1 viral proteins and progression of HIV-1 viral infection to AIDS. On the other hand, there is much less research that investigates the possible effects of the persistent presence of HIV-1 viral proteins on the expression of the MOR and the analgesic and rewarding effects of MOR ligands such as morphine. While researchers have made a great deal of progress in the past several years, the overall investigation of the interaction between opiates such as morphine and HIV-1 viral proteins is largely unilateral. It has become widely accepted that drugs of abuse interact with HIV-1 viral proteins, but the mechanisms by which this takes place are only recently being discovered. Molecular and behavioral research suggests a feedback interaction between morphine and HIV-1 viral proteins. This interaction is mediated largely by the MOR as well as interplay between MOR ligands and cytokines, chemokines and their receptors. Some of the mechanisms underlying the feedback interaction between morphine and HIV-1 viral proteins has been demonstrated using cell culture and the recently engineered HIV-1 transgenic (HIV-1Tg) rat models.     

Increased plasma concentration of cross-linked fibrin polymers in acute myocardial infarction

Thrombin cleaves fibrinopeptides from fibrinogen, converting it to fibrin monomer, and activates factor XIII, which catalyzes the formation of intermolecular epsilon-(gamma-glutamyl)-lysine bonds to stabilize the fibrin polymer. The formation of factor XIIIa-catalyzed fibrin polymers during clotting of plasma and purified fibrinogen in vivo was followed by a sodium dodecyl sulfate agarose gel technique, and an increase in both amount and size of gamma-chain cross-linked polymers was demonstrated before visible clot formation. Plasma from patients presenting with acute myocardial infarction showed increases in the plasma concentration of fibrin polymer and in the proportion of total fibrinogen present as polymer, as determined by a quantitative adaptation of the electrophoretic technique. The plasma concentration in patients with subendocardial or transmural myocardial infarction showed significant (p less than .005) increases to 4.0 +/- 1.0% and 3.6 +/- .8%, respectively, as compared with the concentration in normal plasma (0.8 +/- 0.1%). There was no difference in plasma concentration in samples from patients with transmural compared with those with subendocardial myocardial infarction. This study provides the first demonstration of factor XIIIa cross-linked fibrin polymers in thrombotic disease and indicates the presence of increased activity of both thrombin and factor XIIIa in patients with acute myocardial infarction.     

Home administration of high-dose oral busulfan in patients undergoing hematopoietic stem cell transplantation

We report our experience with oral busulfan (BU) in 159 consecutive patients to evaluate the safety of home administration. Patients received a myeloablative BU-containing regimen, including oral anticonvulsant and antiemetic prophylaxis, followed by hematopoietic stem cell transplantation. Comprehensive verbal and written education was provided. Pharmacokinetic monitoring was performed and dose adjustments were made to target an area under the plasma concentration-time curve (AUC) of 900-1500 micromol.min/l. Safety was assessed by evaluating therapy-related toxicities, including seizures, venoocclusive disease (VOD) and patient tolerability. The utilization of pharmacokinetic monitoring was reviewed as a secondary end point. Of the 143 patients evaluated for BU-related seizures and VOD, only two (1.4%) experienced a generalized seizure and four patients (3%) were diagnosed with VOD. VOD resolved in three patients and was a contributing cause of death in one patient. Additional BU dosing owing to nausea and/or vomiting occurred in 28 patients (18%) and five patients (3%) were hospitalized. The median measured AUC was 1405 micromol.min/l, 68% of patients required a dose adjustment, and the median total administered BU dose was 13.6 mg/kg. In conclusion, high-dose oral BU can be safely administered on an outpatient basis.     

