[Walking among doctors and patients. Stories and reflections.] / Un viaggio fra dottori e malati. Storie e riflessioni.

The clinician - the doctor who treats sick people - should be able to establish a good human relationship with his or her patients and their family; should be able to reach a diagnosis even in patients with rare diseases, or atypical presentations - or should refer the patient to a senior colleague; and should be able to recommend the best treatment (or no treatment at all). And he - or she - should be able to draw these abilities from the "deliberate practice" according to Ericsson, i.e. from the combination of experience with reflection - not, or with much lesser strength, from the medical literature as suggested by Evidence-Based Medicine. The diagnosis is often an easy task, i.e. by pattern recognition or recognizing a frequent illness script - "fast thinking" in the vocabulary of Kahneman; or a difficult task, sometimes very difficult for rare diseases or atypical presentations - "slow thinking" of Kahneman. The decisions about the use of therapeutic interventions, whether for individuals or entire healthcare systems, should be based on the totality of the available evidence. The idea that evidence can be reliably or usefully placed in "hierarchies" is illusory, and the pedestal deserved to the RCT is inappropriate.

[Individual response to treatment: from Withering to contemporary medicine]. / La risposta individuale ai trattamenti. Da Withering alla medicina di oggi.

This is an essay dealing with the 1785 cohort study by William Withering (the "account"), in which he reported the results of the treatment with foxglove (Digitalis purpurea) in 163 patients suffering from various forms of hydropsy (water retention). Withering reported the results of all patients, and classified them into responders and non-responders. He identified the responders as suffering from heart failure. In the 18th century, medical treatments were judged as successful if they complied with the criteria a priori of the theory of the four humors, and not on the patient's response to the treatment. Withering was the first not only to compare the patient's conditions before and after treatment, but also to identify the individual clinical characteristics of the patients who responded. In modern medicine, drugs are released on the market and approved for use after what is known as "population-derived clinical research", principally randomized controlled trials, and guidelines. More than 200 years ago, Withering anticipated the current and growing trend towards individual responses to treatment, and personalized medicine.

[Evidence-based medicine: a new paradigm for medicine and a brand for the megastore of medicinal literature]. / Evidence-based medicine: nuovo paradigma della medicinae marchio di garanzia nel supermercato della letteratura medica.

The current debate about the state of evidence based medicine (EBM) led to hypothesize a "crisis", claiming the need for a "renaissance" of the EBM movement. During the last two decades, EBM contributed to make medical practice more scientific, as clinical epidemiology became a science basic for clinical medicine. The traditional hierarchical structure of medicine was thwarted, and endorsing clinical decisions with the best available evidence became a moral obligation. However, although the benefits from the widespread diffusion of EBM are well known and sometimes overemphasized, the negative consequences of a mechanistic and dogmatic application of EBM cannot be ignored. For example, the need of combining scientific evidence with clinical expertise was claimed, but what's expertise not defined. Diagnostic studies are underdeveloped as compared with intervention trials. Furthermore, outcomes are mainly confined to simple accuracy measurements, and hypotheses generation, the first crucial phase of the diagnostic pathway frequently omitted. These limitations may have reduced the potential of EBM, contributing to its criticisms.

The ethical problem of randomization.

The Fondazione Umberto Veronesi ethics committee recently published a statement concerning the inherent ethical issues of randomized clinical trials (RCTs), mainly focusing on randomization, raising many questions, and suggesting possible solutions. The main concern is that the patients enrolled in a RCT are used to improve medical knowledge, but they cannot be the beneficiaries of the results of the trials in which they are participating. Possible solutions come from a wider use of clinical and administrative databases, and an early termination of trials. We discuss this statement, emphasizing that the scientific and ethical reason for embarking on a clinical trial is uncertainty. The uncertainty regarding the comparative benefits and harms of each compared treatment (clinical equipoise) warrants equity in allocation. Randomization allows one to obtain unbiased evidence that we cannot know in advance. The expected probability of a new treatment to be successful describes the limits within which a study can be acceptable both from an ethical as well as a scientific point of view. Most people accept enrollment in a RCT if the probability of success of the experimental treatment is between 50 and 70%. The assumption and concern that there is a conflict between "scientific" and "ethical" aspects of a clinical trial due to randomization should at least be mitigated, considering that only scientifically sounded studies can be considered ethical. Randomization remains the appropriate approach to ensure the study's internal validity. Different aspects seem to be more important, from the ethical point of view, considering RCT and their publication.

Hepato-biliary clinical trials and their inclusion in the Cochrane Hepato-Biliary Group register and reviews.

BACKGROUND AND AIMS: The Cochrane Hepato-Biliary Group (CHBG) is one of the 52 collaborative review groups within The Cochrane Collaboration. The activities of the CHBG focus on collecting hepato-biliary randomized clinical trials (RCT) and controlled clinical trials (CCT), and including them in systematic reviews with meta-analyses of the trials. In this overview, we present the growth of The CHBG Controlled Trials Register, as well as the systematic reviews that have been produced since March 1996. RESULTS: The CHBG register includes almost 11,000 RCT and 700 CCT publications. The earliest RCT in the register were published in 1955, and the earliest CCT in 1945. From 1945 to 1980, there were less than 100 publications each year. From 1981 to 1997, their number increased from over 100 to 600 a year. After 1997, the number of publications seems to have been decreasing. The CHBG has published 199 protocols for systematic reviews and 107 systematic reviews through to August 2009 in which 21% of the RCT and CCT were included. The CHBG reviews have been cited approximately 1200 times. CONCLUSIONS: A large amount of work has been carried out since 1996. However, there is still much to do, as the CHBG register contains a great number of RCT and CCT on topics that have not yet been systematically reviewed.

