Duloxetine and escitalopram for hot flushes: efficacy and compliance in breast cancer survivors.

Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) might be an effective treatment for hot flushes (HFs) in breast cancer survivors (BCSs). This study aims to compare the efficacy and tolerability of duloxetine (SNRI) versus escitalopram (SSRI) in reducing frequency and severity of HFs in BCSs and to assess the effect on depression. Thirty-four symptomatic BCSs with emotional impairment received randomly duloxetine 60 mg daily or escitalopram 20 mg daily for 12 weeks. Patients were asked to record in a diary HF frequency and severity at baseline and after 4 and 12 weeks of treatment. Depression was evaluated through validated questionnaires (Beck Depression Inventory and Montgomery Asberg Depression Rating Scale) at baseline and after 4 and 12 weeks of treatment. Both drugs showed a significant reduction of HF frequency and severity after 12 weeks of treatment with no significant difference between the two groups. A significant improvement in depression symptoms was observed at the end of the study period within both the groups, without difference between the two drugs. In conclusion, escitalopram and duloxetine are both effective treatment for the relief of HFs in BCSs, with similar beneficial effect. A significant improvement of depression was obtained with no major side effects.

Loco-regional recurrence in 2064 patients with breast cancer treated with mastectomy without adjuvant radiotherapy.

INTRODUCTION: We investigated the incidence of loco-regional recurrence in a sub-group of patients who underwent mastectomy without adjuvant radiotherapy to evaluate the effect of each specific clinical or pathological parameter that could be associated with a higher local relapse rate. PATIENTS AND METHODS: Two thousand and sixty-four patients were treated from January 1971 to December 2003 at the University of Florence. RESULTS: At the time of analysis 18.3% of patients (378/2064) had isolated loco-regional failures. Univariate analysis showed an association of borderline statistical significance with pathological tumour size. Elderly age at diagnosis had a low incidence of local recurrence but the results did not reach statistical significant. The number of positive axillary lymph node did not show any influence for local recurrence. CONCLUSION: In our series we noted a higher relapse rate only related to the pathological tumour size without any correlation with number of positive axillary nodes. Radiotherapy after mastectomy still remains controversial, but in our series the number of positive axillary lymph node did not seem enough to justify adjuvant treatment.

Expression of the retinoblastoma-related gene Rb2/p130 correlates with clinical outcome in endometrial cancer.

PURPOSE: The retinoblastoma gene is the prototype of tumor-suppressor genes and has been shown to be involved in the pathogenesis and progression of several human malignancies. In this study, we determined the relation between the expression of a newly discovered retinoblastoma-related gene Rb2/p130 and outcome in patients with endometrial carcinoma. PATIENTS AND METHODS: pRb2/p130 expression was determined immunohistochemically in specimens of endometrial carcinoma (stages I to IV) from 100 patients who underwent surgery as the first treatment. The pRb2/p130 status was analyzed in relation to the length of disease-free survival and disease-specific survival. RESULTS: Decreased levels of pRb2/p130 in endometrial cancer cells was significantly associated with a decreased probability of remaining disease-free after treatment (P = .003) and with decreased probability of survival (P < .0001). In a multivariate analysis, pRb2/p130 status (P = .004), tumor stage (P = .009), and ploidy status (P = .02) were independent predictors of clinical outcome. The risk of dying of disease was increased substantially (risk ratio, 4.91; 95% confidence interval, 1.66 to 14.54) among patients with decreased levels of pRb2/p130 in tumor cells. CONCLUSION: In patients with endometrial carcinoma who did not receive radiotherapy or chemotherapy before surgery, the presence of decreased levels of pRb2/p130 in tumor cells is associated with a significantly increased risk of recurrence and death of disease, independent of tumor stage and ploidy status.

Sex steroid modulation of AT2 receptors in human myometrium.

