Mental health, pain symptoms and systemic comorbidities in women with endometriosis: a cross-sectional study.

INTRODUCTION: Endometriosis is a gynecological disease with a severe impact on quality of life. The aim of this study is to assess mental health status in a group of women with endometriosis, investigating their clinical history, pain symptoms and systemic comorbidities. METHODS: An observational cross-sectional study was performed on a group of Italian Caucasian women with endometriosis (n = 134). All patients filled the 'Patient Health Questionnaire' (PHQ), a self-administered screening tool for mental health disorders. The characteristics of endometriosis, pain symptoms and their severity, the presence and types of comorbid systemic disorders were added into the same survey. RESULTS: According to PHQ algorithms, 59% of patients were affected by at least one psychiatric disorder, with a significant correlation with pain symptoms (p = 0.0026). Patients with severe pain showed a higher incidence of multiple psychiatric disorders (p = 0.026) and somatoform disorder than those with mild pain (p = 0.0009). There was no correlation between the presence of psychiatric disorders and age, BMI, parity, infertility, need for surgery, number of intervention, localization of endometriotic lesions and systemic comorbidities. DISCUSSION: Women with endometriosis showed a high frequency of PHQ results positive for psychiatric disorders, with a significant association with pain severity.

Sexual pain in women: quality of sex life and marital relations.

Common gynecological and dermatological conditions resulting in sexual pain are often observed in gynecological practice and are easily diagnosed with visual observation and laboratory tests. The lower genital tract diseases we are referring to are vaginitis, vaginoses, dermatoses, hypoestrogenism and endometriosis. All of them affect the vaginal mucosa with diverse mechanisms, their effects lasting for only few days or many months. Furthermore, they change the women's sense of wellbeing sometimes significantly and for a long period. The conditions we mentioned above are recognized promptly with basic gynecological interventions but when burning or sharp pain occurs with light pressure (as in case of penetration attempts) without physical signs we must suspect the genitopelvic pain penetration disorder. This condition was defined for the first time in the Diagnostic and Statistical Manual of Mental Disorders-5 and its dimensions include difficulty or pain at penetration associated with fear, anxiety, and pelvic floor hypertonus. Pain is most often localized at the vulvar vestibule and described as burning, pressure, and itching. These dimensions are iconic of sexual pain associated with vulvodyina and vaginismus but are common also in fibromyalgia, a syndrome of widespread chronic pain of unknown origin; sexual pain in fibromyalgia is mostly attributed both to the joint pathology and to the lower sensitive threshold that are the pathognomonic signs of this condition. In our study we analyzed the characteristics of pain as reported for each disease to evaluate its influence on sexuality and marital relations.

Abnormal uterine bleeding unrelated to structural uterine abnormalities: management in the perimenopausal period.

Abnormal uterine bleeding (AUB) is one of the commonest health problems encountered by women and a frequent phenomenon during menopausal transition. The clinical management of AUB must follow a standardized classification system to obtain the better diagnostic pathway and the optimal therapy. The PALM-COEIN classification system has been approved by the International Federation of Gynecology and Obstetrics (FIGO); it recognizes structural causes of AUB, which can be measured visually with imaging techniques or histopathology, and non-structural entities such as coagulopathies, ovulatory dysfunctions, endometrial and iatrogenic causes and disorders not yet classified. In this review we aim to evaluate the management of nonstructural causes of AUB during the menopausal transition, when commonly women experience changes in menstrual bleeding patterns and unexpected bleedings which affect their quality of life.

The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients.

