Maurizio Belfiglio

A Meta-analysis of Trials on Aldose Reductase Inhibitors in Diabetic Peripheral Neuropathy

Peripheral neuropathy is one of the most common and disabling long‐term seque lae 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.

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.

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.

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.

Randomized Trial of 2 Versus 5 Years of Adjuvant Tamoxifen for Women Aged 50 Years or Older With Early Breast Cancer: Italian Interdisciplinary Group for 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.

Patterns of Care of an Italian Diabetic Population

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.

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.

AbstractObjective: 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 physicians 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 HbA1c, 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 HbA1c 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 ≥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.

Identifying Patients at Risk for Microalbuminuria via Interaction of the Components of the Metabolic Syndrome: A Cross-Sectional Analytic Study

BACKGROUND AND OBJECTIVES The objective of this study was to investigate correlates of risk for having microalbuminuria in individuals with one or more cardiovascular risk factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 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. RESULTS The prevalence of microalbuminuria was 5.9%. Patients who did not have hypertension and had postload glycemia < 140 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 glycemia > or = 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 triglycerides > 150 mg/dl and fibrinogen levels in the upper tertile were associated with a significantly higher risk for microalbuminuria. CONCLUSIONS 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.

Interobserver Variability of Clinical Target Volume Delineation in Supra-Diaphragmatic Hodgkin's Disease A Multi-institutional Experience

Background:To determine interobserver variability in clinical target volume (CTV) of supra-diaphragmatic Hodgkin’s lymphoma.Materials and Methods:At the 2008 AIRO (Italian Society of Radiation Oncology) Meeting, the Radiation Oncology Department of Chieti proposed a multi-institutional contouring dummy-run of two cases of early stage supra-diaphragmatic Hodgkin’s lymphoma after chemotherapy. Clinical history, diagnostics, and planning CT imaging were available on Chieti’s radiotherapy website (www.radioterapia.unich.it). Participating centers were requested to delineate the CTV and submit it to the coordinating center. To quantify interobserver variability of CTV delineations, the total volume, craniocaudal, laterolateral, and anteroposterior diameters were calculated.Results:A total of 18 institutions for case A and 15 institutions for case B submitted the targets. Case A presented significant variability in total volume (range: 74.1–1,157.1 cc), craniocaudal (range: 6.5–22.5 cm; median: 16.25 cm), anteroposterior (range: 5.04–14.82 cm; median: 10.28 cm), and laterolateral diameters (range: 8.23–22.88 cm; median: 15.5 cm). Mean CTV was 464.8 cc (standard deviation: 280.5 cc). Case B presented significant variability in total volume (range: 341.8–1,662 cc), cranio-caudal (range: 8.0–28.5 cm; median: 23 cm), anteroposterior (range: 7.9–1.8 cm; median: 11.1 cm), and laterolateral diameters (range: 12.9–24.0 cm; median: 18.8 cm). Mean CTV was 926.0 cc (standard deviation: 445.7 cc).Conclusion:This significant variability confirms the need to apply specific guidelines to improve contouring uniformity in Hodgkin’s lymphoma.Ziel:Diese Studie wurde durchgeführt, um die Inter-Beobachter-Variabilität des klinischen Zielvolumens bei supradiaphragmatischem Hodgkin-Lymphom festzustellen.Methodik:Beim 18. Treffen der AIRO (Italienischen Gesellschaft für Radioonkologie) in Mailand (November 2008) schlug die Abteilung für Strahlentherapie/Radioonkologie von Chieti eine multiinstitutionelle Zielvolumen-Konturierung („Dummy-run“) von zwei Fällen supradiaphragmatischer Hodgkin-Lymphome im frühen Stadium nach der Chemotherapie vor. Informationen über den klinischer Verlauf, die diagnostischen Befunde und die Planungs-CT-Bildgebung standen auf der Website (www.radioterapia.unich.it) der Abteilung für Strahlentherapie/Radioonkologie der Universität Chieti zur Verfügung. Die teilnehmenden Zentren wurden gebeten, die klinischen Zielvolumina zu definieren und ihre Ergebnisse bei der Koordinierungsstelle einzureichen. Um die Inter-Beobachter-Variabilität bei der Konturierung des klinischen Zielvolumens zu quantifizieren, wurden das Gesamtvolumen (cc), die kraniokaudalen, laterolateralen und die anteroposterioren Durchmesser (cm) berechnet.Ergebnisse:18 Zentren bezüglich des Falls A und 15 Zentren bezüglich des Falls B haben Zielvolumen-Definitionen eingereicht. Dabei wurden signifikante Variationen bei der Konturierung des klinischen Zielvolumens festgestellt. Der Range der Volumendefinition im Fall A reichte von 74,1 bis zu 1157,1 cc (Abbildung 1). Diese Variationen wurden bei der Messung der kraniokaudalen (durchschnittlich 16,25 cm; Range 6,5–22,5 cm) (Abbildung 2), anteroposterioren (durchschnittlich 10,28 cm; Range 5,04–14,82 cm) (Abbildung 3) und laterolateralen Durchmesser (durchschnittlich 15,5 cm; Range 8,23–22,88 cm) (Abbildung 4) bestätigt (Tabelle 1). Der Durchschnitt der klinischen Zielvolumina war 464,8 cc mit einer Standardabweichung von 280,5 cc. Der Range der Volumendefinition im Fall B reichte von 341,8 bis zu 1662 cc (Abbildung 1); und diese Variationen wurden bei der Messung der kraniokaudalen (durchschnittlich 23 cm; Range 8,0–28,5 cm) (Abbildung 5), anteroposterioren (durchschnittlich 11,1 cm; Range 7,9–14,8 cm) (Abbildung 6) und laterolateralen Durchmesser (durchschnittlich 18,8 cm; Range 12,9–24,0 cm) (Abbildung 7) bestätigt (Tabelle 2). Der Durchschnitt der klinischen Zielvolumina war 926,0 cc mit einer Standardabweichung von 445,7 cc.Schlussfolgerung:Diese signifikante Variabilität bestätigt die Notwendigkeit der Anwendung von spezifischen Guidelines, um die Uniformität der Konturierung bei Hodgkin-Lymphomen zu verbessern.

