Impact of early access to a palliative/supportive care intervention on pain management in patients with cancer.

BACKGROUND: No study has so far addressed whether differences do exist in the management of cancer pain between patients receiving usual care by primary specialists and those receiving early palliative/supportive intervention. PATIENTS AND METHODS: A multicentre cross-sectional study in 32 Italian Hospitals has included 1450 patients, receiving analgesic therapy for cancer pain: 602 with access to primary specialist alone (standard care, SC) and 848 with early access to a palliative/supportive care (ePSC) team, concomitant with primary oncology care. RESULTS: Statistically significant differences in the analgesic drug administration according to care model have been evident: non-opioids were more frequently used in SC (9.5% versus 2%; P<0.001), while strong opioids in ePSC group (80% versus 63%; P<0.001). The number of patients with severe pain was lower in ePSC compared with SC group (31% versus 17%; P<0.001). Results of multivariate analysis have shown that ePSC integrated with primary oncologic care (relative risk 0.69; 95% confidence interval 0.48-0.99; P=0.045) was an independent factor associated with a 31% reduced risk of suffering from severe pain. CONCLUSIONS: An ePSC team provides the most effective standard of analgesic therapy for cancer pain. A randomized clinical trial is needed to confirm these findings.

Updating clinical recommendations for breast, colorectal and lung cancer treatments: an opportunity to improve methodology and clinical relevance.

BACKGROUND: clinical guidelines can improve quality of care summarising available knowledge and proposing recommendations for health care decisions. Being up to date is one of their quality requisites. Little experience is available on when and how guidelines should be updated. We report on the update process of evidence-based clinical recommendations on anticancer drugs. METHODS: three multidisciplinary panels, supported by methodology experts, updated the recommendations. The methodologists were in charge of the qualitative and quantitative synthesis of the evidence. The panels were responsible for the final decision about risk/benefit profile of the drugs and strength of the recommendations. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used. RESULTS: six recommendations out of 15 were completely updated in 8 months time. In four cases, the strength of the recommendation changed; in two of them, we moved from a weak to a strong positive one. Despite the increased certainty about the positive risk/benefit profile, this was translated in a change in the strength of the recommendation only in one case out of three. Three recommendations were refined making them more clinically specific. CONCLUSIONS: accumulation of evidence is an opportunity for guideline panels to refine methodological rigour, clinical relevance and to foster consensus on recommendations. This requires time and resource investments.

Impact of setting of care on pain management in patients with cancer: a multicentre cross-sectional study.

BACKGROUND: No study has so far addressed whether differences do exist in the management of cancer-related pain in patients admitted to oncology and non-oncology settings. PATIENTS AND METHODS: A multicentre cross-sectional study in 48 Italian hospitals has enrolled 819 patients receiving analgesic therapy for cancer-related pain. Demographics and clinical and analgesic therapy information have been prospectively collected by standardized forms. Adequacy of pain management has been evaluated by the Pain Management Index (PMI). RESULTS: Differences in the analgesic drug administration according to settings of care have been evident, non-opioids more frequently being administered in non-oncology units (19.6% versus 7.0%; P < 0.0001), while strong opioids are more frequently used in the oncology units (69.5% versus 51.9%; P < 0.0001). The number of patients receiving inadequate therapy (PMI < 0) has lowered in oncology compared with non-oncology units (11.3% versus 18.8%; P = 0.0024). Results of multiple logistic regression analysis have shown that the admission to non-oncology setting [odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.15-2.67; P = 0.0096] and the absence of metastatic disease (OR = 1.60, 95% CI = 1.04-2.44; P = 0.0317) were independent factors associated with an increased risk of receiving an inadequate analgesic therapy. CONCLUSION: Oncology wards provide the most adequate standard of analgesic therapy for cancer-related pain.

Clinical and histopathological risk factors to predict sentinel lymph node positivity, disease-free and overall survival in clinical stages I-II AJCC skin melanoma: outcome analysis from a single-institution prospectively collected database.