In contrast to the abundant expression of the AT2 subtype of angiotensin II (AII) receptors during fetal development, AT2 receptor in adult life is expressed in few tissues. We now report studies on the presence and hormonal regulation of AT2 receptor in human pregnant and nonpregnant myometrium obtained from a large study population (n = 50). AT2 receptor subtypes have been characterized using self- and cross-competition curves among [125I]CGP42112A (a selective AT2 ligand), [125I](Sar1,Ile8)AII (a unselective antagonist), the corresponding unlabeled ligands, and several peptidic and nonpeptidic analogs with different affinities for the AT1 and AT2 receptor subtypes. We found that the human nonpregnant uterus expresses almost exclusively the AT2 subtype, and that [125I]CGP42112A is a selective probe to study human AT2 receptor. By using [125I]CGP42112A, we demonstrated that the density of AT2 receptor in human myometrium is dramatically affected by the hormonal milieu. Indeed, in the estrogen-dominant uterus of normal cycling women in the proliferative phase and that of perimenopausal women with anovulatory cycles, the density of binding sites was very high [1565 +/- 246 fmol/mg protein (n = 11) and 2176 +/- 429 (n = 7), respectively]. The concomitant presence of progestogens blunted the estrogen effect [term pregnancy, 61 +/- 12 fmol/mg protein (n = 5); secretive phase of the cycle, 453 +/- 154 (n = 10); combined oral contraceptive, 243 +/- 74 fmol/mg protein (n = 6)]. Very low concentrations of binding sites are also present in the sex steroid-deprived uterus of postmenopausal women (100 +/- 12 fmol/mg protein; n = 8) and the uterus of fertile women chronically treated with GnRH agonists (199 +/- 100 fmol/mg protein; n = 3). Hence, these data confirm the presence of AT2 receptors in human uterus and indicate their regulation by sex steroids.

Identification, characterization, and biological activity of endothelin receptors in human ovary.

We previously reported the expression of endothelin-1 (ET-1) in granulosa cells (GCs) of the human ovary and the presence of ET-1-like immunoreactivity in human follicular fluid obtained from women in an in vitro fertilization program. In follicular fluid, but not in plasma, the levels of ET-1-like immunoreactivity were higher in gonadotropin-stimulated vs. spontaneous cycles, suggesting hormonal regulation of follicular ET-1. To identify and characterize ET receptors in human ovary, we performed autoradiography, radioligand binding, and functional studies. Mathematical analysis of families of self- and cross-competition curves among [125I]ET-1, [125I]ET-3, and selective analogs indicates that human ovary expresses both subtypes of ET receptors, i.e. ETA and ETB receptors. However, the concentration of the ETB site was 100-fold lower than that of the ETA one. By using [125I]ET-1, we demonstrated that the density of binding sites in human ovary is not affected by the hormonal milieu (similar concentrations in normal cycling, postmenopausal, and combined oral contraceptive-treated women). In situ binding studies indicate that the majority of ETA and ETB receptors are expressed in the blood vessels of the ovary. In particular, ETA receptors are abundant in the ovulatory follicles and localized in the theca interna, in close proximity to the granulosa layer. Few GCs of the ovulatory follicle were specifically labeled. Conversely, in the rat ovary, used as a control, ETB receptors were predominantly expressed and localized in GCs. Accordingly, ETB receptors negatively regulated estrogen accumulation in rat GCs. In human granulosa-luteal cells, neither ET-1 (unselective ligand) nor ET-3 or sarafotoxin 6c (ETB ligands) affected estrogen or progesterone secretion. ET-1 was 2.5-fold more potent than noradrenaline in eliciting contraction of ovarian artery, acting through the ETA receptor. Our results indicate that in human ovary, at variance with rat ovary, the endothelin system is primarily involved in the regulation of ovarian blood flow and not steroidogenesis.

Expression of endothelin-1 gene and protein in human granulosa cells.

