Expression of the mage gene family in primary and metastatic human breast cancer: Implications for tumor antigen-specific immunotherapy

Some human tumors express known antigens that can be utilized as targets for specific immunotherapy. An absolute requirement for the efficacy of this therapeutic strategy is an adequate expression of the candidate antigen by all cells of the primary and metastatic tumor. To examine the presence and distribution of tumor-associated antigens in metastatic breast cancer, we used PCR analysis and ethidium bromide staining to test the expression of genes of the MAGE family in 28 primary tumors and related metastatic samples. Overall, samples obtained from 7 of 28 patients revealed positive. However, 2 of 3 primary tumors positive for MAGE-1 and/or MAGE-3 had corresponding negative metastatic lesions. On the contrary, 4 of the 25 MAGE-negative primary tumors gave rise to positive metastatic nodes. Our results confirm in vivo, at the molecular level, the tumor-antigen heterogeneity previously observed at the cellular level by in vitro analysis. Our data strongly suggest that, at least in patients with breast cancer, multiple different antigens would be required to optimize the recognition of neoplastic cells in immunotherapeutic protocols using MAGE products as target antigens. © 1995 Wiley-Liss, Inc.     

Mitomycin C plus vindesine plus etoposide (MEV) versus mitomycin C plus vindesine plus cisplatin (MVP) in stage IV non-small-cell lung cancer: A phase III multicentre randomised trial

PURPOSE:: To compare mitomycin C plus vindesine plus etoposide (MEV) vs.mitomycin C plus vindesine plus cisplatin (MVP) in the treatmentof stage IV non-small-cell lung cancer. PATIENTS AND METHODS:: 204 patients were entered in a phase III multicentre randomisedtrial from June 1990 to December 1994 and stratified accordingto the ECOG performance status (0–1 vs. 2). MVP was givenin the following dosages: mitomycin C 8 mg/m² + vindesine 3mg/m² + cisplatin 100 mg/m² i.v. day 1 and vindesine 3 mg/m²i.v. day 8 with cycles repeated every 4 weeks. MEV was givenin the following dosages: mitomycin C 8 mg/m² + vindesine 3mg/m² i.v. day 1 and etoposide 100 mg/m² i.v. days 1 to 3 withcycles repeated every 3 weeks. For both treatments a maximumof 6 cycles was planned. Response and toxicity were evaluatedaccording to WHO. Subjective responses were assessed by numericalscales. Analyses were made on the basis of intent to treat. RESULTS:: The objective response rate was 21.4% (1 CR + 21 PR among 103patients) in the MEV and 28.7% (1 CR + 28 PR among 101 patients)in the MVP arm (P=0.48). Symptoms were similar in the two arms.196 patients progressed and 182 died. The median times to progressionwere 10 weeks (95% CI 9–12) and 12 weeks (95% CI 10–15)and median survivals were 29 weeks (95% CI 25–36) and28 weeks (95% CI 25–35) in the MEV and MVP arms, respectively.The relative risks of progressing and of dying were 0.89 (95%CL 0.66–1.20) and 0.96 CL 0.71–1.30), respectively,for patients receiving MVP as compared with those receivingMEV at multivariate analysis adjusted by sex, age, histologictype, number of metastatic sites, performance status at entry,and centre. CONCLUSIONS:: In the present study, no significant dfferences were observedin response rate, survival or palliation of symptoms betweenthe MEV and MVP regimens, while toxicity was significantly morefrequent and severe with MVP. Thus, MEV should be considereda reasonable alternative to the MVP regimen in the treatmentof stage IV NSCLC. chemotherapy, non-cisplatin-containing, regimen, stage IV NSCLC     

Simultaneous measurement of seminal L-carnitine, alpha,1-4-glucosidase, and glycerylphosphorylcholine in azoospermic and oligozoospermic patients

