A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

[The praise of uncertainty: a systematic living review to evaluate the efficacy and safety of drug treatments for patients with covid-19.] / L'elogio dell'incertezza: una revisione sistematica living per valutare l'efficacia e la sicurezza dei trattamenti farmacologici per pazienti affetti da covid-19.

BACKGROUND: SARS-CoV-2 is a coronavirus that causes a disease which can leads to a severe form of fatal pneumonia. At december 2020 in Italy, more than 2 million people have contracted the virus and 78,755 people have died. The scientific community is studying and testing numerous compounds that can be effective and safe for treating people with covid-19. AIM: To synthesize and evaluate the quality of evidence of efficacy and safety for the treatment. The available evidence is summarized in a living systematic review, a review that is constantly updated on the basis of the results of the new clinical studies. METHODS: A bibliographic search is launched weekly on the electronic databases and on the main clinical trial registers. Two researchers independently select the articles and assess the quality of the studies using the criteria developed by the Cochrane Collaboration, the certainty of the overall quality of the evidence is assessed using the GRADE criteria. RESULTS: At 31/12/2020, 101 randomized controlled studies were included that consider 72 different comparisons and include a total of 55,281 patients. 37 drugs are tested with respect to the standard treatment, 6 are evaluated against placebo and finally 29 compare different drugs with each other. By selecting studies that evaluate the efficacy and safety of a drug compared to standard treatment, which include at least 2 studies and which have low to high certainty of evidence, results show that corticosteroids, remdesivir, favipiravir, immunoglobulins, colchicine, and umbilical cord mesenchymal stem cell infusion could reduce overall mortality. No differences for the risk of any adverse events are observed between convalescent plasma and remdesivir compared to standard treatment. Remdesivir probably reduces the risk of serious adverse events; a similar effect, although less strong, is also noted for tocilizumab and the lopinavir-ritonavir combination. In contrast, hydroxychloroquine, corticosteroids and convalescent plasma transfusion are associated with safety concerns with respect to the risk of serious adverse events. CONCLUSIONS: The 101 studies included consider 72 comparisons and numerous outcomes, the results often coming from single studies and of small dimensions, and for 61% with a very low certainty of evidence, are difficult to summarize and the final result is to increase the uncertainty rather than providing useful information to the clinic and research. From all the work carried out it seems to us that the pandemic has highlighted the many shadows of scientific literature as tool to improve knowledge.

[Effects of electronic cigarettes on health: a systematic review of the available evidence.] / Effetti delle sigarette elettroniche sulla salute: una revisione sistematica delle prove disponibili.

BACKGROUND: In recent years there has been an enormous development in the use of electronic cigarettes (e-cig). In Italy, in the 2019, the users of e-cig are about 900.000. E-cig users tend to overlook the absolute risk of the e-cig product in favor of the relative risk compared to traditional ones. This is also due to the fact that at the moment there are large knowledge gaps on the health effects of using e-cig. Recently reports have emerged regarding serious health adverse effects (AE) related to their use. As of December 2019, the American Centers for Disease Control and Prevention (CDC) reported 2409 cases of lung disease associated with the use of e-cig, and 52 deaths. AIM: To summarize the available evidence on the health effects of electronic cigarettes. METHODS: We searched systematic reviews (SR) of the literature published up to September 2019. RESULTS: The systematic searches led to the identification of 14 SRs (1037 studies included of which 77 provided useful information for this review) that met the inclusion criteria. Given the heterogeneity of the comparisons and of the outcome measures considered, the results are described narratively. Effects on the respiratory system: cough, phlegm, asthma and bronchitis symptoms, cases of chronic bronchitis and COPD have also been reported. Effects on the oropharyngeal system: lesions in the oral cavity, villous black tongue, allergic reactions, endogenous formation of carcinogens, development of oral cancer. Effects on the cardiovascular system: increased heart rate, increased systolic and diastolic pressure. Effects on skin and annexes: squamous and pruritic dermatitis. Any adverse effect: the most frequently reported AEs are cough, dry mouth, shortness of breath, irritation of the mouth and throat and headache. Effects of exposure to e-cig passive smoking: increase in cotinine levels in exposed environments. CONCLUSIONS: These results, based on evidence from very low to moderate, show a series of possible risks linked to the use of e-cig. However, there is a need for further well-conducted studies with longer follow-up periods to confirm these results.

