Protein tyrosine kinase activity in 350 T1/T2, N0/N1 breast cancer. Preliminary results

Protein tyrosine kinases (PTKs) are a family of enzymes sharing a highly conserved catalytic domain which phosphorylates substrate proteins on tyrosine residues. PTKs play a major role in the transduction of the mitogenic signal and are involved in the control of cell proliferation, differentiation, and transformation processes. PTKs can be subdivided into two major types: membrane associated PTKs consisting essentially of growth factor receptors (receptor tyrosine kinases or RTKs) and cytosolic PTKs involved in the intracellular transduction of mitogenic and differentiation signals. From January 1988 to January 1992, PTK activity was assayed in cytosolic fractions prepared from 350 T1-T2, N0-N1 M0, breast carcinomas. Enzymatic activity was measured using phosphate transfer from [³²P]-ATP to poly-Glu-Tyr as an artificial substrate. According to our previously reported pilot study, we chose a cut-off value of 12 pmol³²P incorporated min^–1 mg^–1 protein, corresponding to the median value. We found positive PTK levels ( 12 pmol/min/mg) to be correlated with a loss of differentiation according to Scarff-Bloom grade (p < 0.001), negative PR (p = 0.03) and ER status (p = 0.04). With a median follow-up of 30 months (0–82), patients with a positive PTK level presented a smaller 3-year disease free survival than in the PTK negative group of patients (p = 0.07). In Cox multivariate analysis including pT, pN, Scarff-Bloom grade, PR and ER, PTK activity does not emerge as a significant prognostic factor.     

Objective acoustic and aerodynamic measures of breathiness in paralytic dysphonia

This study was designed to determine which objective acoustic or aerodynamic parameters allowed a homogeneous group of patients with unilateral vocal fold paralysis (UVFP) to be distinguished from an age-matched and smoking-matched control group and to search for linear correlations between the objective parameters and the subjective breathiness ratings. Eight patients with recent-onset UVFP and 12 controls were prospectively studied. The acoustic parameters measured for the vowel /a/ at a comfortable frequency and intensity were: jitter, shimmer, harmonics-to-noise ratio, cepstral peak prominence, the difference between the levels of the first two harmonics and the relative energy above 6 kHz. Aerodynamic parameters included the mean flow rate during a sustained /a/ and intraoral pressure during the production of the phoneme /pi/. The long-term average spectrum was calculated for 40 s of text, and the relative average energies in four frequency bands were compared. Six judges rated a mid-/a/ sample using a five-parameter scale with four levels of severity. Nonparametric statistical analysis revealed significant differences ( P<.05) between the UVFP group and the control group for 14 of the 19 parameters studied. Correlations between the objective parameters and perceived breathiness differed in the two groups. Correlations were not always as expected as based on previous literature reports. These measurements provided an objective qualification of voice in patients with UVFP and successfully distinguished them from the normal controls. The objective acoustic and aerodynamic measurements had generally low linear correlations with breathiness ratings in the control group. Higher correlations were seen in the UVFP group, in which breathiness was best correlated with airflow measurements.     

Clinical evaluation of HER-2/neu protein in malignant pleural effusion-associated lung adenocarcinoma and as a tumor marker in pleural effusion diagnosis.

