Long-term prognosis of breast cancer: an analysis of 462 patients in a general hospital in south east Netherlands

In this study the long-term prognosis was analysed of all 462 consecutive female breast cancer patients who were diagnosed and carefully staged between 1970 and 1980 in a 600-bed community hospital in Eindhoven, south east Netherlands. Follow-up of recurrence and causes of death was obtained until 1 January 1993. Observed survival rates at 5, 10 and 20 years were 66%, 45% and 32%, respectively, and the corresponding breast cancer-specific survival rates were 71%, 54% and 44%. The yearly risk for a recurrence of breast cancer after treatment steadily decreased from 10% the first year to 1% after 10 years. In a multivariate survival analysis both tumour size and nodal status appeared to be equally important prognostic factors in the first 5 years after diagnosis. After 5 years only tumour size had independent prognostic value, which was not significant any more after 10 years. In patients with a tumour size < or = 2 cm and without lymph node involvement at diagnosis, the risk for a recurrence was found to be negligible after 10 years. Those patients may be considered cured, although a search for early diagnosis of a second primary breast cancer in this group is still advisable.     

A novel, synergistic interaction between 17 beta-estradiol and glutathione in the protection of neurons against beta-amyloid 25-35-induced toxicity in vitro

The present studies were undertaken to investigate the possibility of an interaction between 17 beta-estradiol (E2) and glutathione in protecting cells against the presence of beta-amyloid 25-35 (betaAP 25-35). We demonstrate that when evaluated individually, supraphysiological concentrations of either E2 (200 nM) or of reduced glutathione (GSH; 325 microM) can protect SK-N-SH human neuroblastoma cells from betaAP 25-35 (20 microM) toxicity. This dose of betaAP 25-35 was chosen based on the LD50 (28.9 microM) obtained in our earlier work. However, in the presence of 3.25 microM GSH, the neuroprotective EC50 of E2 was shifted from 126 +/- 89 nM to 0.033 +/- 0.031 nM, approximately 4000-fold. Similarly, in primary rat cortical neurons, the addition of GSH (3.25 microM) increased the potency of E2 against betaAP 25-35 (10 microM) toxicity, as evidenced by a shift in the EC50 values of E2 from 68 +/- 79 nM in the absence of GSH to 4 +/- 6 nM in its presence. The synergy between E2 and GSH was not antagonized by the addition of the estrogen receptor antagonist, ICI 182,780. Other thiol-containing compounds did not interact synergistically with E2, nor were any synergistic interactions observed between E2 and ascorbic acid or alpha-tocopherol. Based on these data, we propose an estrogen-receptor independent synergistic interaction between glutathione and E2 that dramatically increases the neuroprotective potency of the steroid and may provide insight for the development of new treatment strategies for neurodegenerative diseases.     

Ulcerative colitis and coexisting colorectal cancer: recurrence rate after restorative proctocolectomy

BACKGROUND: The association between mucosal ulcerative colitis (MUC) and adenocarcinoma is well established. METHODS: Records of patients who had undergone restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) from 1983 through 1992 were examined. Of these, 604 had MUC and 27 (4.3%) had MUC with coexisting cancer. Patients were surveyed annually for recurrent disease. Pouch function and quality of life were evaluated with a questionnaire and physical examination. RESULTS: The duration of disease was longer (p = 0.001) in patients with cancer (16.1 +/- 8.0 years) than in those without cancer (9.1 +/- 7.1 years), although the mean age at diagnosis of MUC was the same. Of the 27 patients, 20 had colon cancer and seven had rectal cancer. Multicentricity was found in seven (25.9%) patients. Using the TNM staging classification, 14 patients (51.8%) had stage 1 cancer, eight (29.6%) had stage 2, four (14.8%) had stage 3, and one (3.8%) had stage 4. The patient with stage 4 cancer died 5 months after surgery and was excluded from the follow-up analysis. During a mean follow-up time of 4.3 +/- 2.6 years, cancer recurred in two of the remaining 26 patients (7.7%). In one patient, a local recurrence was found 8 months after surgery, and distant metastases were found in the other patient 35 months after surgery. Both recurrences were in patients with colon cancer. Two of the 26 patients died; one death was related to cancer recurrence (3.8%). Pouch function is good to excellent in all surviving patients. CONCLUSIONS: Restorative proctocolectomy for patients with MUC and coexisting colorectal cancer can be performed with a favorable prognosis and function. It is appropriate for curative intent, given that an adequate margin without tumor is obtained.     

