[The independent research on rare diseases financed by the Italian Medicines Agency.] / La ricerca indipendente sulle malattie rare finanziata dall'Agenzia Italiana del Farmaco.

INTRODUCTION: Rare diseases have a high social and health impact. Since 2005, AIFA has been funding independent clinical research. The objective of this paper is to describe data on independent research on rare diseases financed by the Agency. METHODS: With reference to studies financed by AIFA between 2005-2018 the following data have been collected: financial characteristics, study design, therapeutic area, population included, completion status, availability of study results publications, publication characteristics and conclusions. Data have been analyzed in order to provide information on characteristics and scientific productivity of clinical studies on rare diseases. RESULTS: Between 2005 and 2018, AIFA published 9 Calls for Funding of Independent Research and financed 282 clinical studies, 111 (about 40%) of which were on a rare disease and/or a rare tumor for a total of € 43,455,438. Studies were interventistic in 93.6% (mainly phase II or III). The most represented therapeutic area was oncology (19.9%), followed by neurology (17.1%), and onco-hematology (16.2%). 28.8% of clinical studies enrolled fragile population (children, elderly, pregnant women). Fourty eight studies (43.2%) completed according to protocol, 8 (7.2%) completed with reduced sample size, 18 (16.2%) were prematurely terminated, while 37 of them are still ongoing. In the subgroup of 74 closed studies at least a scientific publication is available for 49 of them. A total of 81 papers are available including two publications related to ongoing studies (range 1-8; mean 1.5; median 1). Cumulative Impact Factor is 619.269 (range for single paper 0.17-34.492). DISCUSSION: A good percentage of clinical studies financed by AIFA were on rare diseases and/or rare tumors. Clinical trials were less likely to complete according to protocol than observational ones, in agreement with literature data; on the other hand once completed, clinical trials were more likely to publish research findings. Overall, 66.2% of closed studies has at least one publication; this percentage is higher if we consider the subgroup of clinical trials and if we consider clinical trials completed according to study protocol (95.3%).

A comparison of EuroQol 5-Dimension health-related utilities using Italian, UK, and US preference weights in a patient sample.

Weights associated with the EuroQol 5-Dimension 3-Level (EQ-5D-3L) instrument represent preferences for health states elicited from general population's samples. Weights have not been calculated for every country; however, empirical research shows that cross-country differences exist. This empirical study aims at investigating the impact of recently developed Italian weights in comparison with UK and US scores on health-related utility calculation using a sample of patients with Crohn's disease. The study is based on a survey on health-related quality of life in patients (n=552) affected by active Crohn's disease conducted in Italy from 2012 to 2013. Utilities computed through the Italian algorithm (mean: 0.76; SD: 0.20; median: 0.81) are generally higher than US (mean: 0.69; SD: 0.22; median: 0.77) and UK (mean: 0.57; SD: 0.32; median: 0.69) utilities, except for extremely severe health states where US values outweigh the Italian ones. UK preference weights generate the highest number of negative results. All the three value distributions are left-skewed due to very low scores associated with the most serious health states (ie, three or four levels equal to 3). As expected, despite the tariff set considered, more severe disease (Harvey Bradshaw Index >16) reduces the mean conditional EQ-5D-3L index (P<0.0001). Kendall's rank correlation between EQ Visual Analog Scale score and EQ-5D-3L index is positive (P<0.0001), even though patients tend to value their health-related quality of life more when responding to EQ-5D-3L questions than on EQ Visual Analog Scale. Regardless of the tariff set considered, ordinary least-square results highlight that more severe disease (Harvey Bradshaw Index >16) reduces the mean conditional EQ-5D-3L index (P<0.0001). Results reveal remarkable differences among the three national tariff sets and especially when severe health states occur, suggesting the need for country-specific preference weights when evaluating utilities, which can be problematic since they have not been calculated for every country yet.

[ProMoFIA_Oncologic: monitoring project of the innovative oncology drugs in Abruzzo]. / ProMoFIA_Oncologici: Progetto di Monitoraggio dei Farmaci Oncologici Innovativi in Abruzzo.