Volume and health outcomes: evidence from systematic reviews and from evaluation of Italian hospital data. / Volumi di attività ed esiti delle cure: prove scientifiche in letteratura ed evidenze empiriche in Italia.

BACKGROUND Improving quality and effectiveness of healthcare is one of the priorities of health policies. Hospital or physician volume represents a measurable variable with an impact on effectiveness of healthcare. An Italian law calls for the definition of «qualitative, structural, technological, and quantitative standards of hospital care¼. There is a need for an evaluation of the available scientific evidence in order to identify qualitative, structural, technological, and quantitative standards of hospital care, including the volume of care above or below which the public and private hospitals may be accredited (or not) to provide specific healthcare interventions. OBJECTIVES To identify conditions/interventions for which an association between volume and outcome has been investigated. To identify conditions/interventions for which an association between volume and outcome has been proved. To analyze the distribution of Italian health providers by volume of activity. To measure the association between volume of care and outcomes of the health providers of the Italian National Health Service (NHS). METHODS Systematic review An overview of systematic reviews was performed searching PubMed, EMBASE, and The Cochrane Library up to November 2016. Studies were evaluated by 2 researchers independently; quality assessment was performed using the AMSTAR checklist. For each health condition and outcome, if available, total number of studies, participants, high volume cut-off values, and metanalysis have been reported. According to the considered outcomes, health topics were classified into 3 groups: positive association: a positive association was demonstrated in the majority of studies/participants and/or a pooled measure (metanalysis) with positive results was reported; lack of association: both studies and/or metanalysis showed no association; no sufficient evidence of association: both results of single studies and metanalysis do not allow to draw firm conclusions on the association between volume and outcome. Analysis of the distribution of Italian hospitals by volume of activity and the association between volume of activity and outcomes: the Italian National Outcome evaluation Programme 2016 The analyses were performed using the Hospital Information System and the National Tax Register (year 2015). For each condition, the number of hospitals by volume of activity was calculated. Hospitals with a volume lower than 3-5 cases/year were excluded. For conditions with more than 1,500 cases/year and frequency of outcome ≥1%, the association between volume of care and outcome was analyzed estimating risk-adjusted outcomes. RESULTS Bibliographic searches identified 80 reviews, evaluating 48 different clinical areas. The main outcome considered was intrahospital/30-day mortality. The other outcomes vary depending on the type of condition or intervention in study. The relationship between hospital volume and outcomes was considered in 47 out of 48 conditions: 34 conditions showed evidence of a positive association; • 14 conditions consider cancer surgery for bladder, breast, colon, rectum, colon rectum, oesophagus, kidney, liver, lung, ovaries, pancreas, prostate, stomach, head and neck; • 11 conditions consider cardiocerebrovascular area: nonruptured and ruptured abdominal aortic aneurysm, acute myocardial infarction, brain aneurysm, carotid endarterectomy, coronary angioplasty, coronary artery bypass, paediatric heart surgery, revascularization of lower limbs, stroke, subarachnoid haemorrhage; • 2 conditions consider orthopaedic area: knee arthroplasty, hip fracture; • 7 conditions consider other areas: AIDS, bariatric surgery, cholecystectomy, intensive care unit, neonatal intensive care unit, sepsis, and traumas; for 3 conditions, no association was demonstrated: hip arthroplasty, dialysis, and thyroidectomy. for the remaining 10 conditions, the available evidence does not allow to draw firm conclusions about the association between hospital volume and considered outcomes: surgery for testicular cancer and intracranial tumours, paediatric oncology, aortofemoral bypass, cardiac catheterization, appendectomy, colectomy, inguinal hernia, respiratory failure, and hysterectomy. The relationship between volume of clinician/surgeon and outcomes was assessed only through the literature re view; to date, it is not possible to analyze this association for Italian health provider hospitals, since information on the clinician/surgeon on the hospital discharge chart is missing. The literature found a positive association for 21 conditions: 9 consider surgery for cancer: bladder, breast, colon, colon rectum, pancreas, prostate, rectum, stomach, and head and neck; 5 consider the cardiocerebrovascular area: ruptured and nonruptured abdominal aortic aneurysm, carotid endarterectomy, paediatric heart surgery, and revascularization of the lower limbs; 2 consider the orthopaedic area: knee and hip arthroplasty; 5 consider other areas: AIDS, bariatric surgery, hysterectomy, intensive care