Interobserver variability of clinical target volume delineation in supra-diaphragmatic Hodgkin’s disease

Background:To determine interobserver variability in clinical target volume (CTV) of supra-diaphragmatic Hodgkin’s lymphoma.Materials and Methods:At the 2008 AIRO (Italian Society of Radiation Oncology) Meeting, the Radiation Oncology Department of Chieti proposed a multi-institutional contouring dummy-run of two cases of early stage supra-diaphragmatic Hodgkin’s lymphoma after chemotherapy. Clinical history, diagnostics, and planning CT imaging were available on Chieti’s radiotherapy website (www.radioterapia.unich.it). Participating centers were requested to delineate the CTV and submit it to the coordinating center. To quantify interobserver variability of CTV delineations, the total volume, craniocaudal, laterolateral, and anteroposterior diameters were calculated.Results:A total of 18 institutions for case A and 15 institutions for case B submitted the targets. Case A presented significant variability in total volume (range: 74.1–1,157.1 cc), craniocaudal (range: 6.5–22.5 cm; median: 16.25 cm), anteroposterior (range: 5.04–14.82 cm; median: 10.28 cm), and laterolateral diameters (range: 8.23–22.88 cm; median: 15.5 cm). Mean CTV was 464.8 cc (standard deviation: 280.5 cc). Case B presented significant variability in total volume (range: 341.8–1,662 cc), cranio-caudal (range: 8.0–28.5 cm; median: 23 cm), anteroposterior (range: 7.9–1.8 cm; median: 11.1 cm), and laterolateral diameters (range: 12.9–24.0 cm; median: 18.8 cm). Mean CTV was 926.0 cc (standard deviation: 445.7 cc).Conclusion:This significant variability confirms the need to apply specific guidelines to improve contouring uniformity in Hodgkin’s lymphoma.Ziel:Diese Studie wurde durchgeführt, um die Inter-Beobachter-Variabilität des klinischen Zielvolumens bei supradiaphragmatischem Hodgkin-Lymphom festzustellen.Methodik:Beim 18. Treffen der AIRO (Italienischen Gesellschaft für Radioonkologie) in Mailand (November 2008) schlug die Abteilung für Strahlentherapie/Radioonkologie von Chieti eine multiinstitutionelle Zielvolumen-Konturierung („Dummy-run“) von zwei Fällen supradiaphragmatischer Hodgkin-Lymphome im frühen Stadium nach der Chemotherapie vor. Informationen über den klinischer Verlauf, die diagnostischen Befunde und die Planungs-CT-Bildgebung standen auf der Website (www.radioterapia.unich.it) der Abteilung für Strahlentherapie/Radioonkologie der Universität Chieti zur Verfügung. Die teilnehmenden Zentren wurden gebeten, die klinischen Zielvolumina zu definieren und ihre Ergebnisse bei der Koordinierungsstelle einzureichen. Um die Inter-Beobachter-Variabilität bei der Konturierung des klinischen Zielvolumens zu quantifizieren, wurden das Gesamtvolumen (cc), die kraniokaudalen, laterolateralen und die anteroposterioren Durchmesser (cm) berechnet.Ergebnisse:18 Zentren bezüglich des Falls A und 15 Zentren bezüglich des Falls B haben Zielvolumen-Definitionen eingereicht. Dabei wurden signifikante Variationen bei der Konturierung des klinischen Zielvolumens festgestellt. Der Range der Volumendefinition im Fall A reichte von 74,1 bis zu 1157,1 cc (Abbildung 1). Diese Variationen wurden bei der Messung der kraniokaudalen (durchschnittlich 16,25 cm; Range 6,5–22,5 cm) (Abbildung 2), anteroposterioren (durchschnittlich 10,28 cm; Range 5,04–14,82 cm) (Abbildung 3) und laterolateralen Durchmesser (durchschnittlich 15,5 cm; Range 8,23–22,88 cm) (Abbildung 4) bestätigt (Tabelle 1). Der Durchschnitt der klinischen Zielvolumina war 464,8 cc mit einer Standardabweichung von 280,5 cc. Der Range der Volumendefinition im Fall B reichte von 341,8 bis zu 1662 cc (Abbildung 1); und diese Variationen wurden bei der Messung der kraniokaudalen (durchschnittlich 23 cm; Range 8,0–28,5 cm) (Abbildung 5), anteroposterioren (durchschnittlich 11,1 cm; Range 7,9–14,8 cm) (Abbildung 6) und laterolateralen Durchmesser (durchschnittlich 18,8 cm; Range 12,9–24,0 cm) (Abbildung 7) bestätigt (Tabelle 2). Der Durchschnitt der klinischen Zielvolumina war 926,0 cc mit einer Standardabweichung von 445,7 cc.Schlussfolgerung:Diese signifikante Variabilität bestätigt die Notwendigkeit der Anwendung von spezifischen Guidelines, um die Uniformität der Konturierung bei Hodgkin-Lymphomen zu verbessern.