INTRODUCTION: The unmet therapeutic needs lead to accelerated registration of new oncology drugs, even with incomplete information of the benefit-risk ratio. METHODS: In Italy the Onco-AIFA Register was established to monitor oncology drugs when used according to authorized indications and to assure their appropriate use in clinical practice. In the Abruzzo region, an observational longitudinal study (ProMoFIA_Oncologici) was performed to evaluate in standard clinical practice all patients treated with these new oncology drugs for any indication. RESULTS: During the period 2008-2011, 3435 patients were observed: in 62.2% of patients, the use of these drugs was eligible also for the Onco-AIFA Register; in 22.7% it was in-label but not monitored in the Onco-AIFA; in 15.1% the use was off-label. DISCUSSION: The study findings showed a widespread use of the new oncology drugs beyond the Onco-AIFA indications, as well as their off-label use.

Hospital discharge database as a tool to monitor incidence, survival and burden of cancer in adolescents and young adults.

AIMS AND BACKGROUND: Cancer in young patients (15-39 years) is unique for the distribution of types, therapeutic options and clinical evolution. Administrative databases represent well-documented tools in epidemiology, and in oncology they are very important in those realities without cancer registries. Our study aimed to analyze the occurrence, outcomes and burden of cancer in young patients through the analysis of hospital discharge records. METHODS: Hospital discharge databases and civil registries were analyzed through record linkage technique. Annual incidence rate (AIR), standardized incidence rate (SR), overall survival, hospitalization rate, and mean number of hospitalizations were evaluated. RESULTS: Among 2,330,459 young adults, 1846 new cancer patients had been hospitalized in the analyzed period. The SR was 69.3/100,000/year: 1051, 56.9%, were females (AIR 91.0 and SR 76.0) and 795, 43.1%, were males (AIR 67.6 and SR 62.5). Hematological disease was more frequent in males than females (25.5% vs 14.7%, P <0.0001), whereas solid tumors were more frequent among females (85.3% vs 74.5, P <0.0001). The distribution by diagnostic group showed that among females breast cancer was the most frequent (n = 272, SR 17.2), whereas among males genitourinary tract cancer (n = 245, SR 19.2), especially testicular cancer (n = 187, SR 15.1), was the most frequent. Metastatic disease at diagnosis was already present in 198 patients with a solid cancer (13.3%), whereas 213 (11.5%) developed metastasis in the following years. At 12 months from the diagnosis, 87 of 1488 patients with solid cancers and 35 of 358 patients with hematologic disease failed: overall survival was 94% and 90%, respectively. Patients with a new diagnosis of cancer had produced 6663 hospitalizations, 4640 (69.6%) of which were due to solid tumors, 3992 (59.9%) produced by patients over 29 years old, and 3606 (54.1%) by females. The percentage of day hospital admissions increased proportionally with patient age: 25.7% of all hospitalizations among older adolescents (15-20 years) and 32.9% among young adults of 34-39 years. CONCLUSIONS: Administrative data have clear advantages in terms of availability and large numbers. Comparison of our results with the literature showed that a health care delivery database can provide useful information for clinical-epidemiologic evaluations in oncology as well as for the analysis of health services utilization.

Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy in metastatic breast cancer.

PURPOSE: Whether combination chemotherapy offers an advantage over sequential therapy in metastatic breast cancer (MBC) is still an unsettled issue. Polychemotherapy regimens containing taxanes has been shown to increase overall survival (OS), time to tumor progression (TTP), and overall response rate (ORR) when compared with regimens that did not contain a taxanes, while taxane-based doublets have a statistically significant benefit over single-agent taxane only for progression-free survival. However, the term "taxanes" generally includes both paclitaxel and docetaxel, drugs with different clinical activity. Aim of this work is to compare OS, TTP, and ORR in patients with MBC receiving docetaxel alone or in combination with chemotherapy using a formal meta-analysis. METHODS: We performed a systematic review of all published trials comparing docetaxel alone or in combination with other chemotherapeutic agents in MBC. RESULTS: Three randomized clinical trials including 1,313 patients were retrieved. A significant reduction of risk ratio was found in TTP (P ≤ 0.0001) but not in OS (P = 0.48) or ORR (P = 0.10) for patients treated with a chemotherapy agent plus docetaxel compared with docetaxel alone. Treatment with docetaxel alone is associated with a lower incidence of grade 3 diarrhea and stomatitis (diarrhea, P = 0.011; stomatitis, P = 0.0004). CONCLUSION: Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP, but not for OS and ORR in MBC. This review confirms that it is unlikely that any single agent or combination chemotherapy regimen will emerge as superior in MBC, due to its heterogeneous nature.