BACKGROUND: The androgen receptor splice variant 7 (AR-V7) is associated with resistance to hormonal therapy in castration-resistant prostate cancer (CRPC). Due to limitations of the methods available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice. OBJECTIVE: To confirm AR-V7 as a predictor of resistance to hormonal therapy and develop a new approach to assess AR-V7 by highly sensitive digital droplet polymerase chain reaction (ddPCR) in plasma-derived exosomal RNA. DESIGN, SETTING, AND PARTICIPANTS: Plasma samples were collected from 36 CRPC patients before they began second-line hormonal treatment. Exosomes were isolated and RNA extracted for analysis of AR-V7 by ddPCR. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The absolute target gene concentration as copies per milliliter (copies/ml) was determined by ddPCR. Statistical analyses were performed with SPSS software (IBM Corp., Armonk, NY, USA). RESULTS AND LIMITATIONS: A total of 26 patients received abiraterone and 10 enzalutamide; 39% of patients were found to be AR-V7 positive (AR-V7+). Median progression-free survival was significantly longer in AR-V7 negative (AR-V7-) versus AR-V7+ patients (20 vs 3 mo; p<0.001). Overall survival was significantly shorter in AR-V7+ participants at baseline compared with AR-V7- participants (8 mo vs not reached; p<0.001). CONCLUSIONS: This study demonstrates that plasma-derived exosomal RNA is a reliable source of AR-V7 that can be detected sensitively by ddPCR assay. We also showed that resistance to hormonal therapy may be predicted by AR-V7, making it a clinically relevant biomarker. PATIENT SUMMARY: We report a first study on a method for androgen receptor splice variant 7 (AR-V7) detection in RNA extracted from cancer cell vesicles released in blood. Results confirmed the role of AR-V7 as a predictive biomarker of resistance to hormonal therapy. Our assay showed that vesicles are a reliable source of AR-V7 RNA and that the method is fast, highly sensitive, and affordable.

Maternal anemia effects during pregnancy on male and female fetuses: are there any differences?

OBJECTIVE: Sideropenic anemia is a common pregnancy disorder. The relationship between anemia and adverse pregnancy outcome are contradictory, and it is related to the severity of the hemoglobin deficit. The aim of the study was to evaluate the relationship between maternal mild anemia at third trimester of pregnancy, fetal birth weight and fetal gender. STUDY DESIGN: A retrospective study including 1131 single physiological term pregnancies was conducted. According to maternal Hb levels during the third trimester, pregnant women enrolled were divided in two groups: Group A (n = 156) with Hb ≤ 11 g/dl and Group B (n = 975) with Hb ≥ 11,1 g/dl. RESULTS: Maternal characteristics, gestational age at delivery, Apgar score and post-partum hemorrhage were similar between groups. However, when neonatal sex was considerate, female newborns of anemic women had a higher birth weight (p = 0.01). Moreover, anemic women showed a significantly higher rate of emergency cesarean section (p = 0.006), in particular when the newborn was a male (p= 0.03). CONCLUSION: Maternal mild anemia in third trimester of pregnancy correlates with fetal birth weight, influencing fetal growth and delivery outcome on the basis of fetal gender. Even though the reason of this phenomenon is still unknown, these new data may represent a novel parameter to add significant prognostic information in relation to maternal mild anemia and neonatal outcome.

Potential influence of in utero and early neonatal exposures on the later development of endometriosis.

OBJECTIVE: To investigate the possible correlation between maternal characteristics, in utero and early neonatal life exposures, and the development of endometriosis in adult life. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): A group of 161 patients with endometriosis and a control group of 230 women undergoing laparoscopy for benign adnexal diseases and free of endometriosis. INTERVENTION(S): All women included in the study were requested to answer a series of questions about their mothers' gestational data and on their own perinatal and early postnatal lives. MAIN OUTCOME MEASURE(S): Odds ratio, adjusted odds ratios, and 95% confidence intervals for the associations between maternal characteristics during the patient's pregnancy, in utero exposure to obstetrical and perinatal complications, and the type of feeding received during the neonatal period with the development of endometriosis in adult life. RESULT(S): Mothers of women with endometriosis were significantly more likely to be affected by endometriosis or uterine fibroids, with a higher incidence of smoking during pregnancy. Women with endometriosis were more frequently born prematurely, with a significantly lower birth weight, and their mothers experienced preeclampsia during their pregnancies more often than control subjects. They were also more frequently formula fed than breast fed in early life. However, only prematurity and formula feeding were retained in the multivariate analysis model. CONCLUSION(S): Among intrauterine and early neonatal exposures, prematurity and formula feeding were risk factors for the development of endometriosis in adult life. Further studies should evaluate the underlying biologic mechanisms.

Akt1 rs2498801 is related to survival in head and neck squamous cell cancer treated with radiotherapy.