Previous studies in animal models indicated an autocrine/paracrine action of endothelin-1 (ET-1) in the ovary. We now report evidence on the presence of ET-1 in human ovary during reproductive life. Immunohistochemical and in situ hybridization studies demonstrated a positive signal into cytoplasm of granulosa cells (GC) of follicles at different growth stages. The concentration of ET-1-like immunoreactivity (ET-1-LI) was also measured by a specific RIA in human follicular fluid (FF). FF samples were obtained from women in an in vitro fertilization program undergoing gonadotropin stimulation (group A; n = 24) or no treatment (group B; n = 7). The mean (+/-SD) ET-1-LI FF level in group A (4.85 +/- 2.06 pg/mL) was significantly higher than that in group B (1.29 +/- 0.43 pg/mL; P < 0.01), whereas the corresponding mean plasma levels were not significantly different and were not correlated to respective FF values. Our results indicate for the first time the presence of ET-1 and its messenger ribonucleic acid in the GC of the human ovary. The higher ET-1-LI levels found in the FF from women undergoing gonadotropin treatment suggest a modulation by gonadotropins and/or ovarian steroids of ET-1 production by GC.

Management of benign adnexal masses by vaginal route.

Until recently, surgical treatment of a benign adnexal mass implied a laparotomy. In recent years, the development of laparoscopic surgery, as well as ultrasound-guided aspiration techniques, have significantly modified the treatment options for these patients. These procedures have shown considerable advantages. They have reduced surgical trauma and have shortened the hospital stay. We present the results of our experience on the feasibility of a trans-vaginal surgical approach for the removal of benign adnexal masses. This technique, using traditional and cheap surgical instruments, allows the surgeon to excise benign adnexal masses, by entering the peritoneum through the posterior vaginal fornix and thus avoids the trauma of laparotomy. Fifty-four patients were operated on by this technique at our Department. The mean age was 39 years (range 21-66). In all cases, the operation was completed by the trans-vaginal approach. The median operative time was 30 minutes (range 20-45), and no blood transfusion was needed. The pathological diagnoses were as follows: functional ovarian cyst; 19, endometriotic cyst; 18, dermoid cyst; 11, parovarian cyst; 4 and peduncolated fibroid of the uterine fundus; 2 cases. The diameter of the adnexal masses ranged from 3 to 10 cm (median of 6 cm). In 30 cases, a conservative surgery was done (including 2 myomectomies), whereas in 24 cases, the adnexectomy was needed. Median post-operative stay in hospital was 4 days (range 1-14). This study shows the feasibility of trans-vaginal surgical approach for benign adnexal masses. The advantages and limitations of this technique, as well as of the traditional and laparoscopic surgery are considered and discussed. We believe that the transvaginal approach could be useful and cost-effective for the treatment of selected cases of adnexal masses.

Gastric motor responses elicited by vagal stimulation and purine compounds in the atropine-treated rabbit.

1. The effects of vagal inhibitory stimulation and of purine compounds were studied in the rabbit stomach. 2. Gastric motility was assessed by the balloon method. Vagal nerves were electrically stimulated at the neck. Purine compounds were injected intra-arterially. 3. In the atropine-treated rabbit, vagal stimulation caused relaxant motor responses followed by a rebound contraction. 4. Among the purine compounds, only ADP and ATP caused relaxant motor responses similar to the effects of vagal inhibitory stimulation. However, the relaxation produced by ATP was more powerful than that due to ADP, especially at lower infusion rates. 5. Vagal inhibitory responses were recorded during and after infusion of ATP. When relaxation by ATP was fully developed, vagal inhibitory stimulation was ineffective. At the highest infusion rates of ATP, a depression of the vagal inhibitory motility was also observed after cessation of the infusion. 6. Relaxant responses to ATP and vagal inhibitory stimulation were not influenced by theophylline, scarcely affected by alpha,beta-methylene ATP, but were reduced or blocked by reactive blue 2. 7. The results are consistent with ATP being an inhibitory neurotransmitter in the stomach of the rabbit.

Expression of the retinoblastoma-related gene Rb2/p130 is downregulated in atypical endometrial hyperplasia and adenocarcinoma.

