Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms.

OBJECTIVES: To investigate whether there are sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis and to examine their association with symptoms of dysmenorrhea and abnormal uterine bleeding. METHODS: This was a prospective observational study including women referred from a gynecology outpatient center to our university hospital for ultrasound examination. Inclusion criteria were age between 18 and 30 years, regular menstrual cycle and nulligravid status. Exclusion criteria were a past or current history of endometriosis, fibroids, ovarian cysts or lesions, endometrial pathology, current use of hormonal treatments or medications that would affect the menstrual cycle, previous uterine surgery and history of infertility. Women underwent a detailed clinical assessment and a two- (2D) and three-dimensional (3D) transvaginal ultrasound (TVS) examination. 2D-TVS features associated with diffuse adenomyosis were predefined as: (1) heterogeneous myometrium; (2) hypoechoic striation in the myometrium; (3) myometrial anechoic lacunae or cysts; (4) asymmetrical myometrial thickening of the uterine walls with the presence of straight vessels, extending into the hypertrophic myometrium, on power Doppler examination. On 3D-TVS, endomyometrial junctional zone (JZ) was measured as the distance from the basal endometrium to the internal layer of the outer myometrium on coronal section at any level of the uterus, and the smallest (JZmin) and largest (JZmax) JZ thicknesses and their difference (JZdiff) were recorded. 3D-TVS evaluation was considered suggestive for adenomyosis when JZmax ≥ 8 mm and/or JZdiff ≥ 4 mm. The presence of associated symptomatology represented our main outcome: the amount of menstrual loss was assessed by a pictorial blood loss analysis chart (PBAC) and painful symptoms were evaluated using a visual analog scale (VAS). RESULTS: During the observation period, 205 women (median age, 24 (interquartile range, 23-27) years) were enrolled into the study and 156 met the inclusion criteria. According to the 2D-TVS criteria, diffuse adenomyosis was found in 53 (34.0%) women and asymmetrical myometrial thickening of the uterine walls was the most common sonographic feature observed. ANOVA showed a significant relationship between the number of 2D-TVS features of diffuse adenomyosis and VAS score for dysmenorrhea (P = 0.005) as well as PBAC score for menstrual loss (P = 0.03). 3D-TVS showed that women with 2D-TVS features of diffuse adenomyosis had a significantly higher value of JZmax (6.38 ± 2.30 mm, P < 0.001), JZmin (2.07 ± 0.43 mm, P = 0.002) and JZdiff (4.33 ± 1.99 mm, P < 0.001) than did women without these features. Women with sonographic features of diffuse adenomyosis were symptomatic in 83% of cases, reported dysmenorrhea in 79.2% and showed a higher incidence of heavy bleeding than did those without these features (18.9% vs 2.9%; P = 0.001). CONCLUSIONS: Sonographic features suggestive of diffuse adenomyosis may develop earlier in reproductive life than previously thought, and may occur in association with dysmenorrhea and abnormal uterine bleeding in nulligravid women. Their observation in these women should therefore warrant further gynecological investigation.

Premature ovarian insufficiency: from pathogenesis to clinical management.

Premature ovarian insufficiency (POI) represents a condition characterized by the absence of normal ovarian function due to an incipient (by 3-10 years) ovarian aging. In most of the women affected there are no signs or symptoms that precede the interruption of menstruation and the onset of POI and the majority of women have a normal history of menarche, regular menstrual cycles and normal fertility. The possible genetic role in the development of POI has been largely demonstrated and many genes have been involved; on the other hand, ovary is not protected immunologically and the detection of autoantibodies directed against various ovarian targets strongly support the hypothesis of an autoimmune etiology. In approximately 5-10% of women with a diagnosis of POI with a normal karyotype, a spontaneous pregnancy could occur even if the recovery of ovarian function is temporary and poorly predictable. Embryo donation and adoption are other alternatives that should be considered. POI and subsequent loss of reproductive capacity is a devastating condition and a difficult diagnosis for women to accept so it requires an individualized and a multidisciplinary approach. Hormonal replacement therapy (HRT) should be commenced as soon as possible to prevent and to contrast the onset of the symptoms related to hypoestrogenism and to improve the quality of life for these women.

Baseline elevated leukocyte count in peripheral blood is associated with poor survival in patients with advanced non-small cell lung cancer: a prognostic model.