Interim analysis of the use of the anti-idiotype breast cancer vaccine 11D10 (TriAb) in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer

The anti-idiotype monoclonal antibody breast cancer vaccine 11D10 (TriAb) was administered before and after autologous stem cell transplantation (ASCT) in 45 patients with metastatic breast cancer whose disease was responsive to conventional chemotherapy. Evidence of a positive anti-anti-idiotype antibody (Ab3) humoral response was noted at a median of 1.76 months post-ASCT (range, before ASCT-6 months) with this strategy. Maximal Ab3 levels and idiotype-specific T-cell proliferative responses were observed at a median of 3 and 4 months, respectively, after ASCT. The achievement of rapid immune responses after ASCT, during a known period of decreased immunoresponsiveness, opens the possibility of an additional antitumor effect at a time when the tumor burden is relatively small. Moreover, in this interim analysis, patients with the most vigorous humoral and cellular immune responses had a significant improvement in progression-free survival. Further follow-up and evaluation of this approach is warranted.     

Transient reversal of bone marrow aplasia associated with lymphocyte depleted Hodgkin's disease after combination chemotherapy

This report describes a patient with lymphocyte depleted Hodgkin's disease who presented with bone marrow aplasia. The aplastic marrow reverted to normal after initiation of MOPP chemotherapy; however, 4 months after completion of therapy, bone marrow aplasia recurred in the absence of recurrent Hodgkin's disease. The patient remains free of Hodgkin's disease 34 months after completion of chemotherapy. Bone marrow abnormalities in Hodgkin's disease are reviewed and the current understanding of the pathological mechanisms leading to aplastic anemia is discussed.     

Respiratory kinematics during vocalization and nonspeech respiration in children from 9 to 48 months.

The development of respiratory drive for vocalization was studied by observing chest wall kinematics longitudinally in 4 typically developing children from the age of 9 to 48 months. Measurements of the relative contribution of rib cage and abdominal movement during vocalization (i.e., babbling and true words) and rest breathing were obtained every 3 months using respiratory plethysmography (Respitrace). Extending earlier findings in 15-month-olds, 2 methods of analysis of rib cage and abdominal movement were used: (a). a dynamic index of the strength of coupling between the rib cage and abdomen, and (b). a classification scheme describing the moment-by-moment changes in each of the 2 components (C. A. Moore, T. J. Caulfield, and J. R. Green, 2001). The developmental course of relative chest wall kinematics differed between vocalization and rest breathing. The coupling of rib cage and abdomen during vocalization weakened significantly with development, whereas it remained consistently strong for rest breathing throughout the observed period. The developmental changes in frequency of occurrence of relative moment-by-moment changes varied across movement type. The results support previous findings that speech breathing is distinct from rest breathing based on the relative contributions of the rib cage and abdomen. Longitudinal changes are likely responsive to anatomic development, including changes to rib cage shape and compliance.     

Trends and social factors in blood pressure control in Scottish MONICA surveys 1986-1995: the rule of halves revisited

Time trends and social factors in detection, treatment and control of hypertension in the community were examined in four independent Scottish MONICA cross-sectional surveys in 1986, 1989, 1992 and 1995. Residents aged 25-64 years were recruited randomly from general practice lists in north Glasgow, Scotland with stratification by sex and 10-year age groups. A total of 1262 participated in the first survey, 1397 in the second, 1516 in the third and 1836 in the fourth. Differences and trends in proportions of hypertension undetected, detected but untreated, treated but uncontrolled and controlled across the four surveys were tested by chi(2), and the associations of the poor control of hypertension with social factors were estimated by multivariate logistic regression model to derive odds ratios. Using the cut point of >/=160/95 mmHg, proportion of hypertension undetected across the four surveys was 56.3, 44.6, 32.0 and 38.2%, and of treated controlled hypertension was 15.2, 26.4, 32.0 and 32.8% (both trends P<0.001). Multivariate analysis showed that poor control of hypertension was not related to social deprivation, but significantly related to being male, young, of low body mass index and heavy alcohol drinking. Undetected hypertension was significantly related to full-time employment, and untreated hypertension to high social class and possibly education level. These findings suggest that in this part of Scotland the management of hypertension has improved, so the 'rule of halves' no longer applies. Control of blood pressure is not positively associated with social deprivation, but people at a high risk of poor control of hypertension should be targeted.