L-carnitine, alpha,1-4-glucosidase, and glycerylphosphorylcholine were measured in seminal plasma of a selected group of azoospermic men and in an unselected group of oligozoospermic men. In vasectomized subjects the epididymal indices (mean +/- standard error: L-carnitine, 276.9 +/- 27.5 nmol/ejaculate; alpha-glucosidase, 1.2 +/- 0.1 U/ejaculate; and glycerylphosphorylcholine, 1.5 +/- 0.2 mumol/ejaculate) were always below the normal range of fertile subjects (1757.4 +/- 76.7 nmol/ejaculate; 16.4 +/- 0.9 U/ejaculate; and 17.3 +/- 0.7 mumol/ejaculate, respectively). On the contrary in a large number of patients affected by azoospermia because of seminiferous tubular damage (750.4 +/- 83.6 nmol/ejaculate; 6.8 +/- 0.9 U/ejaculate; and 6.1 +/- 0.6 mumol/ejaculate; respectively) and in a few oligozoospermic subjects (1193.7 +/- 72.3 nmol/ejaculate; 10.3 +/- 0.7 U/ejaculate; and 10.8 +/- 0.7 mumol/ejaculate; respectively) the epididymal indices were found in the range of vasectomized subjects, showing an association between seminiferous tubular lesion and epididymal dysfunction. In conclusion, in spite of the low levels of epididymal indices found in patients with obstructive azoospermia, the presence of a large number of subjects with seminiferous tubular lesions without obstruction with similar low values of L-carnitine, alpha-glucosidase, and glycerylphosphorylcholine reduces the usefulness of these indices in differential diagnosis of azoospermia.     

Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation

Development and maintenance of penile erection requires the relaxation of the smooth muscle cells in the cavernous bodies and is essentially mediated by nitric oxide (NO). The penile flaccid state is conversely maintained by the alpha adrenergic neuroeffector system and by other vasoconstrictors, such as endothelin-1 (ET-1). In this study we examined the mechanisms involved in yohimbine-induced relaxation in human and rabbit corpora cavernosa (CC). We essentially found that yohimbine not only blocks contractions induced by adrenergic agonists, but also by non-adrenergic substances, such as ET-1. This effect was unrelated to antagonism at the level of ET receptors, because yohimbine did not affect ET-1-induced increase in intracellular calcium in isolated CC cells. Conversely, our data suggest that yohimbine counteracts ET-1-induced contractions by interfering with NO release from the endothelium. In fact, yohimbine-induced CC relaxation was inhibited by the mechanical removing of the endothelium and by blocking NO formation or signalling via guanylate cyclase and cGMP formation. Conversely, yohimbine activity was strongly increased by inhibiting cGMP degradation. In an experimental model of hypogonadism, performed on rabbits by chronic treatment with a long-lasting GnRH agonist, the relaxant yohimbine activity was also decreased, but completely restored by androgen supplementation. This effect was evident only in preparations in which the main source of NO was present (endothelium) or in which NO formation was not impaired by L-NAME. Our data indicate that the relaxant effect of yohimbine is both endothelium and androgen-dependent. This might justify the lack of efficacy of this drug in treatment of some form of organic erectile dysfunction.     

Practice MRI: Reducing the need for sedation and general anaesthesia in children undergoing MRI

The aim of this study was to evaluate the effectiveness of a practice magnetic resonance unit, in preparing children to undergo magnetic resonance procedures without general anaesthesia (GA) or sedation. The records of children who attended the practice MRI between February 2002 and April 2004 were retrospectively reviewed. Each record was assessed as to whether the child had passed or failed the practice MRI intervention. Those children who were considered to have passed and were proceeded to a clinical non‐GA MRI had the report of the clinical scan reviewed. If the scan had been reported as non‐diagnostic because of movement artefact it was classified as a failed scan, otherwise it was considered a pass. One hundred and thirty‐four children undertook a practice MRI (age range 4.1–16.1 years, median age 7.7 years, 47% boys) and 120/134 (90%) passed the practice session. In all, 117/120 (98%) subsequently had a clinical non‐GA MRI and 110/117 (94%) passed (median age 7.8 years, 47% boys). Preparation is a safe and effective method to reduce the need for sedation and GA in children undergoing a clinical MRI scan. It provides a positive medical experience for children, parents and staff, and results in cost savings for the hospital.     

Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients

Gluconeogenesis (GNG) is enhanced in type 2 diabetes. In experimental animals, insulin at high doses decreases the incorporation of labeled GNG precursors into plasma glucose. Whether physiological hyperinsulinemia has any effect on total GNG in humans has not been determined. We combined the insulin clamp with the (2)H(2)O technique to measure total GNG in 33 subjects with type 2 diabetes (BMI 29.0 +/- 0.6 kg/m(2), fasting plasma glucose 8.1 +/- 0.3 mmol/l) and in 9 nondiabetic BMI-matched subjects after 16 h of fasting and after euglycemic hyperinsulinemia. A primed-constant infusion of 6,6-(2)H-glucose was used to monitor endogenous glucose output (EGO); insulin (40 mU. min(-1). m(-2)) was then infused while clamping plasma glucose for 2 h (at 5.8 +/- 0.1 and 4.9 +/- 0.2 mmol/l for diabetic and control subjects, respectively). In the fasting state, EGO averaged 15.2 +/- 0.4 micromol. min(-1). kg(-1)(ffm) (62% from GNG) in diabetic subjects and 12.2 +/- 0.7 micromol. min(-1). kg(-1)(ffm) (55% from GNG) in control subjects (P < 0.05 or less for both fluxes). Glycogenolysis (EGO - GNG) was similar in the two groups (P = NS). During the last 40 min of the clamp, both EGO and GNG were significantly (P < 0.01 or less, compared with fasting) inhibited (EGO 7.1 +/- 0.9 and 3.6 +/- 0.5 and GNG 7.9 +/- 0.5 and 4.5 +/- 1.0 respectively) but remained significantly (P < 0.05) higher in diabetic subjects, whereas glycogenolysis was suppressed completely and equally in both groups. During hyperinsulinemia, GNG micromol. min(-1). kg(-1)(ffm) in diabetic and control subjects, was reciprocally related to plasma glucose clearance. In conclusion, physiological hyperinsulinemia suppresses GNG by approximately 20%, while completely blocking glycogenolysis. Resistance of GNG (to insulin suppression) and resistance of glucose uptake (to insulin stimulation) are coupled phenomena. In type 2 diabetes, the excess GNG of the fasting state is carried over to the insulinized state, thereby contributing to glucose overproduction under both conditions.     

Expression of HER-2/neu oncoprotein, DNA-ploidy and S-phase fraction in advanced ovarian cancer

The immunohistochemical expression of HER-2/neu and cytofluorimetric data were retrospectively analyzed in a group of primary advanced ovarian cancers. Thirty-three out of 94 (35%) cases showed a specific p185/neu immunoreaction. No correlation between p185/neu expression and any of the clinico-pathologic parameters examined was observed. As far as cytofluorimetric data are concerned, 38 out of 69 (55%) of the tumors were diploid (DNA index = 1) while 31 (45%) were aneuploid (DNA index from 1.10 to 2.50 with a median value of 1.50). Ovarian tumors were defined as of low and high S-phase fraction in 68% and 32% of the cases, respectively. Tumor ploidy and S-phase fraction did not correlate with the clinico-pathologic characteristics or p185/neu oncoprotein expression. Aneuploid tumors had a higher S-phase fraction (mean: 15.81 ± 13.44) than diploid tumors (mean: 8.89 ± 7.98) ( P < 0.01). p185/neu expression failed to affect significantly both overall and progression free survival. On the other hand tumor ploidy was found to be related to the prognosis of advanced ovarian cancer patients although the difference was not statistically significant. As far as progression free survival is concerned, the median time to recurrence was not reached for diploid cases whereas it was 21 months for aneuploid cases ( P < 0.05). The 5-year survival for patients with a low S-phase fraction (58%) was significantly higher than for patients with high S-phase fraction tumors (28%) ( P < 0.01). Median time to recurrence was 48 and 17 months for low and high S-phase fraction tumor patients, respectively ( P < 0.05). However, in a multivariate analysis both tumor ploidy and S-phase fraction did not retain their prognostic value. The assessment of the role of the parameters examined in improving the prognostic characterization of ovarian cancer patients should be investigated in large multicenter clinical trials.     

Double blind, placebo controlled study of nedocromil sodium in asthma

After a two week baseline, 209 asthmatic children (mean age 10 years, range 6-17) were randomly allocated to receive 4 mg nedocromil sodium (n = 110) or placebo (n = 99) four times daily for 12 weeks in addition to their current treatment. The children completed daily diary cards and visited the clinic at four week intervals. Statistically significant differences in favour of nedocromil sodium were seen for clinician assessment of asthma severity and diary card symptom scores, pulmonary function and inhaled beta 2 bronchodilator use. Total symptom score decreased by 50% from baseline in the nedocromil sodium group and by 9% in the placebo group during the final four weeks. Nedocromil sodium was considered very or moderately effective by 78% of children/parents (placebo 59%) and 73% of clinicians (placebo 50%). Nausea, headache and sleepiness, and dyspnoea led to withdrawal of one child from nedocromil sodium and placebo treatments, respectively. Reports of sore throat and headache were marginally greater with the nedocromil sodium treatment. It is concluded that nedocromil sodium was both effective and safe in the treatment of asthma in children.