BACKGROUND: To investigate if the tumour infiltrating lymphocytes (TILs) are able to predict the sentinel lymph node (SLN) positivity, the disease-free survival (DFS) and overall survival (OS) in clinical stages I-II AJCC primary cutaneous melanoma (PCM). METHODS: The study included consecutive patients with PCM, all diagnosed, treated and followed up prospectively. Logistic regression was used to investigate the association between DFS, OS, SLN positivity and Breslow thickness, Clark level, TIL, ulceration, lesion site, gender, regression and age. RESULTS: From November 1998 to October 2008, 1251 consecutive patients with PCM were evaluated. Median age was 51 (range 15-96) with 32.2% (N=393) of them older than 60; 44.8% of them were males. Of the whole series, a total of 404 patients with primary vertical growth phase (VGP) melanoma and no clinical evidence of metastatic disease underwent SLN biopsy. Of these, 74 (18.8%) had a positive SLN. In a multivariate analysis, primary melanoma on the extremities versus that on the axial locations (truncal and head/neck) (OR 0.49, 95% CI 0.25-0.98, p 0.04) and TILs (TILs versus no TILs) (OR 0.47, 95%CI 0.25-0.90, p 0.02) were predictive for lower probability of SLN involvement, while thickness (>4mm versus 0-1mm) (OR 24, 19, 95% CI 4.91-119.13, p<.001) was predictive for higher risk of SLN positivity. A multivariate stepwise analysis confirmed these results. The histological status of the SLN was the most significant predictor of DFS and OS. Patients with a negative SLN had a 5-year DFS of 75.9%, compared with 35.2% in patients with a positive SLN (p<.0001) and a 5-year OS of 88.7% versus 42.9%, respectively (p<.0001). CONCLUSIONS: Our study demonstrates that the absence of TILs predicts SLN metastasis, in multivariate analysis the SLN positivity predicts DFS and OS.

Self-monitoring of blood glucose in non-insulin-treated diabetic patients: a longitudinal evaluation of its impact on metabolic control.

AIMS: In the framework of a nationwide outcomes research programme, we assessed the impact of self-monitoring of blood glucose (SMBG) on metabolic control over 3 years in patients with Type 2 diabetes mellitus (DM2) not treated with insulin. METHODS: The study involved 1896 patients who completed, at 6-month intervals for 3 years, a questionnaire investigating SMBG practice. Clinical information was collected by participating clinicians at the same time intervals. The predictive value of SMBG frequency on long-term metabolic control was estimated using multilevel analysis. The impact of SMBG on metabolic control was also evaluated in distinct and homogeneous subgroups of patients showing different likelihood of performing SMBG, identified using a tree-growing technique (RECPAM). RESULTS: Overall, 22% of the patients were on diet alone and 78% were treated with oral agents; 41% practiced SMBG > or = 1/week (10.3% > or = 1/day). The analysis of metabolic control according to the frequency of SMBG failed to show any significant impact of this practice on HbA1c levels over 3 years. Similarly, changes in SMBG frequency during the study were not related to significant changes in HbA1c levels. RECPAM analysis led to the identification of eight classes, characterized by substantial differences in the likelihood of performing SMBG with a frequency of at least 1/week. Nevertheless, in none of the RECPAM classes identified, did SMBG predict a better metabolic control over 3 years of follow-up. In those RECPAM classes indicating that SMBG was mainly performed to avoid hypoglycaemic episodes, SMBG was associated with a decrease in the frequency of hypoglycaemic episodes during the study. CONCLUSIONS: In a large sample of non-insulin-treated Type 2 diabetic patients, the performance and frequency of SMBG did not predict better metabolic control over 3 years. We could not identify any specific subgroups of patients for whom SMBG practice was associated with lower HbA1c levels during the study.

Randomized trial of 2 versus 5 years of adjuvant tamoxifen for women aged 50 years or older with early breast cancer: Italian Interdisciplinary Group Cancer Evaluation Study of Adjuvant Treatment in Breast Cancer 01.