PURPOSE: We aimed to investigate the prognostic significance of several baseline variables in stage IIIB-IV non-small cell lung cancer to create a model based on independent prognostic factors. METHODS/RESULTS: A total of 320 patients were treated with last generation chemotherapy regimens. The majority of patients received treatment with cisplatin + gemcitabine or gemcitabine alone if older than 70 years or with an ECOG performance status (PS) = 2. Performance status of 2, squamous histology, number of metastatic sites >2, presence of bone, brain, liver and contralateral lung metastases and elevated leukocyte count in peripheral blood were all statistically significant prognostic factors in univariate analyses whereas the other tested variables (sex, stage, age, presence of adrenal gland and skin metastases) were not. Subsequently, a multivariate Cox's regression analysis identified PS 2 (P < 0.001, hazard ratio 2.57), elevated leukocyte count (P < 0.001, hazard ratio 1.79), squamous histology (P = 0.005, hazard ratio 1.45) and presence of brain metastases (P = 0.035, hazard ratio 1.5) as independent prognostic factors for poor survival. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the four independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 10.2 months (95% confidence interval (CI) 8.9-11.6), 5.1 months (95% CI 4.0-6.2) and 2.8 months (95% CI 0.5-5.2), respectively. The high-risk group encompassed PS 2 patients with two or three adjunctive unfavourable independent prognostic factors. CONCLUSIONS: Performance status, white blood cells count, histology and brain metastases resulted in our series prognostic factors of survival in NSCLC patients treated with chemotherapy at a multivariate analysis. Leukocyte count resulted the stronger factor after performance status. If prospectly validated, the proposed prognostic model could be useful to stratify performance status 2 patients in specific future trials.

Cardiotoxicity of epirubicin/paclitaxel-containing regimens: role of cardiac risk factors.

PURPOSE: To evaluate the incidence of clinically relevant cardiac toxicity after treatment with epirubicin/paclitaxel-containing regimens in patients with metastatic breast cancer and to identify high-risk patients in whom the benefit of chemotherapy may be negated by the occurrence of congestive heart failure (CHF). PATIENTS AND METHODS: A total of 105 patients who were referred for epirubicin/paclitaxel treatment were included in this study. Treatment regimens were as follows: (1) epirubicin 90 mg/m(2) plus paclitaxel 135 to 225 mg/m(2) over 3 hours (n = 76); and (2) gemcitabine 1,000 mg/m(2) on days 1 and 4 plus epirubicin/paclitaxel (n = 29). The occurrence of CHF was detected by physical examination, and left ventricular function was evaluated by bidimensional echocardiography to support the diagnosis. Cardiac risk factors examined in this study included age, prior radiotherapy to the chest, hypertension, and diabetes. RESULTS: No patient experienced CHF while on treatment. Nine patients (9%) developed CHF after cumulative epirubicin doses of 1,080 mg/m(2) (n = 4), 720 mg/m(2) (n = 2), 630 mg/m(2) (n = 1), and 540 mg/m(2) (n = 2). One of the two patients who developed CHF after a cumulative epirubicin dose of 540 mg/m(2) had received consolidation with high-dose chemotherapy. Median time to appearance of cardiologic symptoms was 3 months after the end of treatment (range, 3 to 6 months). Overall, the incidence of CHF was 13% and 4% in patients with or without cardiac risk factors, respectively. The cumulative risk of developing CHF was estimated as 7.7% at a cumulative doses of 720 mg/m(2) and 48.7% at a cumulative dose of 1,080 mg/m(2). CONCLUSION: This study shows that the incidence of CHF after an epirubicin/paclitaxel regimen is low up to cumulative epirubicin doses of 990 mg/m(2), thus allowing the safe administration of this regimen even in patients who received epirubicin in the adjuvant setting. However, the risk of developing CHF increases when a cumulative dose exceeding 990 mg/m(2) is reached, concomitantly with the presence of an additional cardiac risk factor.

Increased dose-intensity of gemcitabine in advanced non small cell lung cancer (NSCLC): a multicenter phase II study in elderly patients from the "polmone toscano group" (POLTO).

