Role of the multidisciplinary team in breast cancer management: results from a large international survey involving 39 countries.

BACKGROUND: The optimal management of patients with breast cancer (BC) requires the expertise of specialists from different disciplines. This has led to the evolution of multidisciplinary teams (MDTs), allowing all key professionals to jointly discuss individual patients and to contribute independently to clinical decisions. Data regarding BC MDTs in different regions and countries are scarce. METHODS: The investigators of a large global phase III adjuvant BC trial being conducted by the Breast International Group were invited to respond to a questionnaire about the extent, structure, and function of BC MDTs. RESULTS: One hundred and fifty-two responses from 39 countries were received, and remarkable differences were noted in different geographic regions. Sixty-five percent of the respondents from eastern Europe, 63% from western Europe, 35% from Asia, and 25% from South America declared that MDT was a mandatory part of BC care in their country. Ninety percent of the respondents from Europe stated their MDTs met weekly, compared with only half of the respondents from Asia. CONCLUSION: This survey is perhaps the first large-scale effort to collect information regarding BC MDTs from different parts of the world and provides objective information of frequency, composition, function, and working mechanism of BC MDTs.

Regulation of PDE5 expression in normal prostate, benign prostatic hyperplasia, and adenocarcinoma.

BACKGROUND: Type 5 phosphodiesterase (PDE5) expression in the normal and pathological prostate is controversial. OBJECTIVES: This study aimed at identifying the cell type/s, if any, expressing PDE5 in human healthy or pathological prostate sections in order to further validate the rationale of PDE5 inhibitor (PDE5i) treatment of benign prostatic hyperplasia (BPH) and their safety in the treatment of erectile dysfunction following prostate cancer (PCa) surgery. MATERIALS AND METHODS: By immunohistochemical analysis, we studied PDE5 expression in tissue microarrays containing sections obtained from healthy, BPH, and PCa samples. RESULTS: Our results showed that PDE5 is barely expressed in the epithelial or stromal compartment of normal human prostates, but it is highly expressed in the stromal compartment of BPH sections. We also found that a low but significant number of PCa samples (22%) expressed PDE5 in the epithelial cancer cells but not in stromal cells and that such expression was not correlated with the tumor aggressiveness, according to their Gleason score. DISCUSSION AND CONCLUSION: PDE5 overexpression in the stromal compartment of BPH samples supports the rationale of PDE5 as a target in lower urinary tract symptoms of BPH. PDE5 expression in a significant percentage of PCa samples but the lack of correlation with the Gleason score suggests that this enzyme is not correlated with tumor aggressiveness; however, a role of PDE5 in the minimal residual disease of PCa cannot be excluded.

Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial.

BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. RESULTS: CNS relapse occurred in 4.0% of control patients and 3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. CONCLUSION: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse.

Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.

Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRafV600E mutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.

Electromotive versus passive diffusion of mitomycin C into human bladder wall: concentration-depth profiles studies.

The objectives of these investigations were: (a) to make a preliminary study to assess concentration-depth profiles of mitomycin C (MMC) in the bladder wall at specified time intervals after passive diffusion (PD); and (b) to conduct a major study to compare concentration-depth profiles after PD and electromotive drug administration (EMDA) of MMC. Full thickness sections of viable human bladder wall were placed in two-chamber cells with urothelium exposed to donor compartments containing 40 mg of MMC in 100 ml of 0.96% NaCl solutions and with serosa-facing receptor compartments containing 0.9% NaCl solutions. In the preliminary study during each of nine experimental sessions, five sections of bladder wall were individually exposed to MMC for either 5, 15, 30, 45, or 60 min. In the major study, an anode and a cathode were sited in the donor and receptor compartments, and 14 paired experiments--current (20 mA)/no current--were conducted over a 30-min period. Bladder wall sections were cut serially into 40-microm slices parallel to the urothelium and analyzed by high-performance liquid chromatography for MMC concentration (microg/g wet tissue weight). Tissue viability and morphology and MMC stability were assessed by trypan-blue exclusion test, histological examination, and mass spectrometry analysis. In the preliminary study (PD only), mean MMC concentrations (microg) at 5, 15, 30, 45, and 60 min were: (a) for urothelium, 15.3, 60.0, 58.2, 60.1, and 57.8, respectively; (b) for lamina propria, 2.2, 18.9, 19.3, 16.1, and 17.3, respectively; and (c) for muscularis, 0.4, 2.0, 1.8, 1.3, and 2.4, respectively. In the comparative study, MMC concentrations and coefficients of variation (CV) were as follows: (a) for urothelium after PD, 46.6 with CV = 69%, and after EMDA, 170.0 with CV = 43% (P < 0.0001); (b) for lamina propria after PD, 16.1, with CV = 60%, and after EMDA, 65.6 with CV = 29% (P < 0.0001); and (c) for muscularis after PD, 1.9 with CV = 82%, and after EMDA, 15.9 with CV = 82% (P < 0.0005). All of the bladder sections remained viable, and the chemical structure of MMC was unchanged. It was concluded that EMDA significantly enhances MMC transport into all of the layers of the bladder wall, and sections of viable human bladder are a reliable tool for assessing different modes of drug delivery.

