Hypodiploidy, Ki-67 growth fraction and prognosis of surgically resected lung cancers.

One hundred and thirty-seven lung cancer patients (123 non-small-cell lung cancers (NSCLC), 10 small-cell lung cancers (SCLC) and four carcinoid tumours) who underwent surgery in an attempt at complete resection were prospectively entered in a study whose aim was to determine the prognostic significance of a hypodiploidy or a multiploidy pattern of tumour cell DNA content and a high immunohistochemical reactivity of Ki-67, a nuclear antigen related to the cell cycle. Indirect immunoperoxidase reactivity of Ki-67 on frozen tumour tissue sections was evaluated both visually, using a classical semiquantitative scale, and by means of a computer-assisted image processor. Cell DNA content analysis was done using static computer-assisted cytometry on tumour cytological prints stained by the pararosaline Feulgen-Schiff technique. The ploidy was characterised for each tumour by DNA index (DI), percentage of hypodiploid cells and type of DNA content histogram (near diploid, hyperdiploid, hypodiploid and multiploid). Ki-67 immunostaining was negative in 64 tumours (48%) and positive in 69 (52%). DNA histogram classification disclosed 57 (42%) near diploid tumours. Among the 80 (58%) aneuploid tumours, 16 were hypodiploid, 44 hyperdiploid and 20 multiploid. The prevalence of both a positive Ki-67 immunostaining and an aneuploid DNA histogram differed according to histology as SCLC demonstrated a higher frequency of both features when compared with NSCLC and carcinoid tumours. On the other hand, Ki-67 immunostaining and ploidy did not significantly differ according to degree of differentiation, nodal status and Mountain''s stage grouping. The percentage of cells in the hypodiploid modal DNA was significantly higher for tumours which demonstrated a high Ki-67 immunostaining, suggesting a link between growth fraction and DNA content abnormalities. In univariate analysis, survival did not differ significantly according to either the Ki-67 immunohistochemical reactivity or the DNA index. Patients with a hypodiploid tumour had a shorter survival than patients with other DNA histogram patterns but, owing to the low frequency of hypodiploidy, this difference did not reach statistical significance. In Cox''s proportional hazard model, an SCLC histology, an advanced tumour status, a positive nodal status and a hypodiploid tumour (hazard ratio: 2.070; 95% confidence interval 1.041-4.116) were significant determinants of survival. We conclude that hypodiploidy in lung cancer is a distinct DNA content abnormality as it contributes significantly to prognosis. Neither visually assessed nor computer-generated Ki-67 immunostaining measurements significantly determine prognosis.     

Cancer of the endometrium: analysis of the comparative results and causes of failure in radiosurgical treatment and physical agents alone. 215 cases treated between 1968 and 1978

Two groups of patients (215 cases) with endometrial cancer were treated between 1968 and 1978 either by a combination of radiotherapy and surgery or by radiotherapy alone. In the first group (99 cases) with a mean age of 59 years, results were very favorable for stage T1 and T2 (49/60, 82%) which confirm other results in the literature. The combination of radiotherapy and surgery comprising external irradiation and intracavitary irradiation prior to total hysterectomy did not appear to increase the number of complications to the urinary or digestive tracts. The second group (116 cases) comprised patients treated exclusively by radiotherapy due to the presence of metastatic disease (74 cases) or excessive local-regional extension (37 cases). The cure rate at 5 years appeared satisfactory for stage T1 (35/54, 65%). The differing results between combined radiotherapy and surgery with methods using radiotherapy alone should be partially corrected to take into account the older average age of the second group (69 years). Failures due to the appearance of metastases were approximately similar in both groups (near 6%); on the other hand, local-regional recurrences were more frequent when radiotherapy alone was used, which accounts for the differing results between the two groups. In the second period (1972 to 1978), the group treated exclusively with radiotherapy benefited from a technique used with cervical cancer: external irradiation followed by intracavitary irradiation with a Fletcher-Suit applicator with results similar to those treated in the first period with intracavitary irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bcl-6 p53 mutations in lymphomas carrying the bcl-2/Jh rearrangement

BACKGROUND AND OBJECTIVES: The t(14;18)(q32;q21) chromosomal translocation is the hallmark of follicular lymphomas (FL). The translocation induces the overexpression of the Bcl-2 protein and prolongs the survival of clonogenic cells. Tumor cells may acquire additional molecular alterations that may be associated with histologic progression or with chemo-resistance. DESIGN AND METHODS: We analyzed the distribution and association of bcl-6 and p53 mutations in 55 consecutive bcl-2/Jh+ lymphoma samples derived from 43 patients obtained at the time of diagnosis and, in 5 of these patients, during follow-up. A total of 29 bcl-6 point mutations were detected in seventeen patients (40%) associated with major or minor breakpoints of the bcl-2/Jh fusion gene. In seven cases a p53 mutation was detected. Three cases corresponded to FL with the minor breakpoint in the bcl-2 gene and these patients had a favorable clinical evolution, whereas the 4 patients with p53 mutations and the major breakpoint had a bad clinical outcome with morphologic transformation to high-grade lymphoma in three cases. The sequential analysis of 5 patients showed a different timing in the acquisition of mutations: one patient showed bcl-6 and p53 mutations at diagnosis, another patient showed bcl-6 mutations at diagnosis and acquired a p53 mutation later whereas the third patient had a p53 mutation before the appearance of the bcl-6 mutation. RESULTS: We did not find significant differences in survival between patients with FL who showed exclusively bcl-6 mutations and those without bcl-6 mutations, but those patients with a high International Progostic Index score and p53 mutations showed the lowest overall survival (p = 0.002). INTERPRETATION AND CONCLUSIONS: These findings suggest that bcl-2/Jh lymphomas show molecular heterogeneity and that bcl-6 and p53 mutations may be acquired during the evolution of such lymphomas. Bcl-6 mutations, by themselves, do not seem to be associated with a bad prognosis. Rearrangements at the minor bcl-2 locus may have a different molecular evolution.     

