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Introduction Stroke is one of the major causes of death in the world, but above all is the condition most associated with severe long-term disabilities. It is clear that this condition therefore requires the best therapeutic approach possible to minimize the consequences that this can lead to. The major issues concern the type of treatment to be used for revascularization (carotid endarterectomy [CEA] or stenting of the carotid artery [CAS]) and the timing of the treatment itself. Many studies have been conducted on this issue, but a definitive and unanimous verdict has not yet been reached on account of the great variety of results obtained from the various study group. The aim of this review is to analyze the latest scientific findings focused on revascularization following a symptomatic carotid stenosis (SCS). Evidence acquisition We searched all publications addressing treatments and timing of approach to SCS. Randomized trials, cohort studies and reviews were contemplated in order to give a breadth of clinical data. Medline and Science Direct were searched from January 2013 to April 2017. Evidence synthesis Of the 819 records found, 76 matched our inclusion criteria. After reading the full-text articles, we decided to exclude 54 manuscripts because of the following reasons: 1) no innovative or important content; 2) insufficient data; 3) no clear potential biases or strategies to solve them; 4) no clear endpoints; and 5) inconsistent or arbitrary conclusions. The final set included 22 articles. Conclusions CEA is considered a less problematic method than CAS, especially for patients over the age of 75; CAS remains recommended in patients with a favorable anatomy or high surgical risks. Studies that showed more solid results seem to lead to the conclusion that optimal timing may be between 2 days and the end of the first week from the onset of symptoms in patients who are appropriate candidates for surgery.

The objective of this study was to investigate correlates of risk for having microalbuminuria in individuals with one or more cardiovascular risk factors.The study involved 1919 individuals who attended general practice settings, were aged 55 to 75 yr, and did not have a history of cardiovascular events or diabetes but had one or more cardiovascular risk factors. A tree-based regression technique and multivariate analysis were used to identify distinct, homogeneous subgroups of patients with different likelihood of having microalbuminuria; interaction between correlates of microalbuminuria and risk for microalbuminuria was also investigated.The prevalence of microalbuminuria was 5.9%. Patients who did not have hypertension and had postload glycemia140 mg/dl showed the lowest prevalence of microalbuminuria (1.9%) and represented the reference class. The likelihood of microalbuminuria was seven times higher in men with hypertension and homeostatic model assessment levels in the upper tertile and four times higher in women with the same characteristics. Individuals with hypertension and lower homeostatic model assessment levels and normotensive individuals with postload glycemiaor = 140 mg/dl had a more than three-fold increased likelihood of having microalbuminuria. Treatment with statins was associated with a 54% reduction in the likelihood of having microalbuminuria, whereas levels of triglycerides150 mg/dl and fibrinogen levels in the upper tertile were associated with a significantly higher risk for microalbuminuria.The likelihood of having microalbuminuria in a population-based study of elderly individuals is strongly related to the interaction between the components of the metabolic syndrome, particularly hypertension, insulin resistance, and impaired glucose tolerance.

Background. This study assessed the prognostic effect of lymphatic and blood vessel invasion (LVI and BVI) on survival in a retrospective sample of 1408 patients with breast cancer. Methods. Survival analysis was evaluated by univariate (Kaplan-Meier product limit method and log rank test) and multivariate (Cox model) analysis. Correlations among variables were studied by contingency tables and statistical significance was evaluated by chi-square test. Results. Lymphatic vessel invasion was present in 34.2% of cases, and BVI in 4.2%. Lymphatic vessel invasion correlated with BVI (P < 0.0001), and both were correlated with metastatic axillary lymph nodes and increasing tumor size and grade; BVI was sporadic (only 10 cases) among lymph node negative patients. Although LVI was more frequent among premenopausal patients and those with ductal carcinomas, BVI was unrelated to menopausal status and tumor type. Lymphatic vessel invasion and BVI were associated with poor survival by univariate analysis (P < 0.0001). By multivariate analysis, relative risk of death was significantly increased when LVI was present both in the whole series as well as in the lymph node negative and lymph node positive subgroups; the prognostic role of LVI was independent of menopausal and lymph node status, tumor size, tumor grade, or adjuvant treatment. In the lymph node negative sample, LVI had strong prognostic power. In the lymph node positive sample, the prognostic role of LVI was also independent of the number of lymph nodes with metastases. Blood vessel invasion had no prognostic role in any subgroup. Conclusion. The prevalence of BVI was particularly low in this study, and the question of its possible prognostic role for patients with breast cancer should be assessed with methods that amplify its detection. LVI is a strong prognostic factor for operable patients with breast cancer. In lymph node negative patients, LVI is a predictor of poor prognosis for those who are consequently candidates for adjuvant therapy. Similarly, in lymph node positive patients, LVI is a predictor for a high risk of death for those who are candidates for highly intensive adjuvant strategies. Cancer 1995; 76:1772–8.

