Influence of neoadjuvant chemotherapy on serum tumor markers CA 15-3, MCA, CEA, TPS and TPA in breast cancer patients with operable disease

The mycelial mass of the fungus Polyporus Squamosus strain 64 (PS-64) was disintegrated by mechanical and ultrasound treatments. After centrifugation, the supernatant containing the disintegrate was dialyzed and lyophilized. The resultant PS-64 extract was subsequently investigated as an immunomodulator of IgE and IgG responses to ovalbumin (OA) in (CBAxC57BL/6)F1 mice using passive cutaneous anaphylaxis (PCA) and enzyme-linked immunosorbent assay (ELISA), respectively. Multiple injections of PS-64 extract in doses of 1.5, 15, and 150 mg/kg administered before the primary or secondary immunization of mice with OA resulted in a dose-dependent inhibition of both IgE and IgG antibody responses to OA. In contrast to the inhibition of the anti-OA IgE response noted during the entire 3-week observation period, the anti-OA IgG response was restored to control level by the third week of secondary immunization. The glass microfiber-based whole blood histamine release assay demonstrated that various concentrations of the PS-64 extract did not influence histamine release induced either by anti-IgE or by specific allergens from basophils derived from whole blood of allergen-sensitized patients. Using the hemolytic plaque assay, significant suppression of IgM-secreting cell formation was noted in (CBAxC57BL/6)F1 mice administered various doses of the PS-64 extract before immunization. The PS-64 extract inhibited the in vitro proliferation of human mononuclear cells upon stimulation with phytohemagglutinin (PHA). In a dose-dependent manner, the PS-64 extract also inhibited delayed-type hypersensitivity reaction and skin graft rejection, similar to the effect noted with usage of Cyclosporin A (CsA) in (CBAxC57BL/6)F1 mice. Our investigation suggests that the immunomodulatory effects of PS-64 should be studied further for potential clinical therapeutic utility.     

Dietary flavonoids reduce lipid peroxidation in rats fed polyunsaturated or monounsaturated fat diets

We investigated the influence of dietary flavonoids on alpha-tocopherol status and LDL peroxidation in rats fed diets enriched in either polyunsaturated fatty acids (PUFA) or monounsaturated fatty acids (MUFA). Diets equalized for alpha-tocopherol concentrations were or were not supplemented with 8 g/kg diet of flavonoids (quercetin + catechin, 2:1). After 4 wk of feeding, plasma lipid concentrations were lower in rats fed PUFA than in those fed MUFA with a significant correlation between plasma alpha-tocopherol and cholesterol concentrations, r = 0.94, P < 0. 0001). Dietary lipids influenced the fatty acid composition of VLDL + LDL more than that of HDL or microsomes. The resistance of VLDL + LDL to copper-induced oxidation was higher in rats fed MUFA than in those fed PUFA as assessed by the lower production of conjugated dienes and thiobarbituric acid reactive substances (TBARS) and by the >100% longer lag time for dienes production. (P < 0.0001). Dietary flavonoids significantly reduced by 22% the amounts of dienes produced during 12 h of oxidation in rats fed diets rich in PUFA and lengthened lag time 43% in those fed MUFA. Microsomes of rats fed MUFA produced approximately 50% less TBARS than those of rats fed PUFA (P < 0.0001) and they contained more alpha-tocopherol in rats fed MUFA than in those fed PUFA with higher values (P < 0. 0001) in both groups supplemented with flavonoids (P < 0.0001). Our findings suggest that the intake of dietary flavonoids is beneficial not only when diets are rich in PUFA but also when they are rich in MUFA. It seems likely that these substances contribute to the antioxidant defense and reduce the consumption of alpha-tocopherol in both lipoproteins and membranes.     

Evaluation of benign vs malignant hepatic lesions with positron emission tomography

BACKGROUND: In most malignant cells, the relatively low level of glucose-6-phosphatase leads to accumulation and trapping of [18F]fluorodeoxyglucose (FDG) intracellularly, allowing the visualization of increased uptake compared with normal cells. OBJECTIVES: To assess the value of FDG positron emission tomography (PET) to differentiate benign from malignant hepatic lesions and to determine in which types of hepatic tumors PET can help evaluate stage, monitor response to therapy, and detect recurrence. DESIGN: Prospective blinded-comparison clinical cohort study. SETTING: Tertiary care university hospital and clinic. PATIENTS: One hundred ten consecutive referred patients with hepatic lesions 1 cm or larger on screening computed tomographic (CT) images who were seen for evaluation and potential resection underwent PET imaging. There were 60 men and 50 women with a mean (+/-SD) age of 59 +/- 14 years. Follow-up was 100%. INTERVENTIONS: A PET scan using static imaging was performed on all patients. The PET scan imaging and biopsy, surgery, or both were performed, providing pathological samples within 2 months of PET imaging. All PET images were correlated with CT scan to localize the lesion. However, PET investigators were unaware of any previous interpretation of the CT scan. MAIN OUTCOME MEASURES: Visual interpretation, lesion-to-normal liver background (L/B) ratio of radioactivity, and standard uptake value (SUV) were correlated with pathological diagnosis. RESULTS: All (100%) liver metastases from adenocarcinoma and sarcoma primaries in 66 patients and all cholangiocarcinomas in 8 patients had increased uptake values, L/B ratios greater than 2, and an SUV greater than 3.5. Hepatocellular carcinoma had increased FDG uptake in 16 of 23 patients and poor uptake in 7 patients. All benign hepatic lesions (n = 23), including adenoma and fibronodular hyperplasia, had poor uptake, an L/B ratio of less than 2, and an SUV less than 3.5, except for 1 of 3 abscesses that had definite uptake. CONCLUSIONS: The PET technique using FDG static imaging was useful to differentiate malignant from benign lesions in the liver. Limitations include false-positive results in a minority of abscesses and false-negative results in a minority of hepatocellular carcinoma. The PET technique was useful in tumor staging and detection of recurrence, as well as monitoring response to therapy for all adenocarcinomas and sarcomas and most hepatocellular carcinomas. Therefore, pretherapy PET imaging is recommended to help assess new hepatic lesions.     