BACKGROUND: Radiotherapy (RT) with or without chemotherapy (CT) plays an important role as exclusive treatment in patients with head and neck squamous cell cancer (HNSCC). Unfortunately, in some cases, benefit for patients is not recorded and only treatment-related complications are registered. MATERIALS AND METHODS: Data relating to Akt1 single nucleotide polymorphism (SNP) and response to treatment of 46 patients treated with exclusive RT or RT-CT for HNSCC were evaluated. RESULTS: For heterozygous patients median overall survival was 28.5 months, while for the wild-type group median overall survival was 10.9 (p=0.019). Three-year survival was 85% for mutated Akt1 homozygosis and 40% for patients with a heterozygous status (p=0.019, hazard ratio (HR)=7.960). CONCLUSION: SNP of rs2498804 can recognize patients resistant to RT-CT. Further studies are needed to confirm our data and to investigate the role of Akt SNPs in HNSCC patients.

Endometriosis and perceived stress: impact of surgical and medical treatment.

BACKGROUND: The aim of the study was to investigate the levels of perceived stress in a group of women with a long-term history of endometriosis in conjunction with surgical and/or medical treatments. METHODS: A clinical trial was conducted at the Department of Molecular and Developmental Medicine, University of Siena, in collaboration with a non-profit association of women with endometriosis, A.P.E. Onlus. Patients (n = 204) with a previous diagnosis of endometriosis (for at least 3 years) were included in this study. Each patient completed a semi-structured questionnaire and a validated scale to assess perceived stress, the Perceived Stress Scale (PSS) by e-mail. RESULTS: The study showed that in women with a long-term history of endometriosis, the level of perceived stress was increased by repeated surgical treatments and reduced by some medical treatments. The median PSS value was 23 (range 9-36) and 30.6% of the study population were included in the highest stress category (>26). The highest levels were found in patients who had undergone the most surgery. The use of progestins was associated with a lower perceived stress (p = 0.004) than in the patients treated with gonadotropin-releasing hormones. CONCLUSIONS: Long-term endometriosis has a relevant impact on perceived stress, in particular in those undergoing repeated surgery.

Women with endometriosis at first pregnancy have an increased risk of adverse obstetric outcome.

OBJECTIVE: To evaluate pregnancy, delivery and neonatal outcome in singleton primiparous versus multiparous women with/without endometriosis. METHODS: Multicentric, observational and cohort study on a group of Caucasian pregnant women (n = 2239) interviewed during their hospitalization for delivery in five Italian Gynecologic and Obstetric Units (Siena, Rome, Padua, Varese and Florence). RESULTS: Primiparous women with endometriosis (n = 219) showed significantly higher risk of small for gestational age fetuses (OR: 2.72, 95% CI 1.46-5.06), gestational diabetes (OR: 2.13, 95% CI 1.32-3.44), preterm premature rupture of membranes (OR: 2.93, 95% CI 1.24-6.87) and preterm birth (OR: 2.24, 95% CI 1.46-3.44), and were hospitalized for a longer period of time (p < 0.0001) comparing with control group (n = 1331). Multiparous women with endometriosis (n = 97) delivered significantly more often small for gestational age fetuses (OR: 2.93, 95% CI 1.28-6.67) than control group (n = 592). Newborns of primiparous women with endometriosis needed more frequently intensive care (p = 0.05) and were hospitalized for a longer period of time (p < 0.0001). CONCLUSIONS: Women with endometriosis at first pregnancy have an increased risk of impaired obstetric outcome, while a reduced number of complications occur in the successive gestation. Therefore, it is worthy for obstetricians to increase the surveillance in nulliparous women with endometriosis during pregnancy.

Surgical treatment affects perceived stress differently in women with endometriosis: correlation with severity of pain.