PURPOSE: To compare 2 with 5 years of adjuvant tamoxifen therapy in the treatment of early breast cancer. PATIENTS AND METHODS: Women with breast carcinoma T1-3, N0-3, M0, who were between 50 and 70 years of age, were eligible irrespective of menopausal status, tumor grade, or estrogen receptor (ER) status. Patients who were event-free after 2 years of tamoxifen therapy were randomly assigned to stop or continue tamoxifen therapy for an additional 3 years. The primary end point was length of disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity. RESULTS: From 1989 through 1996, 1,901 patients were randomly assigned either to stop treatment (n = 958) or to receive tamoxifen for 3 additional years (n = 943). The median duration of postrandomization follow-up was 52 months. We found no statistically significant differences between the 5-year arm and the 2-year arm in terms of DFS (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.76 to 1.08) and OS (HR, 1.16; 95% CI, 0.92 to 1.46). In ER-positive patients, a statistically significant prolongation of DFS related to longer treatment duration was observed (HR, 0.74; 95% CI, 0.59 to 0.93), whereas no difference in OS could be detected (HR, 0.98; 95% CI, 0.72 to 1.32). No differences in terms of endometrial cancers, cardiac or cerebrovascular events, or fractures were detected, whereas a doubling in the risk of thromboembolic events was found in the 5-year arm. CONCLUSION: Our results confirm previous research that shows that 5 years of tamoxifen decreases recurrence compared to 2 years in patients with ER-positive tumors.

The impact of blood glucose self-monitoring on metabolic control and quality of life in type 2 diabetic patients: an urgent need for better educational strategies.

OBJECTIVE: The role of self-monitoring of blood glucose (SMBG) in type 2 diabetes is still a matter of debate. In the framework of a nationwide outcomes research program, we investigated the frequency of SMBG and its association with metabolic control and quality of life (QoL). RESEARCH DESIGN AND METHODS: The study involved 3,567 patients with type 2 diabetes who were recruited by 101 outpatient diabetes clinics and 103 general practitioners. Patients completed a questionnaire investigating SMBG practice and QoL (diabetes-related stress, diabetes health distress, diabetes-related worries, and Centers for Epidemiologic Studies-Depression scale). RESULTS: Data on SMBG were available for 2,855 subjects (80% of the entire study population). Overall, 471 patients (17%) stated that they tested their blood glucose levels at home > or =1 time per day, 899 patients (31%) tested their blood glucose levels > or =1 time per week, and 414 patients (14%) tested their blood glucose levels <1 time per week, whereas 1,071 patients (38%) stated that they never practiced SMBG. A higher frequency of SMBG was associated with better metabolic control among subjects who were able to adjust insulin doses, whereas no relationship was found in all other patients, irrespective of the kind of treatment. Multivariate analyses showed that an SMBG frequency > or =1 time per day was significantly related to higher levels of distress, worries, and depressive symptoms in non-insulin-treated patients. CONCLUSIONS: Our findings suggest that SMBG can have an important role in improving metabolic control if it is an integral part of a wider educational strategy devoted to the promotion of patient autonomy. In patients not treated with insulin, self-monitoring is associated with higher HbA(1c) levels and psychological burden. Our data do not support the extension of SMBG to this group.

The relationship between physicians' self-reported target fasting blood glucose levels and metabolic control in type 2 diabetes. The QuED Study Group--quality of care and outcomes in type 2 diabetes.

OBJECTIVE: To investigate the relationship between beliefs of physicians relative to intensive metabolic control in type 2 diabetes and levels of HbA1c obtained in a sample of their patients. RESEARCH DESIGN AND METHODS: Physicians' beliefs were investigated through a questionnaire sent to a sample of self-selected clinicians participating in a nationwide initiative aimed at assessing the relationship between the quality of care delivered to patients with type 2 diabetes and their outcomes. At the same time, physicians were asked to collect clinical data on a random sample of their patients, stratified by age (<65 vs. > or = 65 years). Mean HbA1c levels in the study population were thus evaluated according to target fasting blood glucose (FBG) used by their physicians. RESULTS: Of 456 physicians, 342 (75%) returned the questionnaire. Among the responders, 200 diabetologists and 99 general practitioners (GPs) recruited 3,297 patients; 2,003 of whom were always followed by the same physician and 1,294 of whom were seen by different physicians in the same structure on different occasions. Only 14% of the respondents used target FBG levels < or = 6.1 mmol/l, whereas 38% pursued values >7.8 mmol/l, with no statistically significant difference between diabetologists and GPs. The analysis of the relationship between FBG targets and metabolic control, restricted to those patients always seen by the same physician, showed a strong linear association, with mean HbA1c values of 7.0 +/- 1.6 for patients in the charge of physicians pursuing FBG levels < or = 6.1 mmol/l and 7.8 +/- 1.8 for those followed by physicians who used target values >7.8 mmol/l. After adjusting for patients' and physicians' characteristics, the risk of having HbA1c values > 7.0% was highly correlated with physicians' beliefs. Patients followed by different physicians in the same unit showed a risk of inadequate metabolic control similar to that of patients followed by physicians adopting a nonaggressive policy. CONCLUSIONS: Doctors adopt extremely heterogeneous target FBG levels in patients with type 2 diabetes, which in turn represent an important independent predictor of metabolic control. To improve patient outcomes, physicians-centered educational activities aimed at increasing the awareness of the potential benefits of a tight metabolic control in patients with type 2 diabetes are urgently needed.

Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente).

BACKGROUND: Several studies have investigated the possible role of the adjuvant chemotherapy after curative resection for gastric cancer failing to show a clear indication; previous meta-analyses suggested small survival benefit of adjuvant chemotherapy, but the statistical methods used were open to criticisms. MATERIALS AND METHODS: Randomised trials were identified by means of Medline and CancerLit and by selecting references from relevant articles. Systematic review of all randomised clinical trials of adjuvant chemotherapy for gastric cancer compared with surgery alone, published before January 2000, were considered. Pooling of data was performed using the fixed effect model. Death for any cause was the study endpoint. The hazard ratio and its 95% confidence intervals (95% CI), derived according to the method of Parmar, were the statistics chosen for summarising the relative benefit of chemotherapy versus control. RESULTS: Overall 20 articles (21 comparisons) were considered for analysis. Three studies used single agent chemotherapy, seven combination of 5-fluorouracil (5-FU) with anthracyclin, ten combination of 5-FU without anthracyclines. Information on 3658 patients, 2180 deaths, was collected. Chemotherapy reduced the risk of death by 18% (hazard ratio 0.82, 95% CI: 0.75-0.89, P < 0.001). Association of Anthracyclines to 5-FU did not show a statistically significant improvement when compared with the effect of the other regimens. CONCLUSIONS: Chemotherapy produces a small survival benefit in patients with curatively resected gastric cancer. However, taking into account the limitations of literature based meta-analyses, adjuvant chemotherapy is still to be considered as an investigational approach.

Is adjuvant tamoxifen used optimally in the treatment of breast cancer? Results of an Italian survey.

BACKGROUND: Institutional and physician-related factors can influence the way in which physicians interpret research results. The aim of this study was to determine what physicians know about, and their opinions of, hormone treatment in breast cancer patients, and the factors comprising their medical decision-making. MATERIALS AND METHODS: A questionnaire was mailed to a random sample of physicians inquiring as to their preferences with respect to adjuvant tamoxifen, and the usual duration of the treatment applied in various clinical scenarios (according to a woman's menopausal status, the oestrogen receptor status and the stage of disease). RESULTS: Of 500 physicians identified, 38% returned the questionnaire. Of the non-responders, a random sample of 60 physicians was interviewed by phone. The total number of available questionnaires was 250 (50%). About 3/4 of the doctors would prescribe tamoxifen in older ER+ women and 30%-40% in post-menopausal ER-patients, but only 2/5 would do so in younger ER+ women. The vast majority of physicians considered five years as standard for ER+ patients. Nevertheless, about 1/4 of the doctors chose a shorter treatment duration for node-negative, pre-menopausal patients. A minority of physicians used tamoxifen for longer than five years. Older clinicians were less likely to prescribe tamoxifen, particularly for low-risk patients. CONCLUSIONS: According to the data of the recent EBCTG overview, an additional 20,000 lives could be saved worldwide each year if tamoxifen were given to all early breast cancer patients with hormone-sensitive disease, irrespective of age and disease stage, and for a minimum of five years. Our study, involving a representative sample of physicians practicing in Italy, shows that tamoxifen is not used optimally, with a substantial under-use in younger women and women with node-negative disease.