The impact of a pharmacist as a member of healthcare team on facilitating evidenced-based prescribing of innovative drugs in an Italian oncology department.

AIMS AND BACKGROUND: At the Oncology Department of the Chieti and Ortona Hospitals, the pharmacist designated by the Abruzzo Region to oversee the obligatory monitoring of innovative oncological drugs listed in the database of the Italian Medicines Agency (AIFA) collaborates with oncologists to educate them about evidenced-based prescribing for off-label uses of drugs and to optimize the efficiency of spontaneous reporting of adverse drug reaction (ADR) local system. METHODS: The contribution of the pharmacist as a member of the healthcare team was evaluated using the following indices: the percentage of off-label prescriptions of the innovative drugs monitored, the number of reported ADRs, and the percentage of pharmacist suggestions actually implemented by physicians. RESULTS: In the course of 3 years (2008-2010), the pharmacist monitored a total of 843 patients treated with 716 appropriate uses and 127 off-label uses of drugs, oversaw a reduction in the latter from 28.3% in 2008 to 9.6% in 2010, and contributed to almost tripling the number of reported ADRs, from 10 in 2008 to 27 in 2010. In 2010, the pharmacist identified 60 potentially inappropriate prescribing cases, and proposed more appropriate prescriptions for each case: 68.3% (41) of the suggestions were implemented by the physicians and only 31.7% (19) were not. According to answers to a questionnaire administered at the end of the 2010 to evaluate the usefulness of this particular collaboration, physicians are interested in continuous and extensive collaboration. CONCLUSIONS: This article demonstrates that a pharmacist, active in the department as part of the heath-care team, can facilitate evidenced-based prescribing for off-label uses of drugs and improve spontaneous reporting of ADRs.

Gemcitabine-induced posterior reversible encephalopathy syndrome: a case report.

Gemcitabine is a commonly used chemotherapeutic agent for a variety of tumors. Although this nucleoside analog antineoplastic agent is similar in structure to cytarabine, central nervous system toxicities have rarely been attributed to gemcitabine. The posterior reversible encephalopathy syndrome (PRES) is a condition characterized by reversible neurological and radiological findings that has been associated with use of chemotherapeutic and more recently novel targeted therapies. We describe one case of a 41-year-old woman with PRES under treatment for leiomyosarcoma because of the probable association with gemcitabine. Our case, to our knowledge, represents the seventh published report of this particular toxicity. Naranjo algorithm, efficacious method for assessing the causality of adverse drug reactions (ADRs) from a case report, suggests a direct casual relationship. PRES is probably a rare complication of gemcitabine, but the oncologist should take it into careful consideration, because PRES is reversible with treatment of current hypertension or removal of the causative agent. However, failure to quickly recognize the syndrome and discontinue the offending agent may result in profound and permanent central nervous system dysfunction or death.

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.

Association of socioeconomic status with Breslow thickness and disease-free and overall survival in stage I-II primary cutaneous melanoma.

OBJECTIVE: To investigate the influence of socioeconomic status (SES) on Breslow thickness, disease-free survival, and overall survival in patients with stage I-II primary cutaneous melanoma (PCM). PATIENTS AND METHODS: The study consists of all consecutive patients who were diagnosed as having PCM and were treated and followed up at our hospital between November 1, 1998, and July 31, 2009. Pathologic and sociodemographic characteristics of the patients were obtained. We categorized SES into 3 levels: low (manual employees and skilled/unskilled workers, including farmers, with primary education level), middle (nonmanual employees and clerks with middle education level), and high (professionals, executives, administrators, and entrepreneurs with tertiary education). RESULTS: A total of 1443 consecutive patients were evaluated. In a multivariate logistic regression analysis, sex (female vs male: odds ratio [OR], 1.37; 95% confidence interval [CI], 1.08-1.75), SES (high vs middle: OR, 1.27; 95% CI, 0.96-1.69; high vs low: OR, 1.73; 95% CI, 1.26-2.38), age (<60 vs ≥60 years: OR, 1.35; 95% CI, 1.03-1.78), and family context (single vs living with relatives: OR, 1.37; 95% CI, 0.97-1.94) were the strongest correlates of Breslow thickness. Compared with high SES, the risk of melanoma-related death, adjusted for age and sex, was 7 times higher (hazard ratio, 7.44; 95% CI, 3.27-16.93) and almost 2 times higher (hazard ratio, 1.88; 95% CI, 1.04-3.39) in patients with low SES living alone or living with relatives, respectively. CONCLUSION: In patients with PCM, low SES is associated with thicker melanoma and a poorer clinical outcome.