OBJECTIVE: To investigate the amount of perceived stress in a group of women with different forms of endometriosis-related pain before and after surgical treatment. DESIGN: Prospective clinical trial. SETTING: University hospital. PATIENT(S): A group of women (n = 98) referred to our center for chronic pain and suspected of having endometriosis. INTERVENTION(S): All women suspected of having endometriosis with ultrasonography underwent to a clinical evaluation including assessment of perception of stress. Endometriosis was confirmed histologically by laparoscopy. Painful symptoms and perception of stress were recorded 1 month after surgery. MAIN OUTCOME MEASURE(S): Perceived stress scale (PSS) and visual analog scale for painful symptoms before and 1 month after surgery for endometriosis. RESULT(S): The PSS score before surgery was perceived as "very high" in patients with deep endometriosis (n = 20) or deep endometriosis associated with endometrioma (n = 21); "high" or "medium" PSS was perceived in patients with endometrioma (n = 34) or endometrioma associated with peritoneal endometriosis (n = 23). After the surgical treatment a significant decrease of the "very high" PSS score was shown, as well as when the entire group of patients was considered. When evaluated before and after surgery, according to the severity of pain (dysmenorrhea, dyspareunia, and pelvic pain), a direct correlation was found with the level of PSS. CONCLUSION(S): Patients with deep endometriosis-related pain (dysmenorrhea, pelvic pain, dyspareunia) showed the highest level of perceived stress, which significantly decreased after surgical treatment.

No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT).

BACKGROUND AND PURPOSE: To evaluate the effect of adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation (NACT-RT). The study was funded by the Italian National Research Council (CNR). METHODS: From September 1992 to January 2001, 655 patients with LARC (clinically T3-4, any N) treated with NACT-RT and surgery, were randomized in two arms: follow-up (Arm A) or 6 cycles of ACT with 5 fluorouracil (5FU)-Folinic Acid (Arm B). NACT-RT consisted of 45Gy/28/ff concurrent with 5FU (350mg/sqm) and Folinic Acid (20mg/sqm) on days 1-5 and 29-33; surgery was performed after 4-6weeks. Median follow up was 63·7months. Primary end point was overall survival (OS). RESULTS: 634/655 patients were evaluable (Arm A 310, Arm B 324); 92·5% of Arm A and 91% of Arm B patients received the preoperative treatment as in the protocol; 294 patients of Arm A (94·8%) and 296 of Arm B (91·3%) underwent a radical resection; complete pathologic response and overall downstaging rates did not show any significant difference in the two arms. 83/297 (28%) patients in Arm B, never started ACT. Five year OS and DFS did not show any significant difference in the two treatment arms. Distant metastases occurred in 62 patients (21%) in Arm A and in 58 (19·6%) in Arm B. CONCLUSIONS: In patients with LARC treated with NACT-RT, the addition of ACT did not improve 5year OS and DFS and had no impact on the distant metastasis rate.

Safety and antitumor efficacy of (153)Sm-EDTMP and docetaxel administered sequentially to patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Bone metastases are responsible for most of the morbidity associated with metastatic castration-resistant prostate cancer (mCRPC). Bone-seeking radiopharmaceuticals have been approved for palliation of painful skeletal metastases, but their clinical use is limited by concerns of toxicities both when administered alone and especially when combined with chemotherapy agents. OBJECTIVE: We investigated whether docetaxel administered to mCRPC patients after treatment with samarium-153-labeled ethylene-diamine-tetra-methylene-phosphonic acid (Sm-EDTMP) has increased toxicity and/or reduced antitumor efficacy. MATERIALS AND METHODS: Thirty mCRPC patients with skeletal metastases were enrolled. Patients received standard therapy with docetaxel (75 mg/m intravenously every 21 days for at least six cycles) on average 6 weeks after Sm-EDTMP (37 MBq/kg). Patients were monitored for the presence of toxicities, and antitumor efficacy was assessed by changes in serum prostate-specific antigen levels. Besides standard descriptive statistical analysis, progression-free survival and overall survival were defined using the Kaplan-Meier method. RESULTS: Over 80% of the patients showed favorable biochemical responses. Median time to progression was 9.1 months (mean 9.8, 95% confidence interval 7.8-9.9), and median overall survival was 19.9 months (mean 24.5, 95% confidence interval 16.9-22.8); five patients were still alive over 5 years after enrollment. No additional hematological toxicities were observed when docetaxel was administered after Sm-EDTMP other than those expected when administering the agent alone. CONCLUSION: Prior administration of Sm-EDTMP does not cause additional toxicities for subsequent treatment with docetaxel and does not reduce the antitumor efficacy of the latter. This work justifies further investigations on the possible synergistic effects of combined strategies with the two agents.