The effectiveness, safety and epidemiology of the use of acarbose in the treatment of patients with type II diabetes mellitus. A model of medicine-based evidence.

OBJECTIVE: To assess the efficacy, safety and extent of perceived indications of acarbose, a new antidiabetic agent, under routine clinical practice conditions in an unselected Northern Italian population of type II diabetic patients. METHODS: The study population was assigned to three different groups according to the physician's clinical judgement: group A (acarbose considered as an elective treatment); group B (acarbose considered to be of uncertain benefit): group C (acarbose deemed not to be appropriate). Group B patients were randomized either to continue their standard treatment or to add acarbose to it. Patients with type II diabetes mellitus were recruited from 17 diabetes outpatient clinics from one Italian region (Lombardy). A total of 1027 patients were recruited (group A: 283; group C: 494; group B: 250, of whom 124 were randomly assigned to standard treatment + acarbose and 126 to standard treatment alone). Acarbose was administered for 1 year at a median dose of 100 mg 3 times daily. Drug efficacy was evaluated in terms of mean HbAlc, pre- and post-prandial glycaemic values. Additional endpoints were the proportion of patients with HbA1c levels below 8% at the end of the study period and the proportion of subjects who needed a modification in the standard treatment. The safety and tolerability profiles of the drug were also investigated. Data on HbA1c, fasting and post-prandial blood glucose levels were analysed over time using repeated-measures analysis [Generalized Estimating Equation (GEE) models]. RESULTS: The analysis of Group B showed that, after treatment for 1 year, the mean reduction in HbA1c levels in the acarbose group with respect to the control group was 0.30% (95% confidence limits -0.60 +0.02; P = 0.07), while the mean reduction in post-prandial glycaemia was 17 mg-dl(-1) (95% c.l. -33.5 -0.8; P = 0.04). No difference resulted for fasting blood glucose levels. When looking at the baseline HbA1c levels, it emerged that the mean benefit associated with the use of acarbose was 0.14% (95% c.l. -0.6 +0.28; P = 0.5) in patients with HbAlc levels below 8%, 0.28% (95% c.l. -0.6 +0.05; P = 0.09) in those with values between 8% and 9.9% and 0.65% (95% c.l. -1.36 +0.06; P = 0.07) in those with values > or =10%. Only patients treated with diet+/-oral anti-diabetic agents (OAA) benefited from acarbose treatment (mean benefit = 0.37%, 95% c.l. -0.65 -0.08), while no effect was shown for insulin-treated subjects. The proportion of patients with HbA1c below 8% increased from 31% to 44% in the acarbose group and from 40% to 45% in the control group (absolute difference between baseline and end-of-study values = 8.0% in favour of acarbose-treated patients; P = 0.058). Patients treated with acarbose were significantly more likely to undergo a dose reduction in concomitant diabetic treatments compared with the control group; they were also less likely to require an increase in the dose of standard treatment and to start insulin during the study period. One third of the patients could not assume the drug for the whole study period, mainly due to gastrointestinal side-effects. CONCLUSIONS: The design adopted in this study allowed an integrated evaluation of the overall effectiveness of acarbose in clinical practice. The benefits of the drug in an unselected population of non-insulin-dependent diabetes mellitus (NIDDM) patients are significant but of marginal clinical relevance. Only a better definition of the subgroups of patients who are more likely to benefit from long-term treatment, particularly through possible postponement of secondary OAA failure, will allow a reliable definition of the cost-effectiveness of this complementary component of anti-diabetic strategy.

Patterns of care an Italian diabetic population. The Italian Study Group for the Implementation of the St Vincent Declaration, Società Italiana di Diabetologia, Associazione Medici Diabetologi.