A quantitative study of articular repair in the guinea pig

This study examined the healing of articular defects, with and without carbon fiber implants, and the response of repair tissue to its interim removal in guinea pigs of different ages. These were investigated after the induction of full thickness articular cartilage defects in the patellar groove of skeletally mature and immature guinea pigs. To indicate its capacity for replacement after attrition, repair tissue occurring in untreated (control) and carbon fiber treated (experimental) defects was ablated after 8 weeks, and the animals were sacrificed after an additional 8 weeks. The repair tissue was studied quantitatively at gross and microscopic levels and qualitatively using scanning and transmission electron microscopic study. The principal findings were as follows. The initial formation of repair tissue was variable, but it occurred in most cases. Secondary repair tissue formation consistently occurred after excision. Age did not influence the degree of repair. Carbon fiber implants of the type used impaired healing of small full thickness articular cartilage defects, compared with no treatment. Microscopically, repair tissue contains five main cell types, each with a characteristic surrounding matrix. Intermediate forms also are found. These, together with four of the five main types comprise a morphologic continuum and fit readily into a proposed developmental sequence that may stem from the fibroblast.     

Delayed low density lipoprotein (LDL) catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia

We identified a 38-yr-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. The genetic trait seems to be autosomal recessive. Interestingly, serum concentrations of cholesterol responded well to diet and statins. We had no evidence of an abnormal low density lipoprotein (LDL)-apolipoprotein B (apoB) particle, which was isolated from the patient using the U937 proliferation assay as a functional test of the LDL-binding capacity. The apoB 3500 and apoB 3531 defects were ruled out by PCR. In addition, we found no evidence for a defect within the LDL-receptor by skin fibroblast analysis, linkage analysis, single-strand conformational polymorphism and Southern blot screening across the entire LDL-receptor gene. The in vivo kinetics of radioiodinated LDL-apoB were evaluated in the proband and three normal controls, subsequently. The LDL-apoB isolated from the patient showed a normal catabolism, confirming an intact LDL particle. In contrast the fractional catabolic rate (d-1) of autologous LDL in the subject and the normal controls revealed a remarkable delayed catabolism of the patient's LDL (0.15 vs. 0.33-0.43 d-1). In addition, the elevation of LDL-cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs. 12.7-15.7 mg/kg per day. These data indicate that there is another catabolic defect beyond the apoB and LDL-receptor gene causing familial hypercholesterolemia.     

Ribosomal protein insufficiency and the minute syndrome in Drosophila: a dose-response relationship

Minutes comprise > 50 phenotypically similar mutations scattered throughout the genome of Drosophila, many of which are identified as mutations in ribosomal protein (rp) genes. Common traits of the Minute phenotype are short and thin bristles, slow development, and recessive lethality. By mobilizing a P element inserted in the 5' UTR of M(3)95A, the gene encoding ribosomal protein S3 (RPS3), we have generated two homozygous viable heteroalleles that are partial revertants with respect to the Minute phenotype. Molecular characterization revealed both alleles to be imprecise excisions, leaving 40 and 110 bp, respectively, at the P-element insertion site. The weaker allele (40 bp insert) is associated with a approximately 15% decrease in RPS3 mRNA abundance and displays a moderate Minute phenotype. In the stronger allele (110 bp insert) RPS3 mRNA levels are reduced by approximately 60%, resulting in an extreme Minute phenotype that includes many morphological abnormalities as well as sterility in both males and females due to disruption of early gametogenesis. The results show that there is a correlation between reduced RPS3 mRNA levels and the severity of the Minute phenotype, in which faulty differentiation of somatic tissues and arrest of gametogenesis represent the extreme case. That heteroalleles in M(3)95A can mimic the phenotypic variations that exist between different Minute/rp-gene mutations strongly suggests that all phenotypes primarily are caused by reductions in maximum protein synthesis rates, but that the sensitivity for reduced levels of the individual rp-gene products is different.     

Application of the new classification for cancer of the cardia

BACKGROUND: Cancer of the cardia is now topographically classified into three types: type I, with the tumor center in the distal esophagus treated with subtotal esophagectomy; type II, arising at the gastroesophageal junction and treated with distal esophagectomy and either proximal or total gastrectomy; and type III, subcardial cancer treated with extended total gastrectomy. Our objective was to review the new classifications and compare the outcomes in patients grouped and treated according to these classifications. METHODS: Seventy-four patients with cancer of the cardia--15 with type I, 30 with type II, and 29 with type III cancer--underwent surgical resection at our institution between 1992 and 1997. Postoperative complications, UICC stages, and survival (Kaplan-Meier) were compared. RESULTS: The majority of patients with type I (73%) or type II (53%) cancer had stage I or II tumors, but only 27% of patients with type III cancer had this tumor stage (P < .05). Overall 30-day mortality was 4% and morbidity was 31%. Curative resections were performed in 73% (54 of 74) of the patients with 3-year survival rates of 72% (type I), 68% (type II), and 61% (type III). CONCLUSION: The recommended therapy for the different types of cancer of the cardia results in acceptable morbidity, mortality, and survival rates.     

In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy

Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3-/-) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7, 12-dimethylbenzanthracene-induced tumorigenesis in ST3-/- mice. Moreover, ST3-/- fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.