Familial Mediterranean fever and hyperimmunoglobulinemia D syndrome: two diseases with distinct clinical, serologic, and genetic features

OBJECTIVE: To determine whether the 2 periodic febrile syndromes familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS) are distinct diseases. METHODS: Clinical manifestations of the diseases were analyzed by physicians experienced with FMF and HIDS. Serum immunoglobulin (Ig) levels were studied in 70 patients with FMF using nephelometry or ELISA and compared with Ig levels in 50 patients with HIDS. Genetic linkage of HIDS with the chromosome 16 polymorphic locus RT70, currently used for refined localization of the FMF susceptibility gene (MEFV), was studied in 9 HIDS families (18 patients) using polymerase chain reaction amplification and gel electrophoresis. RESULTS: The main clinical features distinguishing FMF from HIDS were lymphadenectomy, skin eruption, and symmetrical oligoarthritis in HIDS, and monoarthritis, peritonitis, and pleuritis in FMF. Increased IgG levels were found in 12 patients with FMF (17%), IgA in 16 (23%), IgM in 9 (13%), and IgD in 9 (13%), significantly lower than the prevalence reported for HIDS. We found no evidence for genetic linkage between HIDS and the chromosome 16 marker RT70. CONCLUSION: HIDS and FMF are different entities, clinically, immunologically, and genetically.     

In vitro evaluation of a series of N-dodecanoyl-L-amino acid methyl esters as dermal penetration enhancers

A series of N-dodecanoyl-L-amino acid methyl esters (1-10) and n-pentyl N-acetylprolinate (11) were evaluated for dermal enhancement properties using an in vitro diffusion cell technique. Methods of synthesis of these compounds were described. Enhancers were applied 1 h prior to drug treatment. Hydrocortisone was used as the model drug and was applied to excised hairless mouse skin as a saturated suspension in propylene glycol. Enhancement ratios (ER) were determined for permeability coefficient, 24 h diffusion cell receptor concentration (Q24), and 24 h full-thickness skin steroid content. Controls received no enhancer pretreatment of the skin. N-Dodecanoyl-L-proline (10) showed the highest Q24 value for total steroid (ER 13.7) while N-dodecanoyl-L-phenylalanine (5) showed the highest total steroid skin retention (ER 16.5).     

Analysis of the Weinbaum-Jiji model of blood flow in the canine kidney cortex for self-heated thermistors

To investigate which specific kinds of base changes are induced by psoralen adducts in the genomic DNA of diploid human fibroblasts, cells were exposed to 8-methoxypsoralen (8-MOP) at 2-12 microM followed by one dose of UVA (365 nm) irradiation (PUVA-I treatment) or two doses of UVA (PUVA-II treatment). While PUVA-I treatment produced little effect on the induction of cytotoxicity, PUVA-II treatment significantly reduced the fibroblasts' colony-forming ability and resulted in about 10-fold increases in mutation frequency at the D0 dose. Mutations in the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of 36 independent PUVA-II mutants were characterized by direct sequencing of cDNA amplified by the polymerase chain reaction (PCR). Seventeen mutants contained single base substitutions and the other 19 mutants either lacked one or more exons, or had deleted or gained nucleotides in the exon boundaries in their cDNA. The intron--exon boundaries of 10 of these 19 putative splicing mutants were further characterized by direct sequencing of the PCR-amplified hprt gene. The results showed that nine contained single base substitutions at the consensus splicing donor and acceptor sites. One splicing mutant possessed two base substitutions located at exon 8, whereas its splicing sites were intact. Most of the base substitutions occurred at T-A base pairs (24/29). The majority of T.A changes occurred at thymine of 5'TA and 5'ATA on the non-transcribed strand. Four of the five G.C base substitutions were located at guanines of 5'TG sites adjacent 3' to AT or TA sequences. In addition, the occurrence of a specific type of mutation was highly correlated to the 5' flanking bases of TA sites. The mutagenesis of 13 of the 16 mutational events at 5'TA sites on the non-transcribed strand can be explained by the preferential incisions of the photoadducts on the transcribed strand followed by misalignment--realignment during translesion repair synthesis of the bulky lesions on the non-transcribed strand.