Gemcitabine is usually administered at a planned dose-intensity (DI) from 750 to 800 mg/m2/week. Preclinical data have suggested a possible dose-response relationship of gemcitabine. A multicenter phase II study was conducted to evaluate the activity in terms of no progression rate (complete responses+partial responses+stable diseases) of gemcitabine administered at an increased DI (1000 mg/m2/week) in elderly advanced non-small-cell lung cancer (NSCLC) patients. Secondary endpoints were to evaluate tolerability, progression free survival and overall survival. Elderly (age>or=70 years) chemo-naive advanced NSCLC patients, ECOG PS 0-2, were treated with intravenous gemcitabine 1500 mg/m2 intravenous (30 min infusion) on days 1 and 8 every 21 days for four courses. One hundred and twenty-two patients with a median age of 75 years (range 70-84) entered the study. The following grade 3 (NCI-CTC) haematological toxicities were reported (percent of patients): neutropenia 2.4%, thrombocytopenia 1.6%, anaemia 2.4%. No grades 3-4 non-haematological toxicities were observed. Among 111 evaluable patients 52 (46.8%) no progressions, 17 (15.3%) partial responses (WHO criteria), 35 (31.5%) stable diseases and 59 (53.2%) progressions were observed. Median time to progression was 3.2 months and median duration of survival was 5.4 months. The overall 1-year survival rate was 27%. Although increased dose-intensity of gemcitabine in elderly NSCLC patients is feasible without severe toxicities, this does not seem to be associated with an increased activity and efficacy in comparison to standard gemcitabine regimens with lower dose-intensities.

High-dose chemotherapy with autologous haemopoietic support for advanced ovarian cancer in first complete remission: retrospective analysis from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT).

The majority of advanced ovarian cancer patients achieve an objective response following chemotherapy; however, only 20-30% are in remission after 5 years. Intraperitoneal or high-dose chemotherapy (HDC) may prolong disease-free and overall survival (OS) in patients with platinum-sensitive, small volume disease. To better define the subsets of patients who might benefit from HDC, we performed a retrospective analysis on 91 patients in 1st complete remission (CR) treated from 21 centres of the EBMT group. At a median follow-up of 48 months, median time-to-progression (TTP) and OS were 21.2 and 44.4 months, respectively. Tumour grade, stage, residual disease, disease status before HDC, type and year of transplant, source of haemopoietic progenitors and use of haemopoietic growth factors (HGF) after transplant were analysed for TTP and OS. The only significant parameter was the use of HGF: median OS for patients receiving or not receiving HGF was 46.2 vs 17.8 months, respectively (P: 0.035); this difference was maintained after multivariate analysis (P: 0.02). Our analysis does not identify any subgroup of patients in 1st CR who can benefit from HDC; however, median survival of patient with no residual disease has not been reached. The role of HGF after HDC deserves further investigation.

Genes involved in the pathogenesis of premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is defined by the presence of primary or secondary amenorrhea, for at least 4 months, before the age of 40 years associated with follicle stimulating homone levels in menopausal range, exciding 40 UI/L. The diagnosis is confirmed by two blood sample at least 1 month to measure the level of FSH (over 40 UI/L) and level of estradiol (below 50 pmol/L). Ovarian follicular dysfunction and/or depletion of functional primordial follicles characterized this pathology. Abnormal bleeding patterns also include oligomenrrhea and polimenorrhea; because of these irregular menstrual cycles during adolescence, diagnosis could be difficult in young women. Excluding the cases in which an etiopathogenetic agent could be identified, such as in case of chemio- and radiotherapy or extensive surgery, women with autoimmune diseases and/or infections, the etiology of POI remains idiopathic. An important genetic component exists, supported by both a frequent recurring familiar event (20-30%) and the association with other different genetic disorders in particular the X chromosome defects and the implication of some different genes with significant functions in ovarian development. For most of the women the diagnosis of POI is unexpected because of there are no obvious signs or symptoms that precede the cessation of periods with a normal menstrual history, age of menarche and fertility prior to the onset of menopause. The diagnosis of POI has a deleterious psychological impact on the emotional sphere of the women affected: anger, depression, anxiety and sadness are common and the fact that the diagnosis coincides with infertility needs a psychological support. Oral hormonal replacement therapy (HRT) administration is not recommended as first choice of treatment because of the higher hormones concentration with respect to the real hormones necessity of the patients and transdermal HRT may be preferred in women with coagulation disturbances to relief symptoms and to improve to quality of life and the sexuality of these women until the age of 50 years old which is the median age of physiological menopause. Moreover it should be considered the associate comorbidities of POI such as bone loss, cardiovascular disease and endocrine disease.