[Memorandum for the management of clinical trials]. / Pro-memoria per la gestione della sperimentazione clinica.

A critical appraisal of the recent legislation on clinical trials is proposed, together with some reflections on the implications on the practice and principles of clinical experimentation. The possible role and contribution of Ethical Committees is discussed.

Research trends for early cancer biomarker detection in Italy: an integrated program in oncology (PIO) survey.

AIMS AND BACKGROUND: In 2007, an Italian Research Network proposed to the Ministry of Health a concerted action aimed at developing a specific pathway for the analytical and clinical validation of new biomarkers for early cancer diagnosis. The action, funded by the Italian Ministry of Health within the Integrated Program in Oncology (PIO) and coordinated by the National Cancer Institute of Bari, started in 2008 involving 37 national research teams. METHODS: To monitor the methodological and analytical needs of the studies proposed by the research teams of PIO as well as to explore the plausibility of planning external quality assessment programs for early cancer biomarker detection, the coordinating team developed an ad hoc questionnaire that was submitted to each research team. RESULTS: From the collected data it emerged that about 70% of the biomarkers under investigation were analyzed according to nonroutine laboratory practices. The biological material utilized for biomarker assessment consisted of solid tissue (normal or pathological) in 31% of studies, serum in 21%, urine in 15%, plasma in 15%, and whole blood in 11%. Specific training of personnel directly involved in the program was reported by 18% of the teams. In 2008, only 6% of laboratories involved in PIO participated in both external quality assessment and internal quality control schemes specifically designed for the biomarkers under consideration. Standard operating procedures for the determination of about half (52%) of the biomarkers proved to be lacking in at least one phase of the biomarker assessment process. CONCLUSIONS: On the basis of these results, we decided to give priority to the application of a four-phase process for the analytical validation of new potential biomarkers by setting up and applying standard operating procedures and developing external quality assessment and internal quality control schemes as specific steps of the workflow.

The Integrated Oncology Program of the Italian Ministry of Health. Analytical and clinical validation of new biomarkers for early diagnosis: network, resources, methodology, quality control, and data analysis.

In 2007, an Italian cancer research group proposed a specific concerted action aimed at the "analytical and clinica validation of new biomarkers for early diagnosis: Network, resources, methodology, quality control, and data analysis." The proposal united 37 national operative units involved in different biomarker studies and it created a strong coordinative body with the necessary expertise in methodologies, statistical analysis, quality control, and biological resources to perform ad hoc validation studies for new biomarkers of early cancer diagnosis. The action, financed by the Italian Ministry of Health within the Integrated Oncology Program (PIO) coordinated by NCI-Istituto Tumori Bari, started in 2007 and activated 7 projects, each of which focused on disease-specific biomarker studies. Overall, the 37 participating units proposed studies on 50 biomarkers, including analytical and clinical validation procedures. Clusters of units were specifically involved in research of early-detection biomarkers for cancers of the lung, digestive tract, prostate/bladder, and nervous system, as well as female cancers. Furthermore, a cluster involved in biomarkers for bioimaging and infection-related cancers was created. The first investigators' meeting, "Analytical and clinical validation of new biomarkers for early diagnosis," was held on 9 September 2008 in Bari. During this meeting, methodological aspects, scientific programs and preliminary results were presented and discussed.

Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (Short-HER Trial; NCT00629278).