PURPOSE: Lung adenocarcinoma presenting as malignant pleural effusion (MPE) is common in Taiwan. Microscopically, the involved pleurae are infiltrated by numerous tumor foci, which suggests that the cancer cells are highly invasive. Overexpression of HER-2/neu has been related to proliferation, antiapoptosis, and the high invasiveness of various cancer cells. We therefore were interested in studying the role of HER-2/neu in MPE-associated adenocarcinoma cell lung cancer (ADCLC). Experimental Design: The expression of HER-2/neu in pleural effusion was measured by ELISA. The HER-2/neu protein expression on tumor cells was evaluated by immunohistochemical (IHC) staining, and gene amplification was assayed by fluorescence in situ hybridization. RESULTS: The mean value of HER-2/neu in pleural effusions of patients with ADCLC and other nonmalignant lung diseases was 9.9 and 2.7 ng/ml, respectively. The difference is statistically significant (P < 0.001). Compared with cytokeratin 19 fragment CYFRA 21-1, the performance of HER-2/neu as a tumor marker in pleural effusion diagnosis was better. Overexpression of HER-2/neu in tumor tissues was found in 70% (23 of 32) of patients with MPE-associated ADCLC, 30% (13 of 43) with stage I/II non-small cell lung cancer (NSCLC), and 44% (14 of 32) with stage III NSCLC. The incidence of HER-2/neu overexpression in tumor tissues of patients with MPE-associated ADCLC was significantly higher than that of patients with stage I-III NSCLC without MPE. HER-2/neu gene amplification was uncommon (1.9%). The correlation between the IHC H-score in tumor samples and the pleural effusion level of HER-2/neu was significant (P < 0.01). A higher incidence of HER-2/neu expression beyond the cutoff point (5.5 ng/ml) in pleural effusions was also found in patients whose IHC H-scores were >50. CONCLUSIONS: These findings indicate that HER-2/neu is important in the pathogenesis of MPE-associated ADCLC and is a potential tumor marker for a diagnosis of pleural effusion.     

The impact of radiotherapy for carcinoma of the cervix on sexual function assessed using the LENT SOMA scales.

BACKGROUND AND PURPOSE: As there are few studies examining the impact of radiotherapy on sexuality, we assessed the effect of radiotherapy for carcinoma of the cervix on sexual health and the ability of the LENT system to assess sexual function. MATERIALS AND METHODS: Using the vagina and sexual dysfunction scales of the LENT SOMA scales, subjective scores were measured prospectively before initiation of radiotherapy for 89 women, and at the following times after the start of treatment: 21, 70, 200, 400, 600 and 800 days. RESULTS: There was considerable variation in pre-radiotherapy scores that was not related to disease stage (P=0.054), but was related to patient age (P=0.037, for the average vagina scores and P=0.039 for the maximum vagina scores) The scores were influenced by prior surgery (P<0.0005 for maximum and average vagina scores, P=0.042 average and 0.017 maximum sexual dysfunction scores). For 48 patients for whom data were available at the first three time points, the vagina scores decreased significantly by 70 days compared to pre-radiotherapy scores, but not for sexual dysfunction. There was heterogeneity in the pattern of changes of scores over time: for some women there was no change in vagina subsection score, some increased, and some decreased. CONCLUSIONS: The work has shown variation both in pre-treatment sexual function and in the pattern of changes seen following radiotherapy. Our questionnaire proved useful to score subjective sexual and vaginal problems as given in the LENT subjective scales. Further study is needed to assess the effectiveness of the scales in assessing late effects.     

Family history of autoimmune thyroid disease and childhood acute leukemia.

The association between a familial history of autoimmune disease and childhood acute leukemia was investigated in a French case-control study that, overall, was designed to assess the role of perinatal, infectious, environmental, and genetic factors in the etiology of childhood acute leukemia. Familial histories of autoimmune disease in first- and second-degree relatives were compared in 279 incident cases, 240 cases of acute lymphocytic leukemia (ALL) and 39 cases of acute non-lymphoblastic leukemia (ANLL), and 285 controls. Recruitment was frequency matched by age, gender, hospital, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0-2.8) was found. A relationship between thyroid diseases overall and ALL (OR, 2.0; 95% CI, 1.0-3.9) was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave's disease and/or hyperthyroidism and Hashimoto's disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1-10.7 and OR, 5.6; 95% CI, 1.0-31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases (thyroid goiter, thyroid nodule, and unspecified thyroid disorders) (OR, 1.6; 95% CI, 0.7-3.5 and OR, 1.3; 95% CI, 0.2-7.0, respectively, for ALL and ANLL). The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia.     

Antineoplastic effects of partially HLA-matched irradiated blood mononuclear cells in patients with renal cell carcinoma.