Electromotive delivery of mitomycin C into human bladder wall.

The aim of this investigation was to establish an appropriate tissue pharmacokinetic model to compare concentrations of mitomycin C (MMC) in the human bladder wall after either passive delivery or electromotive administration (EMDA) and to evaluate the effects of EMDA on tissue morphology and MMC structure. Tissue sections of human bladder were inserted into two chamber cells with urothelium exposed to donor compartments containing MMC (10 mg in 100 ml of 0.24% NaCl solution) and an anode and with serosa exposed to receptor compartments containing 100 ml of 0.9% NaCl solution and a cathode. Fourteen paired experiments ("current 5 mA/no current") were conducted over 15 min; MMC tissue content was assessed by high-pressure liquid chromatography. Tissue viability and morphology and MMC stability were assessed by trypan blue exclusion test, tissue pH, histological analysis, and mass spectrometry analysis. MMC concentrations were increased, and variability in drug delivery rate was reduced in all tissue in samples exposed to electric current. Tissues were viable and undamaged histologically, and no MMC structural modification was observed. In conclusion, EMDA enhances administration of MMC into viable bladder wall tissue and reduces the variability in drug delivery rates.

Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury.

The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-Kit(TgD814Y) receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-Kit(TgD814Y) mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit(+) cardiac cell number was not different compared with wt mice. However, when c-Kit(TgD814Y) mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit(+)CD31(+) endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45(-)c-Kit(+) cardiac stem cells isolated from transgenic c-Kit(TgD814Y) mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival.

Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.

PURPOSE: To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks). RESULTS: Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION: This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.

Developmental regulation of the thyroid hormone receptor alpha 1 mRNA expression in the rat testis.

The multiplicity of thyroid hormone (TH) effects appears to be mediated by two TH receptors (THRs) encoded by two genes, alpha and beta, and, perhaps, by their various isoforms. The expression of THR beta is correlated with the presence of high affinity binding sites for TH, and all the mutations which cause the syndrome of generalized thyroid hormone resistance occur in THR beta. The function of THR alpha has not been clearly defined as yet. Another enigma in TH action is the effect on the testis. It has been shown that the testis of the adult rat does not respond to TH as measured by an increase in oxygen consumption. Furthermore, it has not been possible to demonstrate the presence of a nuclear high affinity binding site for TH in adult testis. To resolve these problems were measured the levels of THR alpha, its nonhormone binding variant, and THR beta mRNA in the testis at various stages of development. We discovered that the beta-message is absent at all times, whereas the alpha-message is expressed only from fetal through prepubertal stages and is absent in adult testis. THR alpha, but not the beta-mRNA, was detected in immature Sertoli cells in culture, and neither was found in adult Sertoli cell-enriched cultures. Furthermore, THR alpha and its variant mRNA was found, using in situ hybridization, in the seminiferous cords and seminiferous tubules of fetal and prepubertal testis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular and molecular aspects of mouse primordial germ cell migration and proliferation in culture.