Aim. To verify the rationale of a pelvic stop-flow technique for the perfusion of high-doses of mitomycin C and anthacyclines in patients with inoperable, recurrent pelvic cancer. Methods. The stop-flow technique was realized by using percutaneous double-balloon arterial–venous catheters that selectively isolate the pelvic vascular section and a perfusion provided by an extracorporeal pump for 20 min. Ten patients (pts) with unresectable pelvic recurrence from colon-rectal cancer were treated with a combination of Mitomycin C (MMC, 20 mg/sqm) plus doxorubicin (DOXO, 75 mg/sqm; 8 pts) or epirubicin (EPI, 75 mg/sqm; 2 pts) infused into the isolated pelvic compartment. Blood samples were collected from the extracorporeal vascular flow and from peripheral plasma, and analysed for drug quantitation. Results. During the procedure, there were no technical or hemodynamic complications, and no deaths occurred during surgery or in the postoperative period. MMC and DOXO peak levels measured in the extracorporeal system which irrotates the tumor area, were on average 21.6 (range: 4.3–44.3, MMC) and 17.2 (range: 1.8–48.4, DOXO) times higher than those observed in the peripheral blood. Similarly; the area under concentration (AUC) versus time curves measured in the pelvic compartment during stop-flow perfusion were 19.9 (range: 3.8–45.0, MMC) and 13.4 (range: 1.2–26.6, DOXO) times higher than the corresponding value in peripheral circulation. The drug percentage eliminated in the ultra filtrate was only 7.7% (MMC) and 0.9% (DOXO), and the plasmatic AUC0–24 were similar to those observed with iv bolus of equivalent drug doses. Minimal systemic and local toxicities were observed. One complete pathological and 2 partial responses were observed; pain remission in 8/10 patients. Median survival was 12 months (8–31). Conclusion. The endo-arterial administration into the local vasculature produces high pelvic-systemic concentration gradients during the stop-flow perfusion with limited local and systemic toxicity. The encouraging clinical results suggest further evaluation.

Northern Italy has been one of the European regions reporting the highest number of COVID‐19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of most of the available health care resources to treat COVID‐19‐positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID‐19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer‐related outcome. In this article, we attempt to estimate the individual risk–benefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID‐19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources. Implications for Practice Managing patients with breast cancer during the COVID‐19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID‐19‐related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients’ and health workers’ psychological distress., This article discusses strategies employed by an institution in Northern Italy to ensure the continuum of the best possible cancer care during the COVID‐19 pandemic for breast cancer patients while mitigating the risk of infection, despite limited health care resources.

Purpose We evaluate the role of transanal tube drainage (TD) as a conservative treatment for patients with anastomotic leakage (AL). Methods Patients treated for AL who had undergone a low or an ultralow anterior resection with colorectal or coloanal anastomosis for the treatment of rectal cancer between January 2013 and January 2017 were enrolled in this study. The data were collected prospectively and analyzed retrospectively. The primary outcomes were the diagnosis and the management of AL. Results Two hundred thirteen consecutive patients, 122 males and 91 females, were included. The mean age was 66.91 ± 11.15 years, and the median body mass index was 24 kg/m2 (range, 20-35 kg/m2 ). The median tumor distance from the anal verge was 8 cm (range, 4-12 cm). Ninety-three patients (44%) received neoadjuvant therapy for nodal disease and/or locally advanced rectal cancer. Only 13 patients (6%) developed AL. Six patients developed subclinical AL as they had a defunctioning ileostomy at the time of the initial procedure. They were treated conservatively with TD under endoscopic guidance in the endoscopy unit and received intravenous antibiotics. Six weeks after discharge, these 6 patients underwent follow-up flexible sigmoidoscopy which showed a completely healed anastomotic defect with no residual stenosis. Seven patients developed a clinically significant AL and required reoperation with pelvic abscess drainage and Hartmann colostomy formation. Conclusion These results suggest that TD for management of patients with AL is safe, cheap, and effective. Salvaging the anastomosis will help decrease the need for Hartmann colostomy formation. Proper patient selection is important.

Aim. This study aims to compare the early and late outcomes of transanal hemorrhoidal dearterialization (THD) versus stapled hemorrhoidopexy (SH) for the treatment of hemorrhoidal disease. Methods. From January 2013 to December 2014, 100 patients—50 patients on each arm—were randomly allocated to THD or SH groups. The inclusion criteria were grade III and IV hemorrhoids diagnosed by clinical examination and proctoscopy. The primary outcome was to compare the recurrence rate with a minimum follow-up of 2 years, and the secondary outcome was to compare complications rate, time to return to work postsurgery, procedure length, and patient’s satisfaction between the 2 techniques. Results. The mean follow-up period was 33.7 ± 7.6. The recurrence rate was 4% in the SH group and 16% in the THD group ( P = .04). There was no difference in the intraoperative and postoperative complications rate; the pain score was significantly higher in the THD group. The mean operative time was significantly shorter in the SH group compared with the THD group. Patients in the THD group returned to work or routine activities significantly later compared with patients in the SH group. The overall satisfaction rate was also higher in the SH group. Conclusion. Both procedures are simple and easy to perform for the treatment of grade III and IV hemorrhoids. SH showed better results in terms of lower rate of recurrence, lower postoperative pain, quicker return to work, and higher patient satisfaction.