unit, and thyroidectomy. The analysis of the distribution of Italian hospitals concerned the 34 conditions for which the systematic review has shown a positive volume-outcome association. For the following, it was possible to conduct the analysis of the association using national data: unruptured abdominal aortic aneurysm, coronary angioplasty, hip arthroplasty, knee arthroplasty, coronary artery bypass, cancer surgery (colon, liver, breast, pancreas, lung, prostate, kidney, and stomach), laparoscopic cholecystectomy, hip fracture, stroke, acute myocardial infarction. For these conditions, the association between volume and outcome of care was observed. For laparoscopic cholecystectomy and surgery of the breast and stomach cancer, the association between the volume of the discharge (o dismissal) operating unit and the outcome was analyzed. The outcomes differ depending on the condition studied. The shape of the relationship is variable among different conditions, with heterogeneous slope of the curves. DISCUSSION For many conditions, the overview of systematic reviews has shown a strong evidence of association between higher volumes and better outcomes. The quality of the available reviews can be considered good for the consistency of the results between the studies and for the strength of the association; however, this does not mean that the included studies are of good quality. Analyzing national data, potential confounders, including age and comorbidities, have been considered. The systematic review of the literature does not permit to identify predefined volume thresholds. The analysis of national data shows a strong improvement in outcomes in the first part of the curve (from very low to higher volumes) for most conditions. In some cases, the improvement in outcomes remains gradual or constant with the increasing volume of care; in other, the analysis could allow the identification of threshold values beyond which the outcome does not further improve. However, a good knowledge of the relationship between effectiveness of treatments and costs, the geographical distribution and the accessibility to healthcare services are necessary to choose the minimum volumes of care, under which specific health procedures could not been provided in the NHS. Some potential biases due to the use of information systems data should also be considered. The different way of coding among hospitals could lead to a different selection of cases for some conditions. Regarding the definition of the exposure (volume of care), a possible bias could result from misclassification of health providers with high volume of activity. Performing the intervention in different departments/ units of the same hospital would result in an overestimation of the volume of care measured for hospital rather than for department/unit. For the conditions with a further fragmentation within the same structure, the association between volumes of discharge department and outcomes has also been evaluated. In this case, the two curves were different. The limit is to attribute the outcome to the discharge unit, which in case of surgery may not be the intervention unit. A similar bias could occur if the main determinant of the outcome of treatment was the caseload of each surgeon. The results of the analysis may be biased when different operators in the same hospital/unit carried out the same procedure. In any case, the observed association between volumes and outcome is very strong, and it is unlikely to be attributable to biases of the study design. Another aspect on which there is still little evidence is the interaction between volume of the hospital and of the surgeon. A MEDICARE study suggests that in some conditions, especially for specialized surgery, the effect of the surgeon's volume of activity is different depending on the structure volume, whereas it would not differ for some less specialized surgery conditions. The data here presented still show extremely fragmented volumes of both clinical and surgical areas, with a predominance of very low volume structures. Health systems operate, by definition, in a context of limited resources, especially when the amount of resources to allocate to the health system is reduced. In such conditions, the rationalization of the organization of health services based on the volume of care may make resources available to improve the effectiveness of interventions. The identification and certification of services and providers with high volume of activity can help to reduce differences in the access to non-effective procedures. To produce additional evidence to guide the reorganization of the national healthcare system, it will be necessary to design further primary studies to evaluate the effectiveness and safety of policies aimed at concentrating interventions in structures with high volumes of activity.

[Systematic review of safeness and therapeutic efficacy of cannabis in patients with multiple sclerosis, neuropathic pain, and in oncological patients treated with chemotherapy]. / Revisione sistematica sull'efficacia terapeutica e la sicurezza della cannabis per i pazienti affetti da sclerosi multipla, dolore neuropatico cronico e pazienti oncologici che assumono chemioterapie.