The development of mouse primordial germ cells is followed from their first appearance in the extraembryonic mesoderm of the posterior amniotic fold (7 dpc embryo) to their settlement in the genital ridges (12.5 dpc embryo). The role of fibronectin as adhesive substrate and/or in stimulating cell motility during PGC migration is discussed. Recent papers showing how PGCs migrate when cultured in vitro on cellular monolayers are reviewed. The process of PGC homing is proposed to be controlled by chemotaxis as well by developmentally regulated cell-to-cell interactions. Finally, evidence that survival and proliferation of PGCs is strictly dependent on growth factors such as LIF and MGF, and possibly on a cAMP-dependent mechanism is reported.

The role of stem cell factor and of alternative c-kit gene products in the establishment, maintenance and function of germ cells.

The c-kit gene plays a fundamental role during the establishment, the maintenance and the function of germ cells. In the embryonal gonad the c-kit tyrosine kinase receptor and its ligand Stem Cell Factor (SCF) are required for the survival and proliferation of primordial germ cells. In the postnatal animal, c-kit/SCF are required for the production of the mature gametes in response to gonadotropic hormones, i.e. for the survival and/or proliferation of the only proliferating germ cells of the testis, the spermatogonia, and for the growth and maturation of the oocytes. Finally, a truncated c-kit product, tr-kit, specifically expressed in post-meiotic stages of spermatogenesis and present in mature spermatozoa, causes parthenogenetic activation when microinjected into mouse eggs, suggesting that it might play a role in the final function of the gametes, fertilization.

SOHLH1 and SOHLH2 directly down-regulate STIMULATED BY RETINOIC ACID 8 (STRA8) expression.

As the name implies, Stimulated by Retinoic Acid 8 is an early retinoic acid (RA) responsive gene pivotal for the beginning of meiosis in female and male germ cells. Its expression is strictly time-dependent and cell-specific (pre-meiotic germ cells) and likely requires a complex mechanism of regulation. In this study, we demonstrate a direct negative control of SOHLH1 and SOHLH2, 2 germ cell specific bHLH transcription factors, on Stra8 expression. We observed a negative correlation between STRA8 and SOHLH1 expression in prepuberal differentiating mouse KIT(+) spermatogonia and found that SOHLH1 and SOHLH2 were able to directly and cooperatively repress STRA8 expression in cell lines in vitro through binding to its promoter. We also identified 2 canonical E-Box motives in the Stra8 promoter that mediated the negative regulation of SOHLH1 and SOHLH2 on these gene both in the cell lines and KIT(+) spermatogonia. We hypothesize that this novel negative activity of SOHLH1 and SOHLH2 in male cooperates with that of other transcription factors to coordinate spermatogonia differentiation and the RA-induced meiosis and in female ensures STRA8 down-regulation at mid-end stages of meiotic prophase I.

Fgf9 inhibition of meiotic differentiation in spermatogonia is mediated by Erk-dependent activation of Nodal-Smad2/3 signaling and is antagonized by Kit Ligand.

Both fibroblast growth factor 9 (Fgf9) and Kit Ligand (Kl) signal through tyrosine kinase receptors, yet they exert opposite effects on meiotic differentiation in postnatal spermatogonia, Fgf9 acting as a meiosis-inhibiting substance and Kl acting as a promoter of the differentiation process. To understand the molecular mechanisms that might underlie this difference, we tried to dissect the intracellular signaling elicited by these two growth factors. We found that both Fgf9 and Kl stimulate Erk1/2 activation in Kit+ (differentiating) spermatogonia, even though with different time courses, whereas Kl, but not Fgf9, elicits activation of the Pi3k-Akt pathway. Sustained Erk1/2 activity promoted by Fgf9 is required for induction of the autocrine Cripto-Nodal-Smad2/3 signaling loop in these cells. Nodal signaling, in turn, is essential to mediate Fgf9 suppression of the meiotic program, including inhibition of Stra8 and Scp3 expression and induction of the meiotic gatekeeper Nanos2. On the contrary, sustained activation of the Pi3k-Akt pathway is required for the induction of Stra8 expression elicited by Kl and retinoic acid. Moreover, we found that Kl treatment impairs Nodal mRNA expression and Fgf9-mediated Nanos2 induction, reinforcing the antagonistic effect of these two growth factors on the meiotic fate of male germ cells.