Trastuzumab, a monoclonal antibody against the HER2 receptor, is currently approved as a part of adjuvant therapy for patients with HER2-overexpressing breast tumors. The Short-HER study is a phase III randomized, multicentric Italian trial aimed at testing the optimal duration of adjuvant trastuzumab. In this trial, 2500 patients with HER2-positive breast cancer will be randomized to receive the following: (arm A, long) 4 courses of anthracycline- based chemotherapy (doxorubicin/cyclophosphamide or epidoxorubicin/cyclophosphamide) followed by 4 courses of docetaxel or paclitaxel in combination with trastuzumab, followed by 14 additional courses of trastuzumab administered every 3 weeks (for a total of 18 3-weekly doses of trastuzumab); or (arm B, short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab (for a total of 9 weekly doses of trastuzumab) followed by 3 courses of 5-fluorouracil/epirubicin/cyclophosphamide. The primary objective is disease-free survival.

Developing clinical recommendations for breast, colorectal, and lung cancer adjuvant treatments using the GRADE system: a study from the Programma Ricerca e Innovazione Emilia Romagna Oncology Research Group.

PURPOSE: In the area of anticancer drugs, the legitimate search for effective interventions can be jeopardized by the strong pressure for accelerated approval, which may hinder the full assessment of their benefit-risk profile. We aimed to produce drug-specific recommendations using an explicit approach that separates the judgments on quality of evidence from the judgment about strength of recommendations. MATERIALS AND METHODS: We used the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system to develop recommendations for the use of specific anticancer drugs/regimens; 12 clinical questions relevant to adjuvant treatment of breast (three), colorectal (four) and lung (five) cancer have been assessed by multidisciplinary panels supported by a group of methodologists. RESULTS: For nine of 12 questions, recommendations were produced (one strong and six weak in favor and one weak and one strong against the index treatment); for the remaining three questions no specific course of action could be recommended. The perceived benefits to risk balance of the treatment was the most important and statistically significant (P < .01) predictor of panels' recommendations and of their strength, whereas panelists' personal (age, sex) and professional (specialty) characteristics were not statistically associated. CONCLUSION: Because the GRADE system sets out an explicit process going from evaluation of the quality of evidence and benefit-risk profile to the judgment of the strength of recommendations, in this experience, it proved very useful to combine methodologic rigor with the interdisciplinary participation that is important in the definition of evidence based clinical policies.

Quality of diabetes care predicts the development of cardiovascular events: results of the QuED study.

BACKGROUND AND AIM: In the context of the QuED Study we assessed whether a quality of care summary score was able to predict the development of cardiovascular (CV) events in patients with type 2 diabetes. METHODS AND RESULTS: The score was calculated using process and intermediate outcome indicators (HbA1c), blood pressure, low-density lipoprotein cholesterol, microalbuminuria) and ranged from 0 to 40. Overall, 3235 patients were enrolled, of whom 492 developed a CV event after a median follow-up of 5 years. The incidence rate (per 1000 person-years) of CV events was 62.4 in patients with a score < or =10, 54.8 in those with a score between 15 and 20, and 39.8 in those with a score >20. In adjusted multilevel regression models, the risk to develop a CV event was 89% greater in patients with a score of < or =10 (rate ratio [RR]=1.89; 95% confidence interval [CI] 1.43-2.50) and 43% higher in those with a score between 10 and 20 (RR=1.43; 95% CI 1.14-1.79), as compared to those with a score >20. A difference between centers of 5 points in the mean quality score was associated with a difference of 16% in CV event risk (RR=0.84; 95% CI 0.72-0.98). CONCLUSION: Our study documented for the first time a close relationship between a score of quality of diabetes care and long-term outcomes.

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.

Clinical and psychological predictors of incidence of self-reported erectile dysfunction in patients with type 2 diabetes.