The gemcitabine/epirubicin/paclitaxel combination in advanced breast cancer.

The purpose of this study was to determine the response rate of the gemcitabine/epirubicin/paclitaxel combination (GET) and its feasibility as induction chemotherapy before high-dose consolidation treatment in patients with metastatic breast cancer. Patients received gemcitabine 1,000 mg/m2 on days I and 4, epirubicin 90 mg/m2 on day 1, and paclitaxel 175 mg/m2 on day I every 3 weeks for up to eight courses. After six courses of GET, responding patients or those with stable disease entered a high-dose chemotherapy program. All 36 enrolled patients were evaluated for toxicity and response. The GET combination was well tolerated, with myelosuppression the being most common toxicity; grade 4 neutropenia was reported in 56% of patients. The overall response rate was 89% (95% confidence interval, 73.4% to 96.9%), with a 28% complete response rate. The high-dose chemotherapy program resulted in a response rate of 92% and a complete response rate of 44%. As a result of the promising activity demonstrated in this phase II study with GET and following high-dose chemotherapy, three related studies are planned: an in vitro study evaluating the possible synergism of paclitaxel and gemcitabine, a phase III study comparing GET with epirubicin/paclitaxel in metastatic breast cancer, and a phase II trial evaluating GET in patients with operable breast cancer.

Gemcitabine monotherapy in elderly patients with advanced non-small cell lung cancer: a multicenter phase II study.

BACKGROUND: This trial investigated the activity and toxicity of gemcitabine in previously untreated elderly (> 70 years) patients with advanced (stage IIIB-IV) non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From January 1997 to July 1998, 46 patients with advanced NSCLC aged over 70 years with a performance status of 0-2 were entered into the study. Gemcitabine 1000 mg/m2 was administered as a 30-min infusion once a week for 3 weeks followed by a week of rest; cycles were repeated every 4 weeks. RESULTS: Forty-four patients were evaluable for response. One complete response and nine partial responses were observed, for an overall response rate of 22.2% (95% C.I.: 11.3-37.5). The median time to disease progression was 5.1 months (95% C.I.: 3.5-6.7), the median duration of response was 6.3 months, and the median overall survival time 6.75 months (95% C.I.: 5.3-8.2). All patients were evaluable for toxicity (184 cycles, median = 3 cycles/patient) and no grade 4 hematologic toxicities were reported. WHO grade 3 leukopenia, neutropenia and anemia occurred in 3.3, 0.5 and 1.1% of cycles, respectively. Grade 3 skin rash occurred in 4.3% of patients. These side effects led to treatment discontinuation in two patients. CONCLUSION: Our data show that gemcitabine is active and well tolerated in patients aged over 70 years with advanced NSCLC.

HER2 overexpression as a prognostic factor in metastatic breast cancer patients treated with high-dose chemotherapy and autologous stem cell support.

We retrospectively evaluated the predictive and prognostic role of HER2 expression in 44 metastatic breast cancer (MBC) patients treated with high-dose consolidation chemotherapy (HDCT) and autologous stem cell support after induction chemotherapy (IC) with six courses of epirubicin+paclitaxel (22 patients) or gemcitabine+epirubicin+paclitaxel (22 patients). HER2 expression was evaluated by an immunohistochemical method (Herceptest, Dako). A total of 13 patients (29.5%) showed a HER2 overexpression (score 3+). After IC, nine patients were in complete response (CR), 30 in partial response (PR), and five in stable disease (SD); after HDCT, 20 (45.5%) obtained a CR, and 23 were in PR, for a conversion rate of 48.5%. Conversion rate for HER2-positive patients was 87.5 vs 37% for HER2-negative patients (P=0.018). The median progression-free (PFS) and overall survivals (OS) were 17.6 (95% CI 13.2-22.0) and 44 (95% CI 25.9-62.3) months, respectively. Patients with HER2 overexpression experienced a significantly (P=0.0042) shorter median PFS (15.3 months, 95% CI 11.1-19.5) compared to HER2-negative patients (21.3 months, 95% CI 14.3-28.4). The median OS was 27.6 months (95% CI 4.5-50.7) in HER2-positive patients and 50.3 months (95% CI 38.7-62.0) in HER2-negative patients (P=0.345). These results indicate that HER2 overexpression predicts a worse outcome for patients with MBC treated with HDCT, despite the high CR rate obtained in this subset of patients.