BACKGROUND: medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. In the United States, 23 states and Washington DC (May 2015) have introduced laws to permit the medical use of cannabis. Within the European Union, medicinal cannabis laws and praxis vary wildly between Countries. OBJECTIVES: to provide evidence for benefits and harms of cannabis (including extracts and tinctures) treatment for adults in the following indications: control of spasticity and pain in patients with multiple sclerosis; control of pain in patients with chronic neuropathic pain; control of nausea and vomiting in adults with cancer receiving chemotherapy. METHODS: we searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE from inception to September 2016. We also searched for on-going studies via ClinicalTrials.gov and the World Health Organization and International Clinical Trials Registry Platform (ICTRP) search portal. All searches included also non-English language literature. All relevant randomized controlled trials (RCTs) evaluating the safety and efficacy of cannabis (including extracts and tinctures) compared with placebo or other pharmacological agents were included. Three authors independently evaluated the titles and abstracts of studies identified in the literature searches for their eligibility. For studies considered eligible, we retrieved full texts. Three investigators independently extracted data. For the assessment of the quality of evidence, we used the standard methodological procedures recommended by Cochrane and GRADE working Group. RESULTS: 41 trials (4,550 participants) were included; 15 studies considered efficacy and safety of cannabis for patients with multiple sclerosis, 12 for patients with chronic pain, and 14 for patients with cancer receiving chemotherapy. The included studies were published between 1975 and 2015, and the majority of them were conducted in Europe. We judged almost 50% of these studies to be at low risk of bias. The large majority (80%) of the comparisons were with placebo; only 8 studies included patients with cancer receiving chemotherapy comparing cannabis with other antiemetic drugs. Concerning the efficacy of cannabis (compared with placebo) in patients with multiple sclerosis, confidence in the estimate was high in favour of cannabis for spasticity (numerical rating scale and visual analogue scale, but not the Ashworth scale) and pain. For chronic and neuropathic pain (compared with placebo), there was evidence of a small effect; however, confidence in the estimate is low and these results could not be considered conclusive. There is uncertainty whether cannabis, including extracts and tinctures, compared with placebo or other antiemetic drugs reduces nausea and vomiting in patients with cancer requiring chemotherapy, although the confidence in the estimate of the effect was low or very low. In the included studies, many adverse events were reported and none of the studies assessed the development of abuse or dependence. CONCLUSIONS: there is incomplete evidence of the efficacy and safety of medical use of cannabis in the clinical contexts considered in this review. Furthermore, for many of the outcomes considered, the confidence in the estimate of the effect was again low or very low. To give conclusive answers to the efficacy and safety of cannabis used for medical purposes in the clinical contexts considered, further studies are needed, with higher quality, larger sample sizes, and possibly using the same diagnostic tools for evaluating outcomes of interest.

A survey on lifestyle and level of biomarkers of environmental exposure in residents in Civitavecchia (Italy).

BACKGROUND: The assessment of individual exposure to toxicants in industrially contaminated areas is difficult when multiple productions are active close to residential areas. Two thermoelectric power plants and a large harbor have been operating since the '60s in the area of Civitavecchia (North of Rome). METHODS: The ABC (Ambiente e Biomonitoraggio nell'area di Civitavecchia, Environment and Biomonitoring in Civitavecchia) program involved, in the period 2013-2014, residents in Civitavecchia and in the nearby municipalities (Santa Marinella, Allumiere, Tolfa and Tarquinia). They were randomly selected from the Municipal Register's data and their residence addresses were geocoded using GIS techniques. Biomonitoring of the following urinary metals, Sb, Be, Mo, Cd, Sn, W, Ir, Pt, Hg, Tl, V, Cr, Mn, Co, Ni, Cu, Zn, Rh, Pd, As were performed. Glucose and lipid metabolism, liver, renal, and endocrine function were evaluated through blood laboratory tests. Tests of lung functionwere also carried out as well as saturometry (oxygen rate in the blood with an illuminated sensor placed on the fingertip), anthropometric and blood pressure measurements. Information on individual characteristics, histories of exposure, such as the consumption of local food, occupational history, lifestyle and medical history were collected through a validated questionnaire. Samples of nails and hair were also collected. The biological material (blood, urine, nails and hair) was stored in a biobank for future analysis related to the possible mechanisms of biological damage. The study protocol received the approval of the local ethics committee. RESULTS: A total of 1177 residents were enrolled (58% female, 60% with a secondary or graduate school degree). No particular differences in metal concentrations based on the municipality of residence were observed. For arsenic, mercury, lead, and tungsten some differences between the two geographical areas were observed, probably due to different diet, lifestyle (e.g., alcohol consumption, smoking, use of jewelry and piercings, tattoos, physical activity, hormonal and mineral supplements, and drugs), and occupational exposure. CONCLUSIONS: The undergoing study on the association between biomarkers concentration and pollutants concentrations - estimated using a dispersion modeling approach, and adjusting for personal characteristics and concomitant other environmental exposure - could clarify the individual exposure of the residents in this industrial area.