We set out to describe patterns of care of an Italian diabetic population, with reference to the recommendations of the St Vincent Declaration. We investigated different aspects of care received by 2707 patients, of whom 2196 in the charge of 35 Diabetes Outpatient Clinics (DOCs) and 511 cared for by 49 General Practitioners (GPs). Data were collected by interviewing the patients, their physicians and by reviewing medical records. Our data show that diabetes care in Italy differs in many aspects from the recommendations of the St Vincent Declaration. Glycated haemoglobin measurement was lacking in 50% of the patients in the charge of GPs and in 15% of those attending DOCs. While the control of cardiovascular risk factors was satisfactory, information on albumin excretion was not available in one third of the patients. Overall, 79% of the patients had had an eye examination in the previous 12 months. More than one-third of the patients had not received adequate information on different aspects of care, with wide variations according to the setting of care. Forty-two per cent of the patients attending DOCs and 14% of those cared for by GPs practised blood glucose self-monitoring; similarly, insulin therapy self-management was performed by 50% and 19% of the patients attending DOCs and GPs, respectively. Our data call for vigorous efforts aimed at improving the awareness of the potential for reducing major diabetic complications. Therefore, it is essential to promote the incorporation of clearly defined clinical practice guidelines at each level of care.

A meta-analysis of trials on aldose reductase inhibitors in diabetic peripheral neuropathy. The Italian Study Group. The St. Vincent Declaration.

Peripheral neuropathy is one of the most common and disabling long-term sequelae of diabetes mellitus. Aldose reductase inhibitors (ARIs) have been proposed and are increasingly used in many countries for the prevention and treatment of diabetic neuropathy. The aim of this study was to review existing evidence on the effectiveness of ARIs in the treatment of peripheral diabetic neuropathy, with particular reference to the type and clinical relevance of the end point used and to the consistency of results across studies. Thirteen randomized clinical trials (RTCs) comparing ARIs with placebo, published between 1981 and 1993 were included in the meta-analysis. Nerve conduction velocity (NCV) was the only end point reported in all trials. Treatment effect was thus evaluated in terms of NCV mean difference in four different nerves: median motor, median sensory, peroneal motor, and sural sensory. A statistically significant reduction in decline of median motor NCV was present in the treated group as compared to the control group (mean 0.91 ms-1; 95% CI 0.41-1.42 ms-1). For peroneal motor, median sensory, and sural sensory nerves results did not show any clear benefit for patients treated with ARIs. When the analysis was limited to trials with at least 1-year treatment duration, a significant effect was present for peroneal motor NCV (mean 1.24 ms-1; 95% CI 0.32-2.15 ms-1) and a benefit of borderline statistical significance was also present for median motor NCV (mean 0.69 ms-1; 95% CI-0.07-1.45 ms-1). A heterogeneous picture emerged when looking at the results of different studies and serious inconsistencies were also present in the direction of treatment effects among nerves in the same studies. Although the results of 1-year treatment on motor NCV seem encouraging, the uncertainty about the reliability of the end-point employed and the short treatment duration do not allow any clear conclusion about the efficacy of ARIs in the treatment of peripheral diabetic neuropathy.

Epidemiology and determinants of blood glucose self-monitoring in clinical practice.

The aim of this study was to describe the epidemiology of self-monitoring of blood glucose and to identify specific characteristics of those subgroups of diabetic patients treated with insulin that are most likely to monitor their blood glucose according to medical recommendations. Data were collected on 1384 insulin-treated patients, enrolled from 35 diabetic outpatient clinics and 49 general practitioners' offices between December 1993 and June 1994. Seventeen Italian regions out of 20 were included in the study. Our data show that 418 (31%) diabetic patients treated with insulin had never practised blood glucose self-monitoring. In addition, only 242 patients (18.2%) self-monitored their glycemia with a mean frequency of at least once a day (29.7% among insulin-dependent diabetes mellitus (IDDM) and 13.9%, among insulin-treated non-insulin-dependent diabetes mellitus (NIDDM-IT) patients). Patients' characteristics associated with a higher probability of practising blood glucose self-monitoring were age below 50 years, being treated at a diabetic outpatient clinic, hypertension, need of three or more insulin injections per day, history of hypoglycemic episodes, ability to self-manage insulin doses. Our study calls for vigorous efforts aimed at promoting the incorporation of clearly-defined educational programs at each level of care, in order to improve the motivation and self-care of diabetic patients. Furthermore, studies are necessary to identify subgroups of diabetic patients that truly need to self-monitor blood glycemia, and to assess the efficacy of the practice of self-monitoring of blood glucose in improving metabolic control and reducing acute and long-term diabetic complications.

