Nucleolar organizers and mitotic conditions in endometrial hyperplasia and carcinomaĭ

The study deals with the levels of nucleolar organizers (NO) and mitotic conditions in 85 samples of the endometrium (proliferative stage of menstrual cycle--5; glandular hyperplasia--10; adenomatosis--15; atypical hyperplasia--25 and adenocarcinoma--25). These findings point to a significant increase in NO number in atypical hyperplasia and especially in adenocarcinoma. The latter showed an inverse correlation between the index under study and cell differentiation stage. Endometrial mitosis displayed a higher mitotic index, a larger fraction of pathological mitoses and cells passing through metaphase as well as a variety of pathological forms of karyokinesis. A high correlation between NO number and mitotic index was observed for different conditions of the endometrium.     

Individual variations of total and percent free serum prostatic specific antigen: could they change the indication of prostatic biopsy?

The aim of this study was to analyse the individual variations of total and percent free serum prostatic specific antigen (PSA) and to evaluate whether they could change the indication for prostatic biopsy. Prostatic needle biopsy was indicated in 63 patients with serum PSA between 4.0 and 10 ng/ml. A new determination of total and free PSA was done before the biopsy procedure. The time between the determinations ranged from 29 to 59 days. The total and free serum PSA determinations were performed by a double monoclonal antibody radioimmunoassay Tandem and Tandem free PSA. The median coefficient of variation for serum PSA was 12.9 in cancer free patients and 18.8 when cancer was detected, it was 32.6 and 42.2 respectively for percent free serum PSA. A 22.8% rate of discrepancy between the determinations was found when prostatic biopsy was indicated only by percent free PSA lower than 25. Sensitivity ranged from 93.3% to 100, and reduction of unnecessary biopsies between 15.2 and 21.8%. We conclude that individual variations in total and percent free serum PSA could have clinical implications because of the possibility that it changes the indication for a prostatic biopsy.     

Comparison of increased aromatase versus ERα in the generation of mammary hyperplasia and cancer

Factors associated with increased estrogen synthesis increase breast cancer risk. Increased aromatase and estrogen receptor α (ERα) in both normal epithelium and ductal carcinoma in situ lesions are found in conjunction with breast cancer, leading to the idea that altered estrogen signaling pathways predispose the mammary gland to cancer development. Here, we developed a transgenic mouse that conditionally expresses aromatase in the mammary gland, and used it along with a deregulated ERα expression model to investigate the molecular pathways involved in the development of mammary gland preneoplasia and carcinoma. Both increased ERα and aromatase expression led to the development of preneoplasia, but increased preneoplasia, in addition to carcinoma, was found in aromatase overexpressing mice. Increased prevalence of mammary pathologic changes in mice expressing aromatase correlated with increased cyclin E and cyclin-dependent kinase 2 expression. Gain of both ERα and aromatase increased expression of ERα and progesterone receptor, but aromatase produced a higher increase than ERα, accompanied by higher levels of downstream target genes Ccnd1, Myc, and Tnfsf11. In summary, whereas gain of both ERα and aromatase activate abnormal growth pathways in the mammary gland, aromatase induced a wider range of abnormalities that was associated with a higher prevalence of mammary preneoplasia and cancer progression.     

不典型增生(atypical hyperplasia)

又称异形增生或称核结构不良等。它可见于任何组织或细胞,其主要形态学表现为细胞核相对增大,核膜增厚,染色质增多,核形不规则,核浆比例增大,但不具备恶性肿瘤的形态特点等。它属于癌前病变的一种,在某种因素继续作用下,它可以由量变质变,转变为恶性肿瘤。如果某些因素去掉,它又可能恢复到正常状态。有人称不典型增生是一种不稳定状态。但晚近许多学者认为,不典型增生可有两种类型,即炎性不典型增生与瘤性不典型增生。前者DNA分析通常为二倍体,一般不发生恶性转化。后者DNA分析常为增殖     

How useful is GLUT-1 in differentiating mesothelial hyperplasia and fibrosing pleuritis from epithelioid and sarcomatoid mesotheliomas? An international collaborative study

Objective

Mesothelial hyperplasia (MH) and fibrosing pleuritis (FP) can be difficult to distinguish from epithelioid (MM-E) and sarcomatoid (MM-S) malignant pleural mesotheliomas. GLUT-1 has shown variable results regarding its sensitivity and specificity when used to evaluate mesothelial proliferations. We evaluated the utility of GLUT-1 immunostaining in differentiating MH and FP from MM-E and MM-S.

Materials and methods

In this retrospective study, diagnostically well-characterized cases (MH = 31, FP = 29, MM-E = 41, MM-S = 29) were collected and manually stained for GLUT-1. All slides were visually scored by 2 pathologists; using the following system: 0%, 1+ 1–25%, 2+ 26–50% and 3+ >51% cells staining.