A new strategy that takes advantage of the synergism between NMR and LC-HRMS (SYNHMET), and that allows to obtain a unique list of the absolute concentrations of 164 metabolites in urine, is presented. Metabolite identification and quantification by this method in one of the most difficult biofluids to characterize, due to complexity and variability, is more accurate than what can be obtained using the two techniques separately. This result is achieved without the need for chemical reactions to cross-check the data between the two types of spectra, nor the use of analytical standards and calibration curves. The fact that the absolute rather than relative concentration is obtained allows the final dataset to be used to determine a patient's personalized profile. The number of quantifiable metabolites by the application of this method can be expanded in the future with further analysis. We will illustrate the use of SYNHMET in the study of urine samples from healthy subjects, patients with chronic cystitis and bladder cancer.

AIMS: To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis. METHODS: Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan-Meier and by Cox regression. RESULTS: Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival. CONCLUSIONS: Insulin resistance is associated with the aggressiveness of PDAC.

Introduction Rupture of abdominal aortic aneurysm remains a fatal event in up to 65% of cases and emergency open surgery (ruptured open aneurysm repair or rOAR) has a great intraoperative mortality of about 30-50%. The introduction of endovascular repair of abdominal aortic aneurysm (ruptured endovascular aneurysm repair or rEVAR) has rapidly challenged the conventional approach to this catastrophic event. The purpose of this systematic review is to compare the outcomes of open surgical repair and endovascular interventions. Evidence acquisition A literature search was performed using Medline, Scopus, and Science Direct from August 2010 to March 2017 using keywords identified and agreed by the authors. Randomized trials, cohort studies, and case-report series were contemplated to give a breadth of clinical data. Evidence synthesis Ninety-three studies were included in the final analysis. Thirty-five (50.7%) of the listed studies evaluating the within 30 days mortality rates deposed in favor of rEVAR, while the others (comprising all four included RCTs) failed detecting any difference. Late mortality rates were found to be lower in rEVAR group in seven on twenty-seven studies (25.9%), while one (3.7%) reported higher mortality rates following rEVAR performed before 2005, one found lower incidence of mortality at 6 months in the endovascular group but higher rates in the same population at 8 years of follow-up, and the remaining (66.7%) (including all three RCTs) failed finding any benefit of rEVAR on rOAR. A lower incidence of complications was reported by thirteen groups (46.4%), while other thirteen studies did not find any difference between rEVAR and rOAR. Each of these two conclusions was corroborated by one RCTs. Other two studies (7.2%) found higher rates of tracheostomies, myocardial infarction, and acute tubular necrosis or respiratory, urinary complications, and acute renal failure respectively in rOAR group. The majority of studies (59.0%, 72.7%, and 89.3%, respectively) and all RCTs found significantly lower rates of length of hospitalization, intensive care unit transfer, and blood loss with or without transfusion need in rEVAR group. The large majority of the studies did not specified neither the type nor the brands of employed stent grafts. Conclusions The bulk of evidence regarding the comparison between endovascular and open surgery approach to RAAA points to: 1) non-inferiority of rEVAR in terms of early (within 30 days) and late mortality as well as rate of complications and length of hospitalization, with trends of better outcomes associated to the endovascular approach; 2) significantly better outcomes in terms of intensive care unit transfer and blood loss with or without transfusion need in the rEVAR group. These conclusions reflect the results of the available RCTs included in the present review. Thus rEVAR can be considered a safe method in treating RAAA and we suggest that it should be preferred when technically feasible. However, more RCTs are needed in order to give strength of these evidences, bring to definite clinical recommendations regarding this subject, and assess the superiority (if present) of one or more brands of stent grafts over the others.