Testosterone levels as a marker of prognosis to goserelin treatment in metastatic breast cancer.

Testosterone levels were measured in blood and urine of 35 premenopausal metastatic breast cancer patients before starting therapy with the gonadotrophin-releasing hormone (GnRH) analogue, goserelin. The aim of the study was to verify the reliability of testosterone measurement as a marker of prognosis. The time interval between starting therapy and progressive disease (time to progression) was chosen to assess prognosis. Univariate and multivariate analysis showed that only urinary testosterone levels were significantly associated with time to progression (Wald test 6.66, P = 0.01 for univariate and Wald test 7.93, P = 0.0049 for multivariate analysis), whereas no association was found for testosterone in blood. A statistical model is proposed to evaluate probability of progressive disease in relation to testosterone values in urine at different times. According to the model, the probability of progression decreases with increasing urinary testosterone values.

Glial cell line-derived neutrotrophic factor and neurturin can act as paracrine growth factors stimulating DNA synthesis of Ret-expressing spermatogonia.

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are related growth factors which exert trophic effects on several neuronal populations and developing kidney. GDNF-family ligands interact with membrane receptors designated GFRalphas which, in turn, mediate stimulation of the Ret receptor tyrosine kinase. Here we show that Ret, GFRalpha-1 (the GDNF receptor), and GFRalpha-2 (the NTN receptor) are expressed by testicular germ cells, while GDNF and NTN are expressed by Sertoli cells. Both GDNF and NTN stimulate DNA synthesis in spermatogonia. Furthermore, Ret, ligands and co-receptors are expressed in germ cell tumors. Thus, GDNF-family ligands may act as paracrine factors in spermatogenesis and this circuit may be active in germ cell tumors.

Formestane: an effective first-line endocrine treatment for advanced breast cancer.

Formestane, a new selective aromatase inhibitor devoid of severe side-effects, has been shown to be active in patients with advanced breast cancer. To investigate the clinical activity and endocrinological effects of formestane as a first-line treatment, 52 patients were administered two different doses: 24 received 250 mg formestane and 28 received 500 mg formestane i.m. fortnightly. All of the patients had a performance status of 2 or less (ECOG scale), 34 (65%) had a disease-free interval of at least 2 years and 21 (40%) were both oestrogen-receptor- and progesterone-receptor-positive; 20 patients received hormone and 13, received chemotherapeutical adjuvant treatment. Objective responses were obtained in 8 patients in the 250-mg group (33%; 95% CI: 14%-52%) and in 13 patients in the 500-mg group (46%; 95% CI: 28%-64%). The median response duration in the two groups was respectively 11 and 12 months. E2 serum levels of oestradiol had significantly (P < 0.001) decreased to more than 40% below the baseline value in both groups after 15 days of treatment, and remained unchanged thereafter. Local and systemic tolerability was satisfactory. We conclude that formestane is an effective and well-tolerated agent in previously untreated patients, and that these results should be confirmed by further studies.

Doxorubicin followed by docetaxel versus docetaxel followed by doxorubicin in the adjuvant treatment of node positive breast cancer: results of a feasibility study.