Appropriateness and variation of surgical treatment of breast cancer in Italy: when excellence in clinical research does not match with generalized good quality care. Progetto Oncologia Femminile.

To assess appropriateness of surgical care delivered to breast cancer patients in Italy and quantify the use of unnecessary radical procedures, a retrospective charts review of patients treated in 1988-1989 was conducted. A series of 1724 consecutive patients (median age 61 years; range 17-89) treated in 63 hospitals selected from within 8 regions with newly diagnosed operable breast carcinoma was evaluated. Overall, 541 (38%) patients had inappropriate surgery with more than two thirds of it being accounted for by the use of unnecessary mutilating Halsted mastectomy. Substantial geographic variation emerged in the overall rates of appropriateness (range 88-52%) which were not substantially affected by allowance for imbalances in patient- and hospital-related variables. Despite the important contribution given by Italian clinical researchers to the demonstration that less radical surgery can be as good as more radical procedures, still a substantial proportion of breast cancer patients are treated too aggressively. Besides pointing to the urgent need of interventions aimed at facilitating the process of technology transfer in order to promote more appropriate surgical care, these results suggest that efforts to increase patients' participation into treatment decision and awareness about alternative treatment options are warranted.

Variation in use of breast surgery and characteristics of hospitals' surgical staff.

OBJECTIVE: To assess whether and how the characteristics of hospitals' surgical staff can predict utilization of breast conserving surgery. We anticipated that the use of the procedure was more frequent in hospitals with a greater proportion of younger and female surgeons on their staff. SETTING: Sixty-two hospitals with different level of organization for the care of cancer patient from eight Italian regions were included. DESIGN: We collected information on the personal characteristics (age and sex) of all surgeons on the staff of the participating centers. A concurrent pattern of care study was undertaken, in order to assess the utilization of breast conserving procedures. RESULTS: The use of conservative surgery was 16%, 20%, 31%, in centers with 0%, < 20% and 20-50% female surgeons respectively (p = 0.003), while no associations emerged between the mean age of the surgical staff and the use of conservative surgery. This relationship also held true after adjusting for other patients' characteristics, such as stage of disease, age and presence of comorbidity. However, overall the use of patient-related and staff-related characteristics to predict the number of breast conserving surgeries performed in each area was able to explain only 16% of the observed variability in the use of breast conserving surgery. CONCLUSIONS: Even though in this study a large proportion of the observed variation in the use of breast conserving surgery was still left unexplained, this finding suggests that assessing the relationship between doctors' characteristics and the use of scientific evidence is an important topic for health service research and can be of some help in exploring variations in clinical practice styles.

[Geographic variability in the appropriateness of surgical treatment of breast carcinoma]. / Variabilità geografica nell'appropriatezza della terapia chirurgica del carcinoma della mammella.

To assess appropriateness of surgical care delivered to breast cancer patients in Italy and quantify the use of unnecessary radical procedures, a retrospective charts review of patients treated in 1988-1989 was conducted. Information about hospital characteristics was collected directly from administrative departments as a part of a national survey. A series of 1724 consecutive patients (median age 61 years; range 17-89) treated in 63 hospitals selected from within 8 regions, with newly diagnosed operable breast carcinoma was evaluated. Overall, 541 (38%) patients had inappropriate surgery with more than two thirds of it being accounted for by the use of unnecessary mutilating Halsted mastectomy. About one-fourth of patients with stage I-II disease undergone mastectomy according Halsted technique and conservative surgery in patients with small tumors (i.e. tumor size < = 2 cm) was under utilized. Substantial geographic variations emerged in the overall rates of inappropriateness (range 12-48%) which were not substantially affected by allowance for imbalances in patient- and hospital-related variables. Despite the important contribution given by Italian clinical researchers to the demonstration that less radical surgery can be as good as more radical procedures, still a substantial proportion of breast cancer patients are treated too aggressively. Besides pointing to the urgent need of interventions aimed at promoting more appropriate surgical care these results suggest that efforts to increase patients' participation into treatment decision and awareness about alternative treatment options are warranted.

Effect of L-carnitine and acetyl-L-carnitine on the human erythrocyte membrane stability and deformability.