Aim: The standard-of-care in breast cancer (BC) with positive sentinel lymph node (SLN) metastasis includes complete axillary lymph node dissection (ALND); however, almost half of such cases have no further tumor burden. This study aimed to assess the clinicopathological factors that predict non-SLN metastasis to define subgroups of SLN-positive patients in whom the axilla may be staged by SLN biopsy alone, while avoiding unnecessary overtreatment. Patients and Methods: The records of 191 patients with histologically-proven primary BC who underwent a positive (SLN) biopsy between 2005 and 2017 were reviewed. Patients with at least one tumor-involved SLN who underwent completion ALND were enrolled. Demographic and clinicopathological characteristics, including age, primary tumor size and histological grade, lymphovascular invasion, ratio of positive SLNs to the harvested SLNs, SLN metastasis size, and molecular subtype classification according to immunohistochemical biomarker status [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)], were evaluated. Data were collected retrospectively and analyzed using the Mann-Whitney and Chi-square tests (statistical significance: p0.67 [odds ratio (OR)=2.55, p=0.032], luminal BC subtype (OR=2.67, p=0.06), HER2 overexpression (OR=0.4, p=0.016), and ER(+)PR(-)HER2(-) profile (OR=2.95, p=0.027). There was a tendency (statistically insignificant; p>0.05) toward higher incidence of non SLN metastasis with increasing age and histological grade, which could be attributed to the small sample size. Conclusion: According to this study, sentinel nodal ratio and BC subtypes as per ER, PR, and HER2 status significantly predicted the likelihood of additional lymphatic involvement. Validation of these parameters in prospective studies is indicated, and may help individualize treatment modalities.

"Endometriosis" is defined such as the presence of endometrial glands and stroma outside the uterine cavity. This ectopic condition may develop as deeply infiltrating endometriosis (DIE) when a solid mass is located deeper than 5 mm underneath the peritoneum including the intestinal wall. The ideal surgical treatment is still under search, and treatment may range from simple shaving to rectal resection. The aim of the present systematic review is to report and analyze the postoperative outcomes after rectosigmoid resection for endometriosis. We performed a systematic review according to Meta-analysis of Observational Studies in Epidemiology guidelines. The search was carried out in the PubMed database, using the keywords: "rectal resection" AND "endometriosis" and "rectosigmoid resection" AND "endometriosis." The search revealed 380 papers of which 78 were fully analyzed. Thirty-eight articles published between 1998 and 2017 were included. Three thousand seventy-nine patients (mean age 34.28 +/- 2.46) were included. Laparoscopic approach was the most employed (90.3%) followed by the open one (7.9%) and the robotic one (1.7%). Overall operative time was 238.47 +/- 66.82. Conversion rate was 2.7%. In more than 80% of cases, associated procedures were performed. Intraoperative complications were observed in 1% of cases. The overall postoperative complications rate was 18.5% (571 patients), and the most frequent complication was recto-vaginal fistula (74 patients, 2.4%). Postoperative mortality rate was 0.03% and mean hospital stay was 8.88 +/- 3.71 days. Despite the large and extremely various number of associated procedures, rectosigmoid resection is a feasible and safe technique to treat endometriosis.

The aim of this study is to evaluate the long-term results of Muzi's tension free primary closure technique for pilonidal sinus disease (PSD), in terms of patients' discomfort and recurrence rate. This study is a retrospective analysis of prospectively collected data. Five hundred fourteen patients were treated. Postoperative pain (assessed by a visual analog scale, VAS), complications, time needed to return to full-day activities, and recurrence rate were recorded. At 12, 22, and 54 months postoperative, patients' satisfaction was evaluated by a questionnaire scoring from 0 (not satisfied) to 12 (greatly satisfied). The median operative time was 30 min. The overall postoperative complication rate was 2.52%. Median VAS score was 1. The mean of resumption to normal activity was 8.1 days. At median follow-up of 49 months, recurrence rate was 0.4% (two patients). At 12 months' follow-up, the mean satisfaction score was 10.3 +/- 1.7. At 22 and 54 months' follow-up, the score was confirmed. Muzi's tension free primary closure technique has proved to be an effective treatment, showing in the long-term follow-up low recurrence rate and high degree of patient satisfaction. Therefore, we strongly recommend this technique for the treatment of PSD.

Background and objectives Pilonidal sinus is a common problem in the sacrococcygeal region, especially in obese, sedentary young men. The ideal surgical solution is still under debate, and there is a high rate of recurrence. In the present study, we analyzed the long-term results of a video-assisted minimally invasive technique for the treatment of sacrococcygeal pilonidal disease: endoscopic pilonidal sinus treatment (EPSiT). Methods From October 2013 through November 2015, a total of 77 consecutive patients (69 Males and 8 Females, median age: 23 y) were referred to our colorectal units. Sixty-eight patients had a primary sacrococcygeal pilonidal sinus, and 9 had recurrent pilonidal sinus; all underwent EPSiT. A fistuloscope was introduced through an external opening and the sinus cavity was completely ablated under direct vision. Postoperative complications, wound infection rate, recurrence rate, time until return to work, and patient satisfaction score were recorded during follow-up or at the last interview. Clinical data were obtained at 7, 15, and 30 days and at 6, 12, and 24 months after surgery. Results All patients completed the follow-up (median follow-up was 25 (range, 17-40) months. Median operative time was 18 (range, 12-30) minutes. The median hospital stay was 6.5 (range, 5-9) hours, and the median time to return to work was 5 days. Median healing time was 26 (range, 15-45) days. There were no major or minor complications. Six patients experienced recurrence. The overall satisfaction rate was 97%. Conclusions The ideal surgical treatment for pilonidal sinus disease should be simple and effective. In our experience, EPSiT can be performed as a day surgery, with early return to daily activities. This technique is an uneventful procedure, with good aesthetic results and a low recurrence rate.