PURPOSE: We evaluated the predictors of the incidence of erectile dysfunction in patients with type 2 diabetes mellitus and identified subgroups of patients in whom the interaction between clinical and psychological characteristics determined an increase in the risk of erectile dysfunction. MATERIALS AND METHODS: The study was based on 670 individuals. The presence of erectile dysfunction and the severity of depressive symptoms were investigated with a questionnaire filled in every 6 months for 3 years. Poisson regression was used to calculate incidence rates. To evaluate interactions among the different variables and identify distinct and homogeneous subgroups in terms of incidence of erectile dysfunction, RECursive Partitioning and AMalgamation method was used. RESULTS: Overall erectile dysfunction developed in 192 men with type 2 diabetes, with an incidence rate of 166.3 per 1,000 person-years. Age, insulin treatment, hemoglobin A1c greater than 8.0%, total cholesterol greater than 3.88 mmol/l and severity of depressive symptoms represented independent predictors of erectile dysfunction. RECursive Partitioning and AMalgamation analysis identified 5 classes with a marked variation in the risk of erectile dysfunction. Patients with low levels of depressive symptoms and hemoglobin A1c 8.0% or less showed the lowest risk of erectile dysfunction. Compared with this subgroup patients with higher levels of depressive symptoms and treated with insulin had a 3-fold risk of erectile dysfunction. Age, smoking, high cholesterol levels and neuropathy were globally predictive variables associated with an increased risk of erectile dysfunction. CONCLUSIONS: The incidence of erectile dysfunction is predicted by modifiable risk factors. Even in diabetes, psychological problems can contribute to the pathogenesis of erectile dysfunction, in addition to organic causes.

Feasibility and outcome of tandem stem cell autotransplants in multiple myeloma.

BACKGROUND AND OBJECTIVES: Clinical trials have shown that high dose chemotherapy (HDT) with peripheral stem cell autotransplantation is presently the best treatment for patients with symptomatic multiple myeloma (MM). In the context of an outcomes research project, we analyzed the feasibility of this strategy in clinical practice in a large cohort of consecutive, unselected patients with newly diagnosed MM and looked at the major determinants of response of patients enrolled in a HDT with tandem autotransplantation (Total Therapy I, TTI) program. DESIGN AND METHODS: Two hundred and fourteen patients were treated outside of a clinical trial and regularly followed-up at our Center for symptomatic MM. Ninety-seven patients (45%) received conventional chemo-radiotherapy regimens, 110 (51%) entered the TTI program and the remaining 7 patients (3.3%) were enrolled in other programs involving HDT with autotransplantation. RESULTS: Patients enrolled in HDT with tandem autotransplantation programs were 14 years younger and less likely to have co-morbidities than patients treated with conventional therapy. Median overall survivals of the two groups were 60 and 33 months, respectively. Thirteen percent of the patients enrolled in the TTI program did not receive the first HDT with autotransplantation, mostly because of disease progression, and another 16% did not proceed to the second HDT with autotransplantation mainly because of infections or drug-related complications. Most patients achieved complete remission after the second autotransplantation, with acceptable toxicity. However, only patients with a major reduction of the myeloma burden at the end of induction therapy enjoyed significantly prolonged event-free and overall survivals. INTERPRETATION AND CONCLUSIONS: Approximately one third of patients with newly diagnosed symptomatic MM completed the TTI program. These data suggest the need to improve the induction therapy in order to increase both the number of patients able to proceed to autotransplantation programs and to enhance the rate of early response.

Are Type 2 diabetic patients offered adequate foot care? The role of physician and patient characteristics.

In the context of a nationwide outcomes research program on Type 2 diabetes, we investigated physician and patient practices related to foot care. Patients filled in a questionnaire investigating whether they had received information about foot care, how often they had had their feet examined in the last year, and how often they usually checked their feet. Analyses were adjusted for patient case-mix and physician-level clustering. Overall, 3564 patients were recruited by 125 diabetes outpatient clinics (DOCs) and 103 general practitioners (GPs), of whom 6.8% suffered form lower limb complications. The presence of foot complications was correlated with insulin treatment, cigarette smoking, low levels of school education, and the presence of other diabetic complications. More than 50% of the patients reported that they had not had their feet examined by their physician and 28% referred that they had not received foot education. Patients with lower levels of school education and income, as well as overweight individuals, were less likely to receive foot education. Physicians tended to perform foot examination more often in males, low-income patients, those with foot complications, and those treated with insulin, but not in patients with the highest risk of foot complications, that is, those with diabetic neuropathy or peripheral vascular disease (PVD). GPs tended to perform foot examination less frequently than diabetologists do. Foot self-examination was not performed by 33% of the patients. Those individuals who had received foot education or had had their feet examined were more likely to check their feet regularly. A substantial proportion of Type 2 diabetic patients is not offered adequate foot care, even in the presence of major risk factors for lower limb complications. Patient knowledge and practices are strongly related to physicians' attitudes.