PURPOSE: Vaccines, cytokines, and other biologic-based therapies are being developed as antineoplastic agents. Many of these agents are designed to induce an autologous immune response directed against the malignancy. In contrast, hematopoietic stem-cell transplantation is being developed as a form of allogeneic immunotherapy. This study tests the tolerance and antineoplastic activity of sequential infusions of partially HLA-matched allogeneic blood mononuclear cells (obtained from relatives) when administered outside of the context of a hematopoietic stem-cell transplantation. The cells are irradiated to prevent graft-versus-host disease. PATIENTS AND METHODS: Fifteen patients with relapsed or refractory malignancies for which no standard therapy was available were enrolled onto a clinical trial designed to assess the tolerability and antineoplastic effects of irradiated partially HLA-matched blood mononuclear cells obtained from relatives. RESULTS: There was disease regression in three patients with metastatic renal cell carcinoma during treatment. There was disease progression in six patients with metastatic renal cell carcinoma and two patients with metastatic melanoma during treatment. There was no change in disease state in several other patients. CONCLUSION: Irradiated allogeneic blood mononuclear cells administered outside the context of hematopoietic stem-cell transplantation may induce disease responses in patients with relapsed or refractory malignancies. Transfusion of irradiated allogeneic blood mononuclear cells should be developed further as a novel therapeutic antineoplastic approach.     

The relationship between dietary fat intake and risk of colorectal cancer: evidence from the combined analysis of 13 case-control studies

The objective of this study was to examine the effects of the intakeof dietary fat upon colorectal cancer risk in a combined analysis of datafrom 13 case-control studies previously conducted in populations withdiffering colorectal cancer rates and dietary practices. Original datarecords for 5,287 cases of colorectal cancer and 10,470 controls werecombined. Logistic regression analysis was used to estimate odds ratios (OR)for intakes of total energy, total fat and its components, and cholesterol.Positive associations with energy intake were observed for 11 of the 13studies. However, there was little, if any, evidence of anyenergy-independent effect of either total fat with ORs of 1.00, 0.95, 1.01,1.02, and 0.92 for quintiles of residuals of total fat intake (P trend =0.67) or for saturated fat with ORs of 1.00, 1.08, 1.06, 1.21, and 1.06 (Ptrend = 0.39). The analysis suggests that, among these case-control studies,there is no energy-independent association between dietary fat intake andrisk of colorectal cancer. It also suggests that simple substitution of fatby other sources of calories is unlikely to reduce meaningfully the risk ofcolorectal cancer.     

Role of anionic proteins in kidney stone formation: interaction between model anionic polypeptides and calcium oxalate crystals

PURPOSE: We tested the effect of molecular weight and amino acid composition (aspartate versus glutamate) in model peptides on calcium oxalate dihydrate (COD) formation to understand how known urinary inhibitor proteins might control spontaneous crystallization. MATERIALS AND METHODS: Supersaturated solutions of CaCl2 and Na2C2O4 in HEPES buffered saline solution were prepared at various calcium (Ca) to oxalate (Ox) ratios, but constant supersaturation, in the presence of protein inhibitors (polyaspartic acid molecular weight series or polyglutamic acid). The resulting crystals were collected and evaluated with optical microscopy. RESULTS: With no added inhibitors, the crystal size increased with Ca to Ox ratio, while the number of crystals decreased. With protein inhibitors at equivalent mass concentrations, intermediate molecular weight proteins produced a greater proportion of COD in Ca rich conditions than did either extreme. In Ox rich conditions, the proportion of COD was directly related to protein molecular weight. However, at equivalent molar concentrations, the proportion of COD produced was directly related to molecular weight under all conditions. Larger protein concentrations were required to produce COD at high Ox conditions, in proportion to the increased number of crystals produced. Polyglutamic acid had a much weaker effect on crystal structure, but it changed the COM morphology. CONCLUSIONS: The results suggest that a discrete number of protein molecules per crystal were required to direct crystallization toward COD, and that a characteristic size of polypeptide chain can be defined. The charge of the side group was not the sole determinant of this effect, as polyglutamic and polyaspartic acids behaved differently. Calcium oxalate crystal nucleation rates appeared to increase with Ox content.