In this study we examined the effect of carnitine and acetylcarnitine on the human erythrocyte membrane stability and membrane deformability. Since erythrocyte membranes are impermeable to these compounds, we resealed erythrocyte ghosts in the presence of different concentrations of carnitine or acetylcarnitine. Resealed ghosts can be adequately studied in their cellular deformability and membrane stability properties by means of ektacytometry. Both carnitine and acetylcarnitine alter the membrane stability but not membrane deformability of the red cell membrane. Resealed ghosts containing 20, 50, 150, and 300 microM carnitine had 1.1, 1.6, 0.9, and 0.7 times the normal stability. While resealed ghosts containing 20, 50, 150, and 300 microM acetylcarnitine had 1.1, 1.5, 1.3, and 1.2 times the normal stability. Such changes were found to be reversible. We also conducted SDS PAGE of cytoskeletal membrane proteins from membrane fragments and residual membranes produced during membrane stability analysis, and unsheared resealed membranes in those samples where we observed an increase or a decrease of membrane stability. No changes in the cytoskeletal membrane proteins were noticed, even when the samples, prior SDS PAGE analysis, were treated with or without dithiothreitol. In addition, fluorescence steady state anisotropy of DPH in the erythrocyte membrane treated with carnitine or acetylcarnitine shows no modification of the lipid order parameter. Our results would suggest that both carnitine and its acetyl-ester, at physiological concentrations, may increase membrane stability in mature erythrocytes, most likely via a specific interaction with one or more cytoskeletal proteins, and that this effect would manifest when the erythrocytes are subjected to high shear stress.

Effect of propionyl-L-carnitine on rat spinal cord ischaemia and post-ischaemic reperfusion injury.

In this study we have examined the effect of propionyl-L-carnitine (PC) on rat spinal cord ischaemia and post-ischaemic reperfusion injury by evaluating two lipid peroxidation indices, thiobarbituric acid reactive substances (TBARS) and diene conjugation, before and after the addition of an ADP-Fe+2 complex to spinal cord homogenates. Aerobic, ischaemic, and post ischaemic reperfusion rat spinal cord homogenates from PC treated and untreated animals did not show any statistically significant difference in their TBARS and conjugated diene content. The addition of the ADP-Fe+2 complex to these homogenates resulted in an increased production of both the lipid peroxidation indices, though the magnitude of such formation was related to the type of experimental intervention. The post-ischaemic reperfusion samples of untreated rats showed the highest TBARS and conjugated diene content, while ischaemic samples in either treated and untreated rats did not show any statistically significant difference with respect to the aerobic samples. The post-ischaemic reperfusion samples of treated rats showed a statistically significant decrease of TBARS and conjugated diene production in comparison to the untreated samples. In addition, PC was also able to partially inhibit TBARS and conjugated diene formation in linoleic acid micelles exposed to hemoglobin, though it did not protect albumin fragmentation from the irradiation of water with an X-ray source.

Effect of oxidative stress on membrane phospholipid and protein organization in human erythrocytes.

Membrane phospholipid and protein organization was studied in intact human erythrocytes exposed to phenylhydrazine, an oxidative agent inducer. The evaluation of the membrane phospholipid and protein organization was carried out in terms of asymmetric distribution across the membrane bilayer for the phospholipids, and in terms of accessibility of cleavable sites present on the outer membrane surface for the proteins. Treatment of phenylhydrazine-exposed erythrocytes either with bee venom phospholipase A2 or with trinitrobenzenesulfonic acid indicated that phosphatidylserine (PS), which is the only phospholipid not formally present on the outer leaflet of the membrane, was translocated to the outer surface of the cell membrane. The extent of this phenomenon was directly proportional to the concentration of the oxidant having a peak value at 0.1 mM. Phosphatidylcholine and phosphatidylethanolamine conserved their original distribution across the erythrocyte membrane throughout the study. The oxidant, at a dose which did not induce any modification of the sodium dodecyl sulfate-polyacrylamide gel electrophoresis cytoskeleton membrane protein pattern, did not provoke any alteration of the membrane protein surface architecture, although the translocation of PS to the membrane outer leaflet in intact erythrocytes was present.