Aim To investigate the effect of diabetes mellitus (DM) on disease-free and overall post-resection survival of patients with pancreatic ductal adenocarcinoma (PDAC) Methods Prospective observational study on patients admitted for pancreatic disease from January 2008 to October 2012. DM was classified as recent-onset (

Background Identification of a specific diabetes signature associated to pancreatic ductal carcinoma (PDAC) could be a key to detect asymptomatic, early stage tumors. We aim to characterize the clinical signature and the pathogenetic factors of the different types of diabetes associated with PDAC, based on the time between diabetes and cancer diagnosis. Methods Prospective observational study on 364 PDAC patients admitted to a referral center for pancreatic disease. Hospital and/or outpatient medical records were reviewed. Blood biochemical values including fasting blood glucose, insulin and/or C-peptide, glycosylated hemoglobin and anti-islet antibodies were determined. Diabetes onset was assessed after surgery and during follow-up. Results The prevalence of diabetes in patients was 67%. Considering 174 patients (47.8%) already having diabetes when diagnosed with PDAC (long duration, short duration, concomitant), the clinical and biochemical profile was similar to that of patients with type 2 diabetes (T2D). Diabetes was associated with known risk factors (i.e., age, sex, family history for diabetes and increased BMI) and both beta-cell dysfunction and insulin resistance were present. Considering 70 patients (19.2%) with onset of diabetes after PDAC diagnosis (early and late onset), the strongest predictor was the loss of beta-cell mass following pancreatectomy in patients with risk factors for T2D. Conclusion Different types of diabetes according to the time between diabetes and PDAC diagnosis are clinical entities widely overlapping with T2D. Therefore, the success of a strategy considering diabetes onset as a marker of asymptomatic PDAC will largely depend on our ability to identify new diabetes-unrelated biomarkers of PDAC.

OBJECTIVE - Aims of this study were 1) to assess sexual function and endocrine profile among fertile type 1 diabetic women during the follicular and luteal phases of the menstrual cycle, 2) to compare these results with those obtained among healthy fertile women who served as control subjects, and 3) to explore the correlations between sexual function and endocrine milieu among patients and control subjects during the follicular and luteal phases of the menstrual cycle. RESEARCH DESIGN AND METHODS - Fifty fertile women with type 1 diabetes and 47 healthy control subjects completed a semistructured medical interview and filled in self-administered validated instruments to evaluate sexual function, depression, and sexual distress. Venous blood samples were drawn to measure glycated hemoglobin and an endocrine profile during either the follicular or the luteal phase of the menstrual cycle. RESULTS - Type 1 diabetic women had decreased sexual function and increased sexual distress compared with control subjects during the luteal, but not the follicular, phase of the menstrual cycle. During the follicular phase, patients had lower estrogenic basal tone, lower "weak" androgen (namely Delta(4)-androstenedione and dehydroepiandrosterone sulfate) production, and lower free-triiodothyronine and free-thyroxine levels compared with control subjects. During the luteal phase, total testosterone levels were higher in patients than control subjects, while 17 beta-estradiol and progesterone levels were lower in patients than control subjects. CONCLUSIONS - Among type 1 diabetic women, sexual function and sexual distress vary according to the phase of the menstrual cycle. This finding may have implications on the clinical assessment of sexual function in type 1 diabetic women, OBJECTIVE - Aims of this study were 1) to assess sexual function and endocrine profile among fertile type 1 diabetic women during the follicular and luteal phases of the menstrual cycle, 2) to compare these results with those obtained among healthy fertile women who served as control subjects, and 3) to explore the correlations between sexual function and endocrine milieu among patients and control subjects during the follicular and luteal phases of the menstrual cycle. RESEARCH DESIGN AND METHODS - Fifty fertile women with type 1 diabetes and 47 healthy control subjects completed a semistructured medical interview and filled in self-administered validated instruments to evaluate sexual function, depression, and sexual distress. Venous blood samples were drawn to measure glycated hemoglobin and an endocrine profile during either the follicular or the luteal phase of the menstrual cycle. RESULTS - Type 1 diabetic women had decreased sexual function and increased sexual distress compared with control subjects during the luteal, but not the follicular, phase of the menstrual cycle. During the follicular phase, patients had lower estrogenic basal tone, lower "weak" androgen (namely Delta(4)-androstenedione and dehydroepiandrosterone sulfate) production, and lower free-triiodothyronine and free-thyroxine levels compared with control subjects. During the luteal phase, total testosterone levels were higher in patients than control subjects, while 17 beta-estradiol and progesterone levels were lower in patients than control subjects. CONCLUSIONS - Among type 1 diabetic women, sexual function and sexual distress vary according to the phase of the menstrual cycle. This finding may have implications on the clinical assessment of sexual function in type 1 diabetic women

Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs–induced cell death. We show that human breast cancer cells express high levels of PED and that AKT activity regulates PED protein levels. Interestingly, exogenous expression of a dominant-negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy-induced cell death. Thus, AKT-dependent increase of PED expression levels represents a key molecular mechanism for chemoresistance in breast cancer.