Results

All benign cases (n = 60) were negative for GLUT-1 while 45 of 78 (58%) MM [21 of 41 (50%) MM-E, 21 of 29 (72%) MM-S and 3 of 3 biphasic mesothelioma (100%)] had 1+ to 3+ staining. Of the MM-E, 10 had 1+, and 11 had 2+ staining; of the MM-S 3 had 1+, 15 had 2+ and 3 had 3+ staining. Both sarcomatoid and epithelioid components of the 3 biphasic mesotheliomas revealed 1+ staining. All 5 desmoplastic MM were negative.

Conclusions

Positive staining with GLUT-1 is helpful since it is present in half of MM-E and three-quarter of MM-S. Although all reactive mesothelial lesions were negative, the absence of immunoreactivity does not exclude the diagnosis of MM. As with all IHC stains used for diagnostic purposes, GLUT-1 has to be a part of a panel, and the results interpreted in the context of clinical, radiological and histological findings.     

Association between biomarkers of obesity and risk of high-grade prostatic intraepithelial neoplasia and prostate cancer – Evidence of effect modification by prostate size

Prostate enlargement is common with aging and obesity. We investigated the association between obesity and prostate cancer controlling for differential detection related to prostate enlargement. In an analysis of 500 men, we found body mass index, waist–hip ratio, and blood leptin levels were significantly associated with high-grade PC, but only among men without prostate enlargement. Leptin was also significantly associated with high-grade prostatic intraepithelial neoplasia (HGPIN) in the absence of prostate enlargement. Our results suggest obesity advances prostate carcinogenesis, and that detection biases at prostate biopsy may explain past inconsistencies in the association between obesity and PC.     

Prevention and reversal by a non-polar arotinoid (Ro 15–0778) of 3,4-benzpyrene- and cigarette smoke condensate-induced hyperplasia and metaplasia of rodent respiratory epithelia grown in vitro

A non-polar arotinoid, Ro 15–0778, has been investigated for its effect on carcinogen-induced changes in rodent respiratory epithelia in organ culture. In neonatal rat tracheas and fetal mouse lungs grown in vitro, 3,4-benzpyrene and cigarette smoke condensate induce on increased proliferation of epithelial cells associated with a loss of secretory activity and of ciliary function. These changes persist in the absence of carcinogens in explants transferred to control medium. Ro 15–0778 alone has no influence on the normal epithelial growt rate or normal differentiation. However, if combined with either benzpyrene or smoke condensate, the arotinoid antagonizes the carcinogen-induced hyperplasia and metaplasia. During simultaneous treatment, it prevents the increase in mitosis and the loss of secretory activity or ciliary function. In explants pretreated with benzpyrene or cigarette smoke condensate, Ro 15–0778 reverses the high proliferation rate and restores secretory differentiation and ciliary function. The compound is of experimental and clinical interest, since—in contrast to most retinoids—it lacks the signs nd symptoms of the classical hypervitaminosis A syndrome. It may be justified to consider it for the treatment of early precancerous changes of the bronchial tree.     

p53 nuclear accumulation and ERα expression in ductal hyperplasia of breast in a cohort of 215 Chinese women

Introduction

Women with ductal hyperplasia including usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH) have an increased risk of developing invasive ductal carcinoma (IDC) of breast. The importance of several molecular markers in breast cancer has been of considerable interest during recent years such as p53 and estrogen receptor alpha (ERα). However, p53 nuclear accumulation and ERα expression have not been assessed in ductal hyperplasia co-existing with ductal carcinoma in situ (DCIS) or IDC versus pure ductal hyperplasia without DCIS or IDC.

Materials and methods

We investigated p53 nuclear accumulation and ERα expression in breast ductal hyperplasia in a cohort of 215 Chinese women by immunohistochemistry (IHC), which included 129 cases of pure ductal hyperplasia, 86 cases of ductal hyperplasia co-existing with DCIS (41 cases) or IDC (45 cases).

Results

Nuclear p53 accumulation was identified in 22.8% of ADH (31/136), 41.5% of DCIS (17/41) and 42.2% of IDC (19/45), and no case of UDH (0/79). No difference in nuclear p53 accumulation was observed between pure ADH and ADH co-existing with DCIS (ADH/DCIS) or IDC (ADH/IDC) (P > 0.05). The positive rate of ERα expression was lower in ADH (118/136, 86.8%) than that in UDH (79/79, 100%) (P < 0.001), but higher than that in DCIS (28/41, 68.3%) or IDC (26/45, 57.8%) respectively (P < 0.001). The frequency of ERα expression was lower in ADH/DCIS (23/29, 79.31%) and ADH/IDC (23/30, 76.67%) than that in pure ADH (72/77, 93.51%) respectively (P < 0.05). There was a negative weak correlation between p53 nuclear accumulation and ERα expression as for ADH (coefficient correlation -0.51; P < 0.001).

Conclusions

Different pathological types of ductal hyperplasia of breast are accompanied by diversity in patterns of nuclear p53 accumulation and ERα expression. At least some pure ADH is molecularly distinct from ADH/CIS or ADH/IDC which indicated the two types of ADH are molecularly distinct entities although they have the same morphological appearance.     