BACKGROUND: Doxorubicin (A) and Docetaxel (T) are amongst the most active agents in breast cancer treatment. The impact of drug sequencing is an issue still under evaluation. OBJECTIVE: To evaluate the feasibility and tolerability of two A and T-based sequential regimens, in which the sequence of drug administration was reversed. METHODS: The study included patients pts aged < or = 70 years, with operable node positive breast cancer. Two consecutive groups of patients received one of the following regimens: 1) Sequential A-->T-->CMF: Doxorubicin 75 mg/m2, i.v., day 1, q3wks x 3 cycles, followed by Docetaxel 100 mg/m2, i.v., day 1, q3wks x 3 cycles, followed by i.v. CMF days 1 and 8 q4wks x 3 cycles. 2) Sequential T-->A-->CMF: same doses for Doxorubicin and Docetaxel but reverse sequence of administration, followed by oral CMF (CPA 100 mg/m2, oral, days 1-14 + MTX 40 mg/m2, i.v., days 1 and 8 + 5FU 600 mg/m2, i.v., days 1 and 8, q4wks). An analysis of treatment administration and toxicity was performed for the first six cycles of CT, in the two treatment groups. RESULTS: Group 1 with 20 patients and group 2 with 14 patients were balanced in terms of patient and tumour characteristics. There was one early treatment discontinuation in each group due to toxicity (one allergic and one skin reaction to docetaxel). Median relative dose intensity was 100% for both drugs in both groups. The most relevant side effects were (overall incidence, group 1 vs group 2): Myalgia: 45% vs 72%; Arthralgia: 15% vs 57%; Skin: 35% vs 57%; Neurosensory: 55% vs 64%; Stomatitis 65% vs 36%; conjunctivitis 25% vs 57%; Neutropenic Fever 20% vs 21% and Fatigue 80% vs 93%. Grade 3/4 adverse events' rate was low in the two groups. CONCLUSIONS: 1) Both sequences were estimated feasible due to the optimal treatment administration and limited incidence of G3-G4 side effects. 2) The concomitant use of lenograstin might partially explain the reported incidence of myalgia and arthralgia. 3) No conclusion can be drawn on the most tolerable regimen due to the limited number of patients.

Formestane as treatment of advanced breast cancer in elderly women.

AIMS AND BACKGROUND: The number of elderly people is increasing, and the proportion of breast cancer in female cancer patients older than 65 years is 26%. In elderly patients, hormone therapy is widely accepted as the treatment of choice, because of its efficacy and good tolerability compared to chemotherapy. The aim of this study was to evaluate the endocrinologic and clinical activity of formestane (4-hydroxyandrostenedione), a selective aromatase inhibitor, in elderly patients with advanced breast cancer. METHODS: Thirty-five patients older than 65 years, selected from a larger group, were given formestane (250 mg or 500 mg i.m. fortnightly). Patients were evaluable for tumor response after 4 doses of formestane. Blood samples were collected to evaluate E2, FSH, LH, SHBG and DHEAS serum levels at baseline and after 2, 4, 8, 12 and 24 weeks. RESULTS: Thirty patients had PS < or = 1 (ECOG) and only 5 patients had PS = 2. Twenty-six patients were ER positive. Previous hormonal treatment for metastatic disease had been given to 17 patients; only 1 case had received chemotherapy. The overall response rate was 51% (95% C.I. 35-67%) and the median response duration was 9.5 months. Three complete responses were observed on viscera. The best responses were obtained on soft tissues (59%); on bone and viscera the response was respectively 45% and 47%. Local and systemic tolerability was highly satisfactory. Formestane induced prolonged suppression of E2 levels in all of the patients, and a significant reduction in SHBG levels was also observed from month 2 onward. A statistically significant (P = 0.0001) rise in serum FSH was also observed during the therapy. CONCLUSIONS: The study showed that formestane induced a long-lasting suppression of E2 levels and a satisfactory overall response. In our opinion, the drug is an effective and well-tolerated approach in the management of advanced breast cancer in elderly patients.

Leukemia inhibitory factor sustains the survival of mouse primordial germ cells cultured on TM4 feeder layers.

Various growth factors and cytokines were tested for their effects on survival and proliferation of mouse primordial germ cells (PGCs) cultured on TM4 cell feeder layers. Leukemia inhibitory factor was able to sustain the survival of PGCs from 10.5 dpc embryos for at least 3 days and to slow down degeneration of PGCs from 11.5 dpc embryos cultured on TM4 feeder layers.

Molecular biology tools for dissecting sexual behavior.

The tools of molecular biology have just begun to demonstrate the role of genes in controlling sexual behavior and how hormones can influence sexual and reproductive motivation by controlling gene expression. In this review article the use of the new term "molecular sexology" is proposed to indicate the growing evidence that molecular biology techniques can be a useful tool not only to understand the genetic bases of the animal (and soon human) sexual behavior, but also in order to provide the rationale of the use of advanced therapeutic approaches, such as gene transfer, to the symptoms and diseases of sexuality.