The sequential doxorubicin → CMF (CMF = cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF × 6 cycles (CMF); (b) doxorubicin × 4 cycles followed by CMF × 6 cycles (A → CMF); (c) CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (CMF → GT); and (d) doxorubicin × 4 cycles followed by CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (A → CMF → GT). The study used a 2 × 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A × CMF or arms a + c vs b + d) and (2) the effect of adding GT after chemotherapy (arms a + b vs c + d). At a median follow-up of 72 months, A → CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR) = 0.740 (95% confidence interval (CI): 0.556-0.986; P = 0.040) and produced a nonsignificant improvement of overall survival (OS) (HR = 0.764; 95% CI: 0.489-1.193). The addition of GT after chemotherapy significantly improved DFS (HR = 0.74; 95% CI: 0.555-0.987; P = 0.040), with a nonsignificant improvement of OS (HR = 0.84; 95% CI: 0.54-1.32). A → CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients. © 2005 Cancer Research UK.

One hundred and ninety-five aged (mean age: 67+/-4.8 years), non-insulin dependent diabetic patients underwent a randomised single-blind study for investigating the effect of statin administration on insulin resistance and respiratory quotient. After 4 weeks run-in period, all patients were randomised in three groups: placebo (n=67), simvastatin (10 mg/day) (n=61) and atorvastatin (5 mg/day) (n=67). Each treatment period lasted 8 weeks. At the beginning, after the run-in and at the end of the study, insulin resistance was assessed by homeostasis model assessment (HOMA) index, while respiratory quotient (Rq) was evaluated by indirect calorimetry. Statins versus placebo significantly lowered plasma total, LDL-, HDL-cholesterol and triglyceride concentrations and improved insulin resistance and Rq and metabolic control. Atorvastatin had a greater effect than simvastatin on plasma triglyceride concentration (-26.3+/-3.1 vs. -19.7+/-2.8%, P

Aims This randomized, multi-centre, double-blind, stratified, two period, cross-over trial was undertaken to assess the pharmacokinetics and pharmacodynamics of insulin aspart injected immediately before compared with regular human insulin injected 30 min before a Mediterranean-style meal in 37 (23 M, 14 F) patients with Type 2 diabetes. Methods Insulin aspart or regular human insulin was given subcutaneously (0.15 U/kg) in random sequence, using a double-dummy technique (at one visit: human regular insulin at t = −30 min and placebo at t = 0; at the other visit: placebo at t = −30 min and aspart insulin at t = 0). Serum glucose and insulin concentrations (15 points) were measured after each meal for 240 min. Results Post-prandial glycaemic excursions were 20% lower with insulin aspart (IAsp) compared with regular human insulin (HI) treatment [ratio (Iasp/HI) = 0.80, CI = (0.66–0.98), P = 0.034]. The maximum serum glucose (SG) concentration was similar for the two treatments (P = NS). The (median) time to maximum SG was 25 min shorter for IAsp compared with HI (P = 0.048). Maximum serum insulin concentration was higher after IAsp compared with HI (P = 0.023) as well as the area under the 4-h serum insulin curve (P = 0.006). Furthermore, the time to maximum serum insulin concentration was 27 min shorter after IAsp (P = 0.039), even though IAsp was injected 30 min after HI. No adverse events occurred during the trial. Conclusions In patients with Type 2 diabetes a more favourable insulin profile and a better glycaemic control were found with IAsp injected immediately before compared with HI injected 30 min before a Mediterranean-style meal.

To increase the dose-intensity of two drugs in metastatic breast cancer, we tested the feasibility, in phase I studies, of two schedules of epirubicin (E) and cyclophosphamide (C) - sequential (E--> C) and alternating (E/C) - with respect to the standard combination (EC). Drugs were given at three planned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three cycles of cyclophosphamide were administered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E) and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold and 2-fold greater with E/C and E--> C, respectively, than with EC. The third level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77\% of patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8\%). Eighty-one percent of patients on experimental schedules required red blood cell support versus 44.4\% of patients on EC. At the third level, platelet transfusions were more frequent among patients treated with EC (27. 8\%). Non-haematological toxicity was mild: about 20\% of patients experienced grade 3 vomiting, irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient developed heart failure. Fever (61\% of patients) and bone pain (55.5\% of patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G-CSF. The overall response rate was 84.6\%: 5/39 (12.8\%) complete response and 28/39 (71.8\%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19\% (95\% confidence intervals = 7-31\%). Rapidly alternating or sequential cycles of epirubicin and cyclophosphamide with CSF support is a feasible strategy that allows a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombocytopenia with the standard schedule. Overall, this intensified therapy was very active.