Role of epirubicin in advanced breast cancer.

Anthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease. Unfortunately, their clinical value is limited by late-onset ventricular dysfunction. Epirubicin, an anthracycline analogue, does not eliminate the risk of cardiotoxicity but is less cardiotoxic and myelotoxic than doxorubicin at equimolar doses, thereby allowing the safe administration of cumulative doses between 950 and 1000 mg/m2. The inclusion of epirubicin in combination regimens, such as fluorouracil/epirubicin/cyclophosphamide (FEC), has been shown to be safe and active as first-line treatment for metastatic breast cancer. In the past few years, new drugs, including taxanes, have shown a high level of activity as single agents in the treatment of advanced breast cancer. Doxorubicin/paclitaxel combinations have shown high overall response rates (90%) as first-line chemotherapy of advanced breast cancer; however, congestive heart failure has been reported in up to 20% of patients. Epirubicin/paclitaxel combinations have been associated with grade 3 cardiotoxicity (6%) in only one study. We report findings of a trial of combination epirubicin/paclitaxel as first-line treatment of advanced breast cancer, with overall response rates (ORRs) of 84% and a complete response (CR) rate of 19%. Achieving a CR to first-line chemotherapy for advanced breast cancer appears to predict survival, and adding an active drug with a different mechanism of action and nonoverlapping toxicity might increase the percentage of CRs. We therefore tested the feasibility and activity of 6 to 8 courses of first-line treatment with a three-drug combination (gemcitabine 1000 mg/m2 days 1 and 4, epirubicin 90 mg/m2 day 1, and paclitaxel 175 mg/ m2 over 3 hours on day 1) in a phase II study of 36 metastatic breast cancer patients. Treatment was well tolerated, with an ORR of 92% (95% confidence interval: 77.53%-98.25%) and a CR of 31%. In considering retreating patients who progress or relapse after receiving an anthracycline-/taxane-containing regimen with the same active drugs, epirubicin appears ideal in both the adjuvant and metastatic breast cancer settings.

New combinations with epirubicin in advanced breast cancer.

Several trials have shown that anthracyclines and taxanes can be combined to achieve response rates ranging from 70% to 90%, with complete responses ranging from 19% to 41%. In an attempt to increase the activity while maintaining tolerability, gemcitabine (Gemzar) was added to the epirubicin (Ellence)/paclitaxel (Taxol) regimen. Among 36 metastatic breast cancer patients treated with this new combination, the overall response rate was 92%, including 31% with a complete response. Another attempt to improve the outcome of metastatic breast cancer patients involves a phase III multicentric randomized trial (MANTA-1) to evaluate if paclitaxel maintenance therapy after anthracycline/taxane combination therapy can improve time to progression and overall survival. Although anthracyclines are more frequently used in the adjuvant setting, it is important for the clinicians to know whether this class of drugs can be used again for those patients who develop metastatic disease. An analysis of 312 patients treated with epirubicin containing regimens as first-line treatment for metastatic disease shows that epirubicin-based regimens are active in patients already exposed to anthracyclines in the adjuvant setting, and that the risk of cardiac toxicity is low up to a cumulative epirubicin dose of 990 mg/m2.

Epirubicin/taxane combinations in breast cancer: experience from several Italian trials.

Doxorubicin/paclitaxel (Taxol) combinations are very active in advanced breast cancer, with objective response rates up to 90%, but have shown a high incidence of cardiotoxicity. A phase I/II trial replacing doxorubicin with epirubicin (Ellence), a less cardiotoxic analog, produced an objective response rate of 84%, but with a low rate of cardiotoxicity. A careful cardiac monitoring in more than 100 patients treated with this combination has demonstrated that the risk of congestive heart failure is below 10% up to a cumulative epirubicin dose of 990 mg/m2. To examine the possibility that the pharmacokinetic and pharmacodynamic interactions that occur when anthracycline and paclitaxel are administered together might result in subadditive antitumor activity, a phase III study is comparing concomitant vs sequential administration of epirubicin and paclitaxel in patients with advanced breast cancer. A phase I/II study of epirubicin plus docetaxel as first-line chemotherapy for advanced breast cancer patients evaluated the maximum tolerated doses and for subsequent studies recommended epirubicin at 75 mg/m2 plus docetaxel at 80 mg/m2. In the adjuvant setting, an ongoing phase III trial is comparing epirubicin plus paclitaxel vs FEC (fluorouracil, epirubicin, and cyclophosphamide [Cytoxan, Neosar]) in node-positive patients. Preliminary data confirm the cardiac safety of these treatments.

Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors.

Long-acting depot forms of somatostatin analogs administered by intramuscular injections are now available for the treatment of neuroendocrine tumors (NETs). In the present study, we investigated the efficacy and tolerability of a slow-release form of lanreotide in patients with advanced NETs. From July 1996 to January 1999, 25 patients with advanced NETs (12 carcinoids, 13 endocrine pancreatic tumors) were enrolled in the study. Thirteen patients were pretreated with subcutaneous octreotide, chemotherapy, or hepatic metastasis alcoholization. All the patients had measurable disease. Seventeen patients were symptomatic and 20 patients had elevated serum and/or urine markers. Octreotide scintigraphy was positive in 23 of 25 patients. Lanreotide was administered as intramuscular injections at the dose of 30 mg every 2 weeks until there was objective, biochemical, or symptomatic tumor progression. Objective partial responses (PRs) were documented in 2 patients (8%), whereas 10 patients (40%) had tumor stabilization. The PRs were observed in patients with midgut carcinoids, of whom one was pretreated with subcutaneous octreotide. The response duration was 21+ and 24+ months in responding patients; the median duration of disease stabilization was 8.5 months (range, 4-21+). The overall biochemical response rate was 42%, including 2 complete responses (CRs) (10.5%) and 6 PRs (31.5%); all biochemical responses were observed mostly in patients with carcinoid tumors; the duration of response was 18+ and 30+ months for CRs; the median duration of biochemical response was 7 months (range, 4-18+) for PRs. The overall symptomatic response rate was 70% with a median duration of 7.5, 18, and 18+ months for diarrhea, abdominal pain, and flushing, respectively. Median duration of lanreotide treatment was 10 months (range, 2-30+). No significant side effects were reported. Depot lanreotide 30 mg shows significant efficacy in terms of objective response rate and in biochemical and symptomatic control, in pretreated patients as well as nonpretreated patients with advanced NETs. Tolerability is good, with good patient compliance.

[Hospital admissions, diagnostic and therapeutic procedures of patients with colorectal cancer during 5 years after diagnosis: population-based study]. / Ricoveri ospedalieri, prestazioni diagnostiche e terapeutiche nei pazienti affetti da tumore del colonretto durante cinque anni dalla diagnosi: uno studio di popolazione.

This research evaluated basic parameters of care, also in the terms of costs. The study examined a sample of colorectal cancer cases incident in 1987 in the population of Florence's municipality, taken from the data base of Tuscany Cancer Registry (RTT). We collected, for 71 patients, all clinical records, for the five follow-up years and evaluated the diagnostic and therapeutic procedures (blood tests, histologic examination, instrumental investigation and surgical intervention) and the duration of all hospitalisations. Besides, on the basis of the diagnostic and therapeutic procedures and of the discharge diagnosis, each hospitalisation was coded following the DRG system and the economic cost of hospital care was analysed. The average number of hospitalisations and the average length of stay for patient in five follow-up years are respectively 1.9 (SD = 1.3) and 41.3 (SD = 25.8); the length of stay resulted highly correlated with the stage of disease. The mean hospital cost per patient (about ItL 18.000.000 overall) was higher in patients with more advanced disease at diagnosis. In the period of study an average 125.9 blood tests (SD = 110.7), 1.2 histologic examinations (SD = 0.9) and 10.3 instrumental investigations (SD = 9.0) were performed for each patient; 61 subjects (86%) were submitted to surgical intervention, of which 4 had a second intervention, and 1 subject was submitted to surgical intervention for liver's metastases.

[Experimentation with Di Bella polychemotherapy in Tuscany]. / Sperimentazione della multiterapia Di Bella in Toscana.

The study reports the experience of Di Bella Treatment (an unconventional treatment for cancer) for advanced cancer patients in Tuscany. A total of (38 + 140 + 463) patients were treated (38 phase II study, 140 observational study and 463 distributional study) and all the case report forms were collected and analyzed in the Regional Coordinator Center of Pisa. No objective response was observed; as of May 31, 1999 63 patients are in stable disease (1 phase II, 3 observational and 59 distributional study). Percentage of interruptions to treatment due to death, refusal and toxicity were similar between patients O and D, while there are significant differences in terms of progressive disease (O = 52% vs D = 18%) and number of losts to follow up (40% in distributional study). The median duration of treatment was 2.31 months (range: 0-15) in the observational study and 3.2 months (range: 0-13) in the distributional study. The median overall survival time (4.5 months) and the median time to disease progression (2.7 months) were calculated by Kaplan-Meier Method and were based on all treated patients (intention to treat population). Follow-up of the study was stopped at 31.05.1999.

Hormone replacement therapy in menopause and in premature ovarian insufficiency.

Menopause is defined by world health organization (WHO) as the permanent cessation of menstruating resulting from a loss of ovarian follicular activity, after one year of amenorrhea. It signifies the last menstrual cycle and the end of women's fertile and reproductive life. The average age for a women to undergo menopause is 51 years; unlike menarche, whose average age has decreased over the past decades, the age of menopause has remained unchanged. We can distinguish: 1) premenopause, the time interval leading up to menopause; 2) climacteric, the time interval between the reproductive e non-reproductive life; 3) premature menopause, that occurs in 1% of women. Menopause can also be induced iatrogenically as a result of surgery, medical therapy, chemotherapy and radiotherapy. Beyond the life the number of oocytes falls until there are no more suitable follicles for reproduction and the menopause ensues. At the same time, the ability of the ovary to produce hormones falls, leading to an increasing pulsatile release of FSH in order to stimulate the ovary to produce oestrogens. Menopause is characterized by different symptoms such as hot flushes, night sweats, dispareunia, prolapse, vulval itching due to vaginal atrophy and dryness, urinary incontinence, dysuria, and also the psychological aspects don't should be underestimated because of many women suffer of depression, mood instability, insomnia, fatigue and decreased libido. Long term symptoms include osteoporosis, cardiovascular and neuro-degenerative diseases. The main aim of different treatments was symptoms relief. Pharmacological agents and psychological support represent the goal for menopause treatment.

Radioguided occult lesion localization of cervical recurrences from differentiated thyroid cancer: technical feasibility and clinical results.

AIM: We explored the feasibility of radioguided occult lesion localization (ROLL) for radioiodine-negative cervical recurrences from differentiated thyroid cancer (DTC). METHODS: The procedure was performed in 32 patients (3 patients being operated twice); 15/32 patients had had multiple prior lymph node dissections ("hostile" anatomy). 99mTc-albumin macro-aggregates (99mTc-MAA) were injected intra-lesionally under ultrasound guidance; 2 to 18 hours later, a hand-held gamma-probe helped to localize the lesions intraoperatively and to ascertain removal of the radiolabeled lesions. Mini-invasive excision of the radiolabelled lesions was performed in 12 cases (m-ROLL), while a modified radical neck dissection was performed in 23 cases after radioguided lymphadenectomy (d-ROLL). Fifty-nine lesions were radiolabelled (mean size 11±4.5 mm). RESULTS: Radioguidance allowed to identify/remove 56/59 lesions (95%). Some leakage of 99mTc-MAA in the surrounding tissues hampered detection of 3 lesions, which were removed anyway (100% overall localization). Histopathology confirmed metastatic involvement of the radiolabeled lesions and some additional metastases in other nodes. Neither nerve injury nor hypoparathyroidism occurred. After a median follow-up of 29 months, 19 patients were disease-free, 12 patients developed loco-regional recurrences, 1 patient had distant metastases and 1 patient had both loco-regional and distant metastases. Recurrences rates were 33% for m-ROLL and 40% for d-ROLL. CONCLUSIONS: The ROLL technique is feasible in selected patients with loco-regional recurrence from DTC, proving to be particularly useful also in patients already submitted to cervical dissections and/or with small lesions located in surgically difficult sites. It can therefore have a clinical role in the management of cervical DTC recurrences.