Histologic chorioamnionitis at term: implications for the progress of labor and neonatal wellbeing.

OBJECTIVE: The aim of the present study was to evaluate: i) the rate of histologic chorioamnionitis in relation to the onset of labor and mode of delivery; ii) influence of clinical parameters on the risk of histologic chorioamnionitis in laboring women; iii) neonatal outcome in relation to histologic chorioamnionitis. METHODS: A cohort study was conducted on 395 healthy women at term, with singleton uneventful pregnancy, of which 195 with spontaneous onset of labor and 200 with elective cesarean section. All placentas, collected after delivery, were examined for the diagnosis of histologic chorioamnionitis. Mode of delivery, presence of bacterial infection of placenta and membranes, maternal clinical parameters and neonatal outcome were recorded. RESULTS: The rate of histologic chorioamnionitis in women with spontaneous onset of labor was significantly higher than in those experiencing elective cesarean section (28.7% vs. 11.5%). Nulliparity and the duration of labor were independent variables associated with acute histologic chorioamnionitis. The presence of histologic chorioamnionitis did not affect neonatal outcome. CONCLUSIONS: The present study showed a highest rate of histological chorionamniositis in women delivering after spontaneous onset of term labor, although the mode of delivery either vaginally or by emergency cesarean section was not influenced by the presence of this pathological condition.

Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma.

PURPOSE: Sorafenib improves overall survival and time to progression of advanced hepatocellular (aHCC) patients such as demonstrated in 2 phase III trials. However, aHCC patients' outcome is still poor despite these results. In order to improve the efficacy of systemic treatment for aHCC, we evaluated the combination of sorafenib plus 5-fluorouacil infusion in a phase II trial. METHODS: Patients with aHCC not eligible for loco-regional therapies, Child-Pugh A-B, ECOG-PS 0-1, and without history of anti-cancer systemic treatment were enrolled. Treatment schedule was: sorafenib 400 mg/bid continuously and continuum infusion of 5-fluorouracil 200 mg/sqm/daily day 1-14 every 3 weeks. RESULTS: Thirty-nine patients were enrolled: ECOG-PS 0-1: 29-10, Child-Pugh A-B: 36-3. Grade 3/4 (%) toxicities included: diarrhea 5.1/0, mucositis 20.5/2.6, hand foot skin reaction 20.5/0, skin rash 10.5/0, hypertension 10.3/0, hyperbilirubinemia 5.1/2.6, glutamic-oxaloacetic transaminase increase 10.3/0, glutamic-pyruvic transaminase increase 7.7/0, cardiac toxicity (one heart failure, two atrial fibrillation cases) 7.7/0, and bleeding (melena) in 2.6/0. One partial response was observed. Stable disease was obtained in 46.2% of patients with a median duration of 16.2 months. Median time to progression was 8 months (CI 95% = 5.7-10.4), and median overall survival was 13.7 months (CI 95% = 9.5-17.9). CONCLUSIONS: The results show an encouraging disease control rate, time to progression, and overall survival. The combination of sorafenib and 5-fluorouracil was feasible, and the side effects were manageable for patients carefully selected for liver function and performance status.

Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients.

BACKGROUND: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. METHODS: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. RESULTS: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. CONCLUSIONS: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment.

Clinicopathological variables predictive of clinical outcome in patients with FIGO stage Ib2-IIb cervical cancer treated with cisplatin-based neoadjuvant chemotherapy followed by radical hysterectomy.