High-risk early breast cancer patients are usually identified by the number of metastatic axillary nodes. To study whether other easily and inexpensively detectable morphological factors are able to detect high-risk patients, we performed a retrospective analysis of tumour size, and skin/fascia and nipple invasion. The data consisted of 941 node-positive cases registered between 1978 and 1991. Tumour size, and skin/fascia and nipple invasion were closely associated with the number of metastatic nodes (χ2 test). The number of metastatic nodes, tumour size, skin/fascia and nipple invasion significantly affected disease free survival (DFS) and overall survival (OS) at univariate analysis. These results were confirmed by multivariate analysis with a model containing the number of metastatic nodes, tumour diameter categories, skin/fascia invasion, nipple invasion and adjuvant therapy as covariates: all variables significantly and independently affected risk of relapse and of death. All the variables studied were prognostic, within individual nodal categories, for both DFS and OS. In conclusion, the number of metastatic nodes is not the only prognostic tool with which to select high-risk patients for new intensive adjuvant programmes. Tumour size, and skin/fascia invasion or nipple invasion, taken singly or combined, are valuable prognostic factors that can identify patients with few metastatic nodes and poor outcome. On the basis of our data, we believe that a reconsideration of the pT4 category within the pTNM classification is in order, that is, chest wall invasion should be substituted by fascia invasion, and combined skin/fascia invasion could be a subcategory of each class defined by tumour size.

The diagnostic accuracy of frozen section (FS) examination and intraoperative cytology (IOC) has been compared in two different series of breast biopsies in which only one of the two methods has been used. The intraoperative results have been compared with the final histological diagnoses. Five-hundred-ten cases have been investigated by using FS only, and 407 by means of IOC. The two series were comparable because they included the same pathologies; moreover we have subdivided each series into four groups of pathologies to better evaluate the diagnostic accuracy of two methods. The total diagnostic accuracy of FS has been 93.13% vs. 95.-33% of IOC The value of diagnostic accuracy of FS and IOC in the four sub-groups substantially overlapped; there was only a little difference in the group of “various lesions” in which the diagnostic accuracy of IOC was higher. No false positive has been observed in IOC. FS have produced one false positive (0.19%), whereas false negatives have amounted to 1.77% for IOC and to 1.72% for FS. Deferred diagnoses have been 2.95% in IOC and 4.90% in FS examination. For both methods according to Galen and Gambino the following values have been calculated: sensitivity, specificity, efficiency, and predictive value. By comparing the data, the value of the cytological examination in the intraoperative diagnoses results is evident mainly when the latter is coupled with the gross observation. Causes of diagnostic errors clearly overlap both in IOC and in FS: (1) lesions with a fibroadenomatous appearance can involve an overdiagnosis or an underdiagnosis; (2) low-grade lesions like tubular carcinomas or in situ lobular carcinomas can be interpreted as benign; (3) the differential diagnosis of intraductal lesions may be very difficult, and a conservative approach is the best choice; and (4) infiltrating lobular carcinoma may be neglected both in FS and IOC. The few disadvantages of the cytologic method are offset by its low cost, the wider sampling, the possibility of sparing tissue for further investigations (such as steroid receptors, cellular kinetic, electron microscopy, and other biological studies) proved more useful in prognostic evaluation of breast cancer.

Thirty-two patients affected by monolateral breast cancer and five patients with benign mammary pathology were submitted to pre-operative lymphoscintigraphy by sub-areolar injection of nanocolloidal albumin with the aim of evaluating any axillary lymphonodular involvement. The 32 patients, affected by cancer, subsequently underwent a surgical operation so as to permit a pathological-anatomical study of the axillary cavity. A comparison between the clinical and instrumental examinations brought to light the much greater reliability of the latter which gave 87.5% of correct diagnoses. The authors emphasize the absence of false positive results and the excellent sensitivity of the method in bringing to light even limited involvements of the axillary lymphonodes. The authors believe that axillary lymphoscintigraphy deserves to be included in the pre-operative protocols which afford a correct staging of the disease and, consequently, a better assessment of the extent of the surgical action.