The retinoblastoma-related gene Rb2/p130 encodes a protein that is a negative cell-cycle regulator normally expressed in a number of adult tissues. This protein shares many structural and functional features with the product of the retinoblastoma gene, one of the best-studied tumor-suppressor genes, and plays a fundamental role in growth control. The Rb2/p130 gene product associates with specific members of the E2F family and various cyclins, displaying a growth-suppressive activity specific for the G(0)/G(1) phases. It has been reported that Rb2/p130 is involved in the pathogenesis and progression of lung cancer and mesothelioma. We previously demonstrated for the first time that reduced immunohistochemical expression of Rb2/p130 was a strong independent predictor of poor outcome in endometrial cancer. The aim of the present study was to evaluate Rb2/p130 expression in normal, hyperplastic, and neoplastic endometrial lesions to determine whether the protein plays a significant role in endometrial carcinogenesis. We evaluated Rb2/p130 expression by immunohistochemistry staining in 102 specimens chosen to represent a spectrum of endometrial changes, including proliferative endometrium (n = 18), secretory endometrium (n = 18), simple or complex hyperplasia without atypia (n = 18), atypical hyperplasia (n = 18), and invasive carcinoma (n = 30). We found that Rb2/p130 was highly expressed in proliferative endometrium and in hyperplasia without atypia, the mean percentage of stained nuclei being 66% and 60%, respectively, but was downregulated in secretory endometrium, atypical hyperplasia, and carcinoma, with mean scores of 38%, 25%, and 22%, respectively. When categorized on a semiquantitative scale (negative v 1% to 50% v >50% positivity), endometrial cancer displayed significantly less staining than all other endometrial samples (P <.001). Poorly differentiated carcinomas (n = 9) showed a significantly lower immunoreactivity for Rb2/p130 than did well-differentiated carcinomas (n = 11; P =.005) and moderately differentiated carcinomas (n = 10; P =.03). In addition, atypical hyperplasia showed a significantly lower immunoreactivity than either proliferative endometrium (P =.003) or hyperplasia without atypia (P = 0.02). Our findings of a progressive decrease in Rb2/p130 expression from hyperplastic endometrium through atypical hyperplasia to poorly differentiated carcinomas suggest the involvement of this negative cell-cycle regulator in endometrial carcinogenesis. Furthermore, immunostaining for Rb2/p130 may prove diagnostically useful in the often difficult distinction between hyperplastic and atypical hyperplastic endometrium. HUM PATHOL 32:360-367.

Platelet-activating factor in human endometrium.

Platelet-activating factor (PAF) is a phospholipid actively produced by human endometrium and deeply involved in the processes of ovoimplantation and labor. We recently found that PAF represents a new autocrine growth factor for a human adenocarcinoma cell line, HEC-1A. Indeed, biologically active PAF is synthesized by HEC-1A cells, under progesterone control. In HEC-1A cells, PAF regulates intracellular calcium concentration ([Ca2+]), DNA synthesis and expression of early oncogenes. All these effects are blocked by the receptor antagonist L659,989. However, while nanomolar concentrations of PAF mobilize [Ca2+], only micromolar concentrations affect cell growth, suggesting heterogeneity of PAF receptors or signaling. Two distinct populations of PAF receptors are present in HEC-1A cells, which bind PAF in nanomolar and micromolar concentrations, respectively. Since HEC-1A cells are producing elevated concentrations of PAF and micromolar concentrations of the PAF antagonist L659,989 inhibit cell proliferation, an autocrine role for PAF is suggested in HEC-1A cells.

Giant pelvic retroperitoneal liposarcoma.

BACKGROUND: Pelvic retroperitoneal liposarcomas are rare in young women (under 30 years old). We present a case of a giant well-differentiated liposarcoma of the retroperitoneum in a young woman. CASE: A 27-year-old nulligravida presented with rapid abdominal enlargement. Pelvic examination found a huge mass extending from the left adnexa to the epigastric region. At surgery, the pelvic organs were displaced to the right side by a retroperitoneal mass that marginally involved the left fallopian tube. The left ovary, uterus, and right adnexa were not involved and were not removed. No adjuvant irradiation was given. The patient was alive and well 2 years after the operation and was 23 weeks pregnant. CONCLUSION: Gynecologists should be familiar with pelvic retroperitoneal liposarcomas and their treatment.

GnRH analogs in gynecological oncology: a review.