Liposomal daunorubicin, fludarabine, and cytarabine (FLAD) as bridge therapy to stem cell transplant in relapsed and refractory acute leukemia.

Therapeutic options for patients with relapsed or refractory acute leukemia are still undefined and often unsatisfactory. We report the outcome of 79 patients with relapsed-refractory acute leukemia treated with fludarabine, cytarabine, and liposomal daunorubicin (FLAD regimen) followed by hematopoietic stem cell transplantation (HSCT), when clinically indicated, between May 2000 and January 2013. Forty-one patients had acute myeloid leukemia (AML), and 38 had acute lymphoblastic leukemia (ALL). Two patients with myeloid blast crises of CML and three with lymphoid blast crises were included in the AML and ALL subgroups, respectively. Median age was 48 years (range 13-77). FLAD was well tolerated with negligible, nonhematological toxicity. Six patients (7.5 %) died before response evaluation. Forty-seven patients achieved hematologic complete response (CR). Complete remission rate was 53 and 65 % among AML and ALL patients, respectively. No CR was recorded among 11 refractory AML patients. Twenty-four patients (30 %) underwent HSCT. Nine patients received stem cells from an HLA identical sibling, and 15 from an alternative donor (3 unrelated matched, 12 haploidentical sibling). Median overall survival in AML and ALL patients receiving FLAD therapy was 9 and 8 months, respectively. A 5-year projected OS for patients receiving the whole program (FLAD + HSCT) was 24 % for AML patients (median survival 43 months), 28 % for ALL patients treated in relapse (median survival 15 months), and 0 % for ALL patients treated for refractory disease. In this paper, we show that FLAD seems to be an effective bridge therapy to HSCT for a part of poor prognosis acute leukemia patients. However, prospective studies are needed to confirm our results.

De novo AML patients with favourable-intermediate karyotype may benefit from the addition of low-dose gemtuzumab ozogamicin (GO) to fludarabine, Ara-C and idarubicin (FLAI): a contribution to the reopened "GO question".

We report the final results of a prospective trial testing the combination of fludarabine, Ara-C and idarubicin (FLAI) followed by low-dose gemtuzumab ozogamicin (FLAI-GO) in 85 patients aged 60 years or more with CD33+ acute myeloid leukaemia (AML). Median age was 68 years (60-82); karyotype was unfavourable in 21 patients (24%), intermediate in 63 (74%) and favourable in 1 (2%). There were five therapy-related deaths. Of the 80 evaluable patients, 47 achieved complete response (CR) (58%); CR rates were 65 and 32% in good-intermediate/poor karyotype patients, respectively. Median length of CR was 7 months (3-76). The cumulative incidence of relapse was 84% with an actuarial survival of 50.3% at 1 year and 14.4% at 2 years. The study control population is an unselected consecutive historic cohort of 104 patients treated with the FLAI regimen, who were matched for age and prognostic factors. CR rates after FLAI-GO and FLAI were comparable. However, patients with de novo AML and intermediate-favourable karyotype receiving GO had a significantly lower risk of relapse at 2 years as compared to patients not receiving GO (n = 77) (40 vs 80%, p = 0.01) and significantly better disease-free survival (p = 0.018) and overall survival (p = 0.022).