Augmenting the immunogenicity of synthetic MUC1 peptide vaccines in mice

Human mucin MUC1 is abundantly expressed in some cancers of epithelia] origin and is largely restricted to the apical surface of secretory cells in normal tissues. It is, therefore, a potential target for cancer immunotherapy. In preparation for clinical trials, vaccines containing synthetic MUC1 peptides of different lengths and sequences mixed with various adjuvants or covalently attached, using different linker methods, to protein carrier keyhole limpet hemocyanin (KLH) were studied in mice. MUC1 peptides (containing 30 amino acids), plus adjuvants QS-21 or Bacillus Calmette-Guerin, were incapable of inducing antibody. However, MUC1 peptides conjugated to KLH (MUCl-KLH), plus QS-21, induced high titer antibody against the immunizing peptides and against MUC1-expressing tumor cells. Although T-cell responses, including delayed-type hypersensitivity, lymphocyte proliferation, and CTL, were not observed in mice immunized with these vaccines, significant protection from MUC1-expressing tumor cell challenge in mice immunized with MUC1-KLH was observed. Based on these studies, a vaccine containing MUC1-KLH conjugate prepared with m-maleimidobenzoyl-N-hydroxysuccinimide ester linker, plus QS-21, has been constructed for testing in clinical trials.     

Relationship between prophylactic effect of lithium therapy and family history of affective disorders

Lithium therapy response and age of onset (AOO) were studied in 98 patients with bipolar affective disorder (BPAD) who were divided into subgroups depending on type of family history of affective disorders. The highest (33.0 years) and lowest (25.5 years) age of onset were found in nonfamilial patients and in familial patients with a first-degree relative of BPAD, respectively. Nonfamilial patients showed the best response to lithium. There were 0.9 episodes/year off lithium compared to 0.3 episodes/year on lithium (an 88% decrease). A poorer response (a 71% decrease; a reduction from 1.39 episodes per year off lithium to 0.65 on lithium) was found in familial patients with a first-degree relative of BPAD. Differences in serum lithium values between the groups could not explain the observed differences. Thus, familial patients showed a more severe manifestation of the disease with an earlier AOO and a lower prophylactic effect of lithium.     

Diagnosis of phenylketonuria in a 35-year-old mother in relation to prenatal diagnosis of intrauterine growth retardation with microcephaly

BACKGROUND: Some French pregnant women with phenylketonuria (PKU), born before 1978, have not been tested with the Guthrie method during the neonatal period. They have a risk of spontaneous abortion and their infants are often mentally retarded with microcephaly and/or congenital heart anomaly. CASE REPORT: A woman with a moderate mental retardation became pregnant at the age of 31 years. Her newborn had a severe intrauterine growth retardation with microcephaly and developed mental retardation. This mother became pregnant again 4 years later. Repeated fetal ultrasonography showed progressive growth retardation. Maternal blood phenylalanine concentration was 18 mg/100 mL. Therapeutic abortion at 27 weeks of gestational age showed a fetus with several abnormalities, particularly cardiovascular and cerebral. CONCLUSION: It is still possible to meet women with unrecognized atypical PKU. Fetus or infant born with unexplained growth retardation and microcephaly requires search for maternal PKU.     

Pneumatic dilatation is effective long-term treatment for achalasia

Although pneumatic dilatation (PD) has been an established treatment for achalasia for decades, there is limited information on its long-term clinical efficacy. We have followed up the clinical status of patients having PD with a 30- or 35-mm balloon by one of us (D.O.C.) over a 25-year period. Of 144 patients whose initial records were available for review, 31 could not be contacted. Of the remaining 113 patients, 72 (64%) responded to a questionnaire assessing swallowing status and patient satisfaction, and this forms the basis of this report. There were 32 men and 40 women, with mean age 46 years (range: 17-78); mean length of follow-up since PD was 6.5 years (range: 10 months to 25 years). Success was primarily defined by the need for no additional therapy for achalasia other than one or two PD's. PD was effective long-term treatment in 61/72 patients (85%); only four of these required a second PD over this time interval. There was no significant difference in any of the following parameters between patients with a treatment success or failure: age, sex, size of pneumatic dilator, and duration of symptoms prior to PD. Response was significantly better (P < 0.05) in patients having no prior dilatation (43/47; 91%) than in those in whom another physician had performed prior dilatation (18/25; 72%). In response to the question of whether they would select PD again, 68 patients (94%) responded positively. In conclusion, pneumatic dilatation performed using a consistent technique by an experienced physician is effective long-term therapy for achalasia patients of all ages. Most patients require only one dilatation.     

Characterization of a mouse monoclonal IgG3 antibody to the tumor-associated globo H structure produced by immunization with a synthetic glycoconjugate

OBJECTIVE: The objective of this study was to assess the degree of BP Tracking from childhood to adulthood and to evaluate whether high BP levels persist over time and progress to adult hypertension. PATIENTS AND METHODS: Two hundred and twenty-two healthy schoolchildren living in the North of Portugal were assessed at 17 year intervals, starting in 1979 (cohort 1) aged 5 to 18 years, and again in 1996 (cohort 2). Tracking indices (Ti) were calculated as follows: Ti = (2x + y-z) /N/0.89, where x, y and z refer to the total number in the same, adjacent and remote trisections, respectively, and N = x + y + z. If Ti > 1 there is positive tracking. RESULTS AND CONCLUSIONS: For systolic and diastolic blood pressure, all Ti were greater than 1.0. All individuals that remained in the 3rd tertil, 17 years later, weigh more and are more obese than those of the 1st tertil. 56.6% of the individuals that belong to the 3rd tertil are now hypertensive, which means that a significant percentage of the children with high blood pressure in the first survey will be hypertensive in the future.     

Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside

PURPOSE: To perform a double-blind randomized trial with American Joint Commission on Cancer (AJCC) stage III melanoma patients for the following reasons: (1) to confirm our previous finding that patients with antibodies against the melanoma differentiation antigen GM2 have an improved prognosis, and (2) to demonstrate clinical benefit from GM2 antibody induction. PATIENTS AND METHODS: One hundred twenty-two patients with AJCC stage III melanoma who were free of disease after surgery were randomized: 58 to receive treatment with the GM2/BCG vaccine, and 64 to receive treatment with bacille Calmette-Guèrin (BCG) alone. All patients were pretreated with low-dose cyclophosphamide (Cy). RESULTS: GM2 antibody was detected in 50 of 58 patients treated with GM2/BCG and seven of 64 patients treated with BCG alone. With a minimum follow-up period of 51 months, there was a highly significant increase in the disease-free interval (P = .004) and a 17% increase in overall survival (P = .02) in these 57 antibody-positive patients, confirming our earlier experience. Exclusion of all patients with preexisting GM2 antibodies (one in the GM2/BCG group and five in the BCG group) from statistical analysis resulted in a 23% increase in disease-free interval (P = .02) and a 14% increase in overall survival (P = .15) at 51 months for patients treated with the GM2/BCG vaccine. However, when all patients in the two treatment groups were compared as randomized, these increases were 18% for disease-free interval and 11% for survival in the GM2/BCG treatment group, with neither result showing statistical significance. CONCLUSION: (1) Vaccination with GM2/BCG induced immunoglobulin M (IgM) antibodies in most patients. (2) GM2 antibody production was associated with a prolonged disease-free interval and survival. (3) Comparison of the two arms of this trial as randomized fails to show a statistically significant improvement in disease-free interval or survival for patients treated with GM2/BCG vaccines.     

Differential uptake of estramustine phosphate metabolites and its correlation with the levels of estramustine binding protein in prostate tumor tissue

Estracyt (EMP) has been used for the treatment of hormone refractory prostate cancer for many years. Recently, new data from combination studies have given rise to new interest in this old drug. Explanations for the synergy found in the clinic are many, but one major factor may be the previous indication that the drug accumulates in the prostate tumor. We have, therefore, examined the level of the four metabolites, estromustine (EoM), estramustine (EaM), estrone, and estradiol in the tumor and serum of 14 patients with T2 and T3 prostate cancer receiving a single i.v. dose of 600 mg of EMP, about 12 h before radical prostatectomy. Because it has been suggested that the uptake into the prostate tumor is due to binding to the estramustine binding protein (EMBP), we have in addition measured the level of EMBP in the prostate tumor tissue. The main serum and tissue metabolite in all patients was EoM followed by EaM, estrone, and estradiol. The levels for EoM ranged from 63.8-162.8 ng/ml in the serum and from 64.8-1209 ng/ml in the prostate tumor, resulting in a mean ratio for serum to tumor of 1:5. The levels for EaM ranged from 8.3-51.4 ng/ml in the serum and 73.9-563.4 ng/ml in the tumor, giving a mean ratio for serum to tumor of 1:13. The levels of EMBP were higher in T3 tumors than in T2 tumors, 54.1 and 40.7 ng/g tissue, respectively. A significant correlation was found between the levels of EaM (r = 0.60) and the levels of EMBP in the tumor. These data demonstrate that 12 h after a single i.v. dose of 600 mg of EMP the levels of the cytotoxic metabolites EoM and EaM are substantially higher in the tumor than in the serum of the same patient and that a correlation exists between the levels of EaM in the tumor and the levels of EMBP. Thus, this supports the hypothesis that the EMBP is responsible for the retention of EoM and EaM in the prostate tumor.     

Splenic imaging with 99mTc-labeled erythrocytes: a comparative study of cell-damaging methods

Several methods of damaging red blood cells (RBCs) for splenic imaging were compared to determine the optimum approach. The RBCs from donor animals were labeled with 99mTcO4- and damaged by heat, excess acid citrate dextrose (ACD), excess Sn(II) ion, or the sulfhydryl inhibitors N-ethylmaleimide (NEM) or p-hydroxymercuribenzoate (PMB). The organ distributions of undamaged and damaged RBCs were determined in rats, and splenic imaging studies were performed in rabbits. Splenic deposition and spleen-to-liver ratios with heat- or sulfhydryl-damaged 99mTc-RBCs were significantly greater (p less than 0.001) than the values obtained using ACD or Sn(II) ion. Heat-damaging produces good splenic localization of 99mTc-RBCs but requires rigidly controlled incubation conditions. NEM-damaging provides an excellent and predictable alternative approach.