Chronic GnRH analogs (GnRH-A) administration has proven to be effective for the control of some hormone-dependent tumors. GnRH-A are now in the standard treatment of prostatic cancer. In the present paper experimental and clinical data on the use of GnRH-A in gynecologic oncology are reviewed in order to identify a possible role in the therapy of breast, endometrial and ovarian cancer. Besides the indirect hormonal effect of GnRH-A, mediated by the suppression of gonadal steroidogenesis, in vitro evidence suggests a direct anti-proliferative action involving autocrine-paracrine regulation of cellular function. In advanced or recurrent breast cancer objective responses were observed in 157 out of 378 premenopausal patients (41%) and in 18 out of 166 postmenopausal women (10%). In ovarian cancer complete and partial responses were observed in 14 out of 121 (11%). At present, data on advanced endometrial carcinoma are limited: only 18 treated patients are reported, of whom 7 responded (38.8%). However, in general, most of the responses observed were transient. Thus, so far, the use of GnRH-A in gynecologic oncology has to be considered for palliation, after the failure of other better understood treatment modalities. The possible use of GnRH-A as an adjuvant is still under investigation.

Extraperitoneal pelvic lymphadenectomy to complement vaginal operations for cervical and endometrial cancer.

OBJECTIVE: The aim of the current study was to test the applicability of a personal modification of Mitra extraperitoneal pelvic lymphadenectomy in combination with radical vaginal operations for treatment of endometrial and cervical cancer. METHOD: In a prospective series, 82 patients were submitted to extraperitoneal pelvic lymphadenectomy. In 34 cases of stage I endometrial cancer the procedure was combined with a class I vaginal hysterectomy and in 48 cases of cervical cancer stage Ib-IIIb lymphadenectomy was associated with a class II or III radical vaginal hysterectomy. Type of anesthesia, number of lymph nodes removed, operating time, blood loss and postoperative complications were recorded. RESULT: The operation was performed with spinal anesthesia in 43% of the cases. Thirty-seven patients (45%) were high surgical risk because of associated diseases. The median operative time for lymphadenectomy was 20 min for each side; the vaginal procedures took a median of 25 min (class I) and 40 min (class II-III). Blood transfusions were necessary in seven cases (8. 5%). A median of 26 lymph nodes were removed from each patient. Lymphocyst occurred in seven patients (8.5%), retroperitoneal hematoma in two and retroperitoneal abscess in one. CONCLUSION: Extraperitoneal pelvic lymphadenectomy has proven to be a safe and quick technique to complement vaginal operations for endometrial and cervical cancer. Specific features of this approach are: (1) fast, timesaving procedure; (2) possible use of spinal anesthesia; and (3) applicability in high surgical risk patients.

[The "age factor" in ovarian cancer. Clinical, therapeutic and prognostic aspects]. / Il "fattore età" nei carcinomi dell'ovaio. Considerazioni cliniche, terapeutiche, prognostiche.

115 patients affected by ovarian tumors, were studied retrospectively, each with a follow-up of a minimum of 5 years. These cases were subdivided into two subgroups according to the age (younger or older than 65 years) to value the differences, from a prognostic and therapeutic point of view about the age of neoplasm onset. In patients older than 65 years, there were prevalent cases with worse prognosis, linked both to the neoplasm (greater incidence of advanced stages at the moment of the diagnosis; prevalence of tumours of low degree of differentiation), and to the treatment given (less destroying intervention, with a higher frequency of non optimal residual disease; fewer chemotherapeutic cycles for every patient, with lower doses and fewer times of administration of drugs; higher incidence of phenomena of resistance and rejection of the I line therapy). The survival curves were significantly different in the two groups of patients, proving a worse prognosis for older women. At last, a multivaried statistical analysis, revealed that age, like stage, residual disease and the number of chemotherapeutic cycles performed, represent an independent prognostic factor.

Radial scar without associated atypical epithelial proliferation on image-guided 14-gauge needle core biopsy: analysis of 49 cases from a single-centre and review of the literature.