Gender effects on adrenergic receptor expression and lipolysis in white adipose tissue of rats

OBJECTIVE: To investigate the effects of short-term (15 days) cafeteria-diet feeding on the expression of alpha- and beta-adrenergic receptors (AR) and its association with lipolytic stimulation in isolated retroperitoneal white adipocytes. RESEARCH METHODS AND PROCEDURES: Six female and 6 male Wistar rats (4 weeks old) were fed a cafeteria diet plus standard diet for 15 days. The remaining 12 age- and sex-matched rats received a standard diet only. White retroperitoneal adipose tissue was isolated and used for the determination of both alpha(2) and beta-AR expression and for in vitro studies of lipolytic activity. RESULTS: In female control rats, we found higher lipolytic capacities located at the postreceptor level and a lower alpha(2)/beta(3)-AR ratio than male rats. Cafeteria-diet feeding for 15 days decreased lipolytic activity in both male and female rats and altered the alpha(2A)- and beta(3)-AR protein levels with an increase of alpha(2A)-AR in males and a beta(3)-AR decrease in females. DISCUSSION: Our results indicate that a 15-day cafeteria-diet feeding induced an increase in the alpha(2)/beta(3)-AR balance and impaired adipose tissue lipolytic activity, which was higher in males and may contribute to the development of increased fat mass. The higher functionality of alpha(2)-AR, together with the minor role developed by beta(3)-AR and lower lipolytic capacities located at the postreceptor level in cafeteria-diet-fed male rats compared with female rats, may be responsible for the gender-dependent differences observed in this study.     

Counteraction of type 1 diabetic alterations by engineering skeletal muscle to produce insulin: insights from transgenic mice

Insulin replacement therapy in type 1 diabetes is imperfect because proper glycemic control is not always achieved. Most patients develop microvascular, macrovascular, and neurological complications, which increase with the degree of hyperglycemia. Engineered muscle cells continuously secreting basal levels of insulin might be used to improve the efficacy of insulin treatment. Here we examined the control of glucose homeostasis in healthy and diabetic transgenic mice constitutively expressing mature human insulin in skeletal muscle. Fed transgenic mice were normoglycemic and normoinsulinemic and, after an intraperitoneal glucose tolerance test, showed increased glucose disposal. When treated with streptozotocin (STZ), transgenic mice showed increased insulinemia and reduced hyperglycemia when fed and normoglycemia and normoinsulinemia when fasted. Injection of low doses of soluble insulin restored normoglycemia in fed STZ-treated transgenic mice, while STZ-treated controls remained highly hyperglycemic, indicating that diabetic transgenic mice were more sensitive to the hypoglycemic effects of insulin. Furthermore, STZ-treated transgenic mice presented normalization of both skeletal muscle and liver glucose metabolism. These results indicate that skeletal muscle may be a key target tissue for insulin production and suggest that muscle cells secreting basal levels of insulin, in conjunction with insulin therapy, may permit tight regulation of glycemia.     

Combination chemotherapy without cisplatin in the treatment of advanced non-small cell lung cancer

Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy-toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. QUALY methods based on time without symptoms and toxicity allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing non-platinum-based doublets with either single-drug chemotherapy or standard cisplatin-based doublets.     

2000 Standards,Options and Recommendations for prognostic value of oncogenes and tumor suppressor genes in non small cell lung cancer

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French cancer centers (FNCLCC), the 20 French cancer centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines for non small cell lung cancer patients according to the definitions of the Standards, Options and Recommendations project. METHODS: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers. RESULTS: This article presents the chapter "Prognosis significance of oncogenes and tumor suppressor genes" from the full report "Standards, Options and Recommendation for non small cell lung cancer" validated in August 2000. The main recommendations are: 1) No clear clinical prognostic value of oncogenes and tumor suppressor genes (p53, bcl-2, Ki-ras, c-erbB-2, Rb, p16) in non small cell lung cancer, can be established from the available evidences (standard, level of evidence C). 2) Prospective multicenter studies should be performed to assess prognostic significance of oncogenes and tumor suppressor genes in non small cell lung cancer.