Emergency sclerotherapy versus vasoactive drugs for bleeding oesophageal varices in cirrhotic patients.

BACKGROUND: Emergency sclerotherapy is still widely used as a first line therapy for variceal bleeding in patients with cirrhosis, particularly when banding ligation is not available or feasible. However, pharmacological treatment may stop bleeding in the majority of these patients. OBJECTIVES: To assess the benefits and harms of emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis. SEARCH STRATEGY: Search of trials was based on The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded through January 2010. SELECTION CRITERIA: Randomised clinical trials comparing sclerotherapy with vasoactive drugs (vasopressin (with or without nitroglycerin), terlipressin, somatostatin, or octreotide) for acute variceal bleeding in cirrhotic patients. DATA COLLECTION AND ANALYSIS: Outcome measures were failure to control bleeding, five-day treatment failure, rebleeding, mortality, number of blood transfusions, and adverse events. Data were analysed by a random-effects model according to the vasoactive treatment. Sensitivity analyses included combined analysis of all the trials irrespective of the vasoactive drug, type of publication, and risk of bias. MAIN RESULTS: Seventeen trials including 1817 patients were identified. Vasoactive drugs were vasopressin (one trial), terlipressin (one trial), somatostatin (five trials), and octreotide (ten trials). No significant differences were found comparing sclerotherapy with each vasoactive drug for any outcome. Combining all the trials irrespective of the vasoactive drug, the risk differences (95% confidence intervals) were failure to control bleeding -0.02 (-0.06 to 0.02), five-day failure rate -0.05 (-0.10 to 0.01), rebleeding 0.01 (-0.03 to 0.05), mortality (17 randomised trials, 1817 patients) -0.02 (-0.06 to 0.02), and transfused blood units (8 randomised trials, 849 patients) (weighted mean difference) -0.24 (-0.54 to 0.07). Adverse events 0.08 (0.03 to 0.14) and serious adverse events 0.05 (0.02 to 0.08) were significantly more frequent with sclerotherapy. AUTHORS' CONCLUSIONS: We found no convincing evidence to support the use of emergency sclerotherapy for variceal bleeding in cirrhosis as the first, single treatment when compared with vasoactive drugs. Vasoactive drugs may be safe and effective whenever endoscopic therapy is not promptly available and seems to be associated with less adverse events than emergency sclerotherapy. Other meta-analyses and guidelines advocate that combined vasoactive drugs and endoscopic therapy is superior to either intervention alone.

[Hepatology: yesterday, today and (maybe) tomorrow]. / Epatologia: ieri, oggi e (forse) domani.

Hepatology was born as a separate medical specialty around the fifties of the last century, its importance progressively grows because of the severity and high prevalence of the liver diseases. The net balance of 50 years of hepatology is definitely positive: prevention (e.g. the fall of post-transfusion HB and HC virus infections), diagnosis and better treatments have achieved better survival and quality of life in liver disease. However, deviations, errors and obsolescence of once highly credited judgements and treatments have occurred, as in any other area of medicine. This review looks back at the main pieces of the progress, and reports some previous errors and inappropriate treatments, speculating on their possible reasons.

Ultrasonographic features of peritoneal cestodiasis caused by Mesocestoides sp. in a dog and in a cat.

Peritoneal infections caused by Mesocestoides spp. are rare in dogs and cats. Little data exist on the role of abdominal ultrasonography for diagnosis and therapy management of the disease. We describe the ultrasonographic features of peritoneal cestodiasis in a dog and in a cat. In the dog, abdominal ultrasound allowed both a presumptive diagnosis and the collection of tissue samples to confirm peritoneal larval infection. Ultrasound was also very useful for therapy management. In the second patient the ultrasonographic features of tetrathyridial infection in a cat in which the parasite was observed as an incidental finding during ovariohysterectomy are described.

Hemolytic-uremic syndrome in a dog.

A 3-year-old, spayed, female Boxer was presented because of acute onset of anorexia, vomiting, and hemorrhagic diarrhea. Microangiopathic hemolytic anemia with intravascular hemolysis, thrombocytopenia, and acute renal failure were detected. The dog was treated with fluids, antiemetics, antibiotics, and diuretics. Despite supportive therapy, the dog's condition worsened, and the owners elected euthanasia. Necropsy revealed disseminated petechiae on the parietal peritoneum and serosal surfaces of the intestinal tract. The histologic lesions were consistent with severe arteritis and microvascular thrombosis involving only the renal and intestinal arterioles. The final diagnosis was hemolytic-uremic syndrome (HUS), a rarely described disorder in dogs. The clinical presentation of primarily gastrointestinal clinical signs was similar to that of typical or diarrhea-associated HUS (D+ HUS) in humans (mainly children), which is caused by gastrointestinal proliferation of verocytotoxin-producing Escherichia coli. Bacterial toxins can be adsorbed and cause endothelial injury, activation of hemostasis, and thrombosis, with lesions confined primarily to the kidneys. Although rare, HUS should be considered in the differential diagnosis of dogs with microangiopathic hemolytic anemia.

A decade of trials of interferon-alpha for chronic hepatitis C. A meta-regression analysis.

The most relevant randomized controlled trials of interferon-alpha (IFN) for naive patients with chronic hepatitis C (CHC) published