The purpose of this study was to evaluate the reliability of image-guided 14-gauge needle core biopsy in the diagnosis of radial scar without associated atypical epithelial proliferation, by comparison with definitive histological diagnosis on surgical excision. The records of 8792 consecutive image-guided 14-gauge needle core biopsy of the breast performed from January 1996 to December 2009 were reviewed. Forty-nine cases of radial scar without associated atypical epithelial proliferation were identified and compared with definitive histological diagnosis on surgical excision. The definitive histological diagnosis on surgical excision confirmed the results of image-guided 14-gauge needle core biopsy in 36 of 49 cases (73.5%), in 9 cases (18.3%) radial scar was associated with atypical epithelial proliferation, while 4 cases out of 49 cases were upgraded to carcinoma (3 cases of ductal carcinoma in situ and one case of invasive lobular carcinoma), with an underestimation rate of 8.2%. A diagnosis of radial scar without associated atypical epithelial proliferation on image-guided 14-gauge needle core biopsy does not exclude a malignancy on surgical excision; consequently during the multidisciplinary discussion further assessment by surgical excision or vacuum-assisted excision, as recently reported, needs to be considered to obtain a definitive histological diagnosis.

Ovarian cancer in the elderly: feasibility of surgery and chemotherapy in 89 geriatric patients.

Gynecological oncologists are faced with an increasing proportion of geriatric ovarian cancer patients. Comorbidities are frequently a matter of concern in this age group, and what is adequate treatment for such patients is still debated. The aims of this study were to analyze the feasibility of standard surgery and chemotherapy in a series of elderly ovarian cancer patients (>/=70 years) and to investigate the influence of age (70-75 vs >75 years) on survival. We retrospectively evaluated 89 elderly patients treated at our department between 1985 and 2005. Comorbidities, type of surgical procedure, complications, drugs and schedules of chemotherapy, number of cycles, toxicity, and clinical outcome were registered. Comorbidities were present in 71.9%. Only six patients were inoperable. Among the 83 patients who underwent surgery, 76.4% received adequate surgical treatment. Severe postoperative complications occurred in 16.8%, operative mortality was zero. A total of 801 cycles of chemotherapy were administered to 77 patients (median 10; range 1-38). Overall, G3-G4 toxicity was documented in 61.0%. The rates of dose reduction, treatment delay, and discontinuation were 13.0%, 20.7%, and 3.9%, respectively. Patients who received adequate surgery and those with residual disease <1 cm did significantly better than their counterparts (P= 0.04 and P < 0.001, respectively). No difference in survival according to age (70-75 vs >75 years) was found. Standard surgery and chemotherapy were feasible in elderly ovarian cancer patients. The type of surgery and the amount of residual disease, but not the age of the patients, significantly influenced the clinical outcome.

Expression and amplification of HER-2/neu oncogene in uterine carcinosarcomas: a marker for potential molecularly targeted treatment?

Surgery is the treatment of choice for uterine carcinosarcomas; nevertheless, the poor effect of chemotherapy and radiotherapy represents an insidious problem for patients with metastatic or unresectable disease, and indeed, new therapeutic approaches are clearly required to improve survival of uterine carcinosarcoma patients. The HER-2 oncogene, located on chromosome 17, encodes for a tyrosine kinase growth factor receptor. We analyzed HER-2/neu overexpression by immunohistochemistry in 28 uterine carcinosarcomas. HER-2/neu amplification with fluorescence in situ hybridization (FISH) was tested in positive cases. The expression of HER-2/neu was correlated with disease-free interval and survival (Kaplan-Meier estimates). We observed HER-2/neu overexpression in nine cases (32.1%) and HER-2/neu amplification in all the four HER-2/neu 3+ score positive cases tested by FISH. HER-2/neu expression was not correlated with clinical outcome. Patients with disease limited to the uterus (stages I-II) displayed a significantly better disease-free survival (P= 0.004) and actuarial survival (P= 0.01). Demonstration of HER-2/neu overexpression and amplification in uterine carcinosarcoma may represent the first rationale step for further investigations. Hence, the results of this analysis may support the challenge of a new therapeutic approach, which could test the role of anti-HER-2 (trastuzumab) in patients with advanced or metastatic uterine carcinosarcoma.