Combined treatment of Dunning R3327 rat prostatic tumor with the 5α-reductase inhibitor PNU 157706 and the antiandrogen bicalutamide

 PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenyl- propyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide], a novel, potent and selective dual 5α-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. Purpose: We investigated the efficacy of treatment with PNU 157706 in combination with the antiandrogen bicalutamide in this prostatic tumor model. Methods: Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with bicalutamide (0.2 and 1 mg/kg per day). Animals were killed 24 h after the last treatment, and ventral prostates were removed for testosterone (T) and dihydrotestosterone (DHT) determination. Results: PNU 157706 reduced the growth of established tumors by 39%; bicalutamide proved ineffective at 0.2 mg/kg per day, but reduced tumor growth by 45% at a dose of 1 mg/kg per day. The combination of PNU 157706 with both doses of bicalutamide caused an additive tumor growth inhibition (50% and 64%). Castration resulted in marked tumor growth inhibition (72%). Ventral prostate weight was markedly reduced by PNU 157706 (78%) treatment and by bicalutamide (59% and 77%); combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (88%), whereas prostatic T increased slightly (60%). Concomitant treatment with bicalutamide antagonized the T increase induced by PNU 157706 and did not modify the already remarkable suppression of DHT. Conclusions: These data show that the inhibitory effect of PNU 157706 and bicalutamide on Dunning prostatic tumor growth is additive, thus suggesting a possible role of PNU 157706 in the therapy of advanced prostate cancer, in combination with antiandrogens, to provide an effective peripheral androgen ablation therapy with minimal side effects. Received: 1 February 1999 / Accepted: 8 June 1999     

Current results of neutron therapy at the UCL, for soft tissue sarcomas and prostatic adenocarcinomas. Université Catholique de Louvain

From March 1978 to August 1985, 630 patients were treated with fast neutrons at the UCL cyclotron of Louvain-la-Neuve. Neutrons are produced by bombarding a beryllium target with 65 MeV protons. A CNPF of 2.8 was adopted. As far as soft tissue sarcomas are concerned, 32 patients were irradiated after "radical" surgery: only 2 local recurrences were observed (follow-up from 6 months to more that 5 years). On the other hand, in a group of 26 patients with large inoperable, recurrent of incompletely resected tumours, local control could not be achieved in 14 cases. In the whole group of these 58 patients, 12 severe complications were observed; their frequency increases with field size which in turn reflects tumour extent. Locally extended prostatic adenocarcinomas (stage C) were treated with mixed schedule irradiation (3 neutron and 2 photon fractions per week). A local control rate of 93% at 1 year, of 83% at 2 years, and 90% at 3 years was achieved (28, 23 and 10 patients respectively). The early and late tolerance was excellent; only one complication was observed.     

Is sextant biopsy a valid method in diagnosis of prostatic cancer?

We evaluated effectiveness of a laterally directed sextant biopsy on large prostates and analysed the results of this biopsy technique in a group of men with obstructive voiding symptoms and suspected prostatic cancer (PC). Biopsy was performed in 386 men because of elevated PSA and/or abnormality in digital rectal examinations (DRE). The mean prostate volume was 79.6 +/- 39.1 cm3, and in 72.3% of the cases the volume of the prostate was > or = 50 cm3. PC was diagnosed in 107 of 386 cases (27.7%). In groups of patients with < 50 cm3 (small), 50 to 79 cm3 (medium) and > or = 80 cm3 (large) prostate volume and normal DRE, PC was detected in 27.5, 19.4 and 9.5% of cases, respectively (p < 0.018). PC detection rate was statistically insignificant (SI) in the same groups of patients with abnormal findings at DRE, 49.2, 54.2 and 51.9%, respectively (SI). Repeat sextant biopsy revealed PC in 14.5% patients. After TURP prostatic cancer was found in 7.7% patients who had undergone biopsy two times before. Thus, our results show that laterally directed sextant biopsy is an effective method of PC detection among suspected patients (PSA > 4 ng/ml) with large volume prostates and abnormal findings at DRE. An extensive biopsy protocol should be considered as a more appropriate method for markedly enlarged prostates with normal DRE findings but also for repeat biopsies.     

Is maximal androgenic blockade necessary in the treatment of prostatic cancer?

As the literature data give arguments both pro and contra wide use of maximal androgenic block (MAB) in the treatment of prostatic cancer, the authors studied MAB in 200 patients. They came to the conclusion that MAB can be applied in patients with symptoms of disseminated prostatic cancer as neoadjuvant therapy before prostatectomy and as neoadjuvant and adjuvant therapy in planning radiotherapy.     

Can p503s,p504s and p510s gene expression in peripheral-blood be useful as a marker of prostatic cancer?

Background  

The aim of the study was to investigate whether p503S, p504S and p510S gene expression in peripheral-blood be useful as a diagnostic or prognostic marker of prostatic cancer.     

Altered TGF-β signaling in a subpopulation of human stromal cells promotes prostatic carcinogenesis

Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells.     

Atypical ductal hyperplasia in men with gynecomastia: what is their breast cancer risk?

Breast Cancer Research and Treatment - Atypical ductal hyperplasia (ADH) significantly increases the risk of breast cancer in women. However, little is known about the implications of ADH in men....