The aim of this retrospective investigation was to assess the prognostic relevance of some pre-treatment clinical variables and histological findings assessed on the surgical samples of 46 patients with stage Ib(2)-IIb cervical cancer treated with cisplatin-based neoadjuvant chemotherapy followed by radical hysterectomy. Seven patients achieved a pathologically documented complete response, 6 had an optimal partial response, 29 had a suboptimal partial response, and 4 had stable disease. As for histological findings on surgical samples, 7 (15.2%) patients had positive lymph nodes, 10 (21.7%) had lymph-vascular space involvement, and 10 (21.7%) had positive parametria and/ or surgical margins. After surgery, 38 patients received further treatment with chemotherapy and/or irradiation. The median follow-up of survivors was 53 months (range, 4-167 months).Thirteen (28.3%) patients developed recurrent tumour, 11 (23.9%) patients died of tumour and one patient died of ictus with no clinical evidence of tumour. Recurrence-free and overall survival were significantly related to tumour stage (Ib(2)-IIa versus IIb, p=0.01 and p=0.02, respectively), pathologically assessed lymph node status (negative versus positive, p=0.0009 and p=0.007), lymph-vascular space status (negative versus positive, p=0.01 and p=0.009), parametrial and/or surgical margin status (negative versus positive, p=0.0001 and p=0.0005), but not to haemoglobin level before chemotherapy, patient age, tumour grade or chemotherapy regimen. A platelet count before chemotherapy above the median value of 272,000/microl was associated with a trend for a shorter recurrence-free survival (p=0.06) and with a significantly shorter overall survival (p=0.04) when compared with a lower platelet count. In conclusion, FIGO stage, lymph node status, lymph-vascular space status, parametrial and/or surgical margin status and pre-treatment platelet count are predictors of clinical outcome in patients with FIGO stage Ib(2)-IIb cervical cancer undergoing cisplatin-based neoadjuvant chemotherapy followed by radical hysterectomy. A multivariate analysis on a larger series of homogeneously treated patients is warranted to better define the clinicopathological risk factors useful to adequately plan the therapeutic strategy.

Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma.

The phosphoinositide 3-kinase/Akt pathway is involved in the pathogenesis of several human cancers. In this study, the biological and prognostic value of phosphoinositide 3-kinase/Akt pathway dysregulation was assessed by immunohistochemistry in a well-characterized series of 72 patients with node-negative breast cancer with a long-term follow-up. Phosphorylated Akt and PTEN expression was reduced in 32% and 12.5% of the tumors, respectively. Phosphorylated Akt or PTEN status was not associated with the main clinicopathologic and biological parameters, whereas their expression was tightly related to their downstream targets cyclin D1 and p27(Kip1) which are involved in cell proliferation. Survival analysis showed a strong association between a shorter disease-free survival and the dysregulated expression of phosphorylated Akt (P = .036), PTEN (P = .003), p27(Kip1) (P = .008), and Ki67 (P = .0007), or the distinct subtypes of breast tumors (luminal, HER2 overexpressing, and basal-like; P = .03). Moreover, multivariate analysis using the Cox proportional-hazards regression model showed that PTEN and Ki67 were independent predictive factors of disease recurrence and that their simultaneous dysregulation strongly increased the hazards ratio of the patients with node-negative breast cancer (hazards ratio, 38.30; P = .0014). In conclusion, our results show that the dysregulation of the phosphoinositide 3-kinase/Akt/PTEN pathway is relevant to the prognosis in node-negative breast carcinoma and that the evaluation of key components of this pathway might be a useful tool to identify the patients with node-negative breast cancer at high-risk of disease recurrence.

Epirubicin plus low-dose trastuzumab in HER2 positive metastatic breast cancer.

PURPOSE: This phase II study, evaluated the activity and cardiotoxicity of first-line epirubicin plus low-dose trastuzumab (LD-T) in patients with HER2 positive MBC. METHODS: Patients received epirubicin 90 mg/sqm every 3 weeks plus weekly LD-T (2 mg/kg loading dose, then 1 mg/kg). After 6/8 cycles of epirubicin, single agent trastuzumab was continued. Cardiotoxicity was defined as signs or symptoms of congestive heart failure (CHF), or >or=15% decline in LVEF without symptoms, or <15% LVEF decline to less than 50%, without symptoms. RESULTS: Forty-five patients were enrolled. Twenty-three received prior adjuvant anthracyclines. Overall response rate was 61.4%. The median time to progression was 7.4 months and the median survival was 32.8 months. Two (4.5%) patients developed CHF. CONCLUSIONS: Epirubicin plus LD-T is an active regimen, however, the relatively high rate of cardiotoxicity together with the availability of less cardiotoxic and active trastuzumab-containing combinations precludes further evaluation of this regimen.