Six unstable C-peptide negative type I diabetic patients who had been previously treated with continuous subcutaneous insulin infusion (CSII) for at least one year without achieving satisfactory metabolic control, were admitted to this study and switched to continuous intraperitoneal insulin infusion (CIPII). The results obtained with the two treatments have been compared from the metabolic and clinical points of view. CIPII produced a decrease in HbA1c (p less than 0.05), in MAGE value (p less than 0.005), in the percentage of blood glucose determinations above 14 mmol/l (p less than 0.05) and below 3.9 mmol/l (p less than 0.05); an increase in serum cholesterol, and a decrease in HDL-cholesterol (p less than 0.05) due to a reduction of the HDL2 fraction (p less than 0.01). A mean body weight reduction of 3 kg was observed during CIPII (p less than 0.01), not related to dietary changes or to a reduction of the daily insulin dose. Twenty-four hour metabolic profiles during CIPII showed lower mean plasma glucose (p less than 0.001), serum free insulin (p less than 0.001), blood beta-OH-butyrate (p less than 0.001), and higher serum glycerol (p less than 0.001) as compared to CSII. It is concluded that CIPII may be of clinical value in the out-patient management of unstable type I diabetic patients, and that metabolic modifications induced by CIPII are not limited to changes in glucose utilization and production, but include changes in triglyceride, cholesterol and lipid metabolism which may have clinical relevance.

Aims and Background It has been demonstrated that breast cancer screening induces a 30% reduction of specific mortality. In May 1990, we started a pilot screening program to assess the feasibility of carrying out such a program in Campania (southern Italy). Herein we report the results of the first round of the program from three municipalities (Giugliano, Mugnano and Qualiano) that lie within the local health district no. 23, close to the city of Naples. Methods Women between the ages of 50 and 69 years were sent a personalized letter inviting them to attend the screening test; those not responding were sent a second invitation. The screening test consisted of clinical examination followed by two-view mammography. Second–level diagnostic tools were sonography, fine needle aspiration (manual, echo-guided and stereotaxic) and surgical biopsy. Results Out of 5,732 women invited for the first round, 1,813 (31.6%) attended the screening. Attendance rate was higher among younger women. Ninety-one women were positive at the screening test and underwent further examination (recall rate, 5.0%). Among them, 19 had surgical biopsy (biopsy rate, 1.0%) that led to breast cancer diagnosis in 11 cases. The benign/malignant biopsy rate was 0.73. Detection rate was 6.07 × 1,000 screened women and varied among age categories, increasing within the 60–69 subgroup; detection rate/expected incidence ratio in the overall group was 4.5 and also increased within the older age category. Seven out of 11 cancers were at UICC stage 0-I. Among 327 self-referring women, 38 were positive (recall rate, 11.6%), and 14 underwent biopsy (biopsy rate, 4.3%), which showed cancer in 7 cases (benign/malignant biopsy rate, 1.0). In addition, 2 inflammatory cancers were diagnosed without surgical biopsy. Thus 9 cancer cases were detected in this group. Self-referring women differed from responding women in that they had a higher frequency of symptoms or familiar history of cancer, and a higher educational level and awareness of preventive medicine. Clinical examination added no diagnostic advantage in the responding group but did not significantly worsen the recall rate. In the self-referring group, one case of inflammatory cancer was missed by mammography and diagnosed by clinical examination. Conclusion The early results (recall rate = 5%, detection rate/expected incidence ratio = 4.5, benign/malignant biopsy rate = 0.73, advanced cancers = 36.4%) are encouraging and indicate the validity of the program. Strategies to improve attendance rate are planned.

We investigated the association between pathological characteristics of primary breast cancer and degree of axillary nodal involvement and obtained a predictive index of the latter from the former. In 2076 cases, 17 histological features, including primary tumour and local invasion variables, were recorded. The whole sample was randomly split in a training (75\% of cases) and a test sample. Simple and multiple correspondence analysis were used to select the variables to enter in a multinomial logit model to build an index predictive of the degree of nodal involvement. The response variable was axillary nodal status coded in four classes (N0, N1-3, N4-9, N > or = 10). The predictive index was then evaluated by testing goodness-of-fit and classification accuracy. Covariates significantly associated with nodal status were tumour size (P < 0.0001), tumour type (P < 0.0001), type of border (P = 0.048), multicentricity (P = 0.003), invasion of lymphatic and blood vessels (P < 0.0001) and nipple invasion (P = 0.006). Goodness-of-fit was validated by high concordance between observed and expected number of cases in each decile of predicted probability in both training and test samples. Classification accuracy analysis showed that true node-positive cases were well recognised (84.5\%), but there was no clear distinction among the classes of node-positive cases. However, 10 year survival analysis showed a superimposible prognostic behaviour between predicted and observed nodal classes. Moreover, misclassified node-negative patients (i.e. those who are predicted positive) showed an outcome closer to patients with 1-3 metastatic nodes than to node-negative ones. In conclusion, the index cannot completely substitute for axillary node information, but it is a predictor of prognosis as accurate as nodal involvement and identifies a subgroup of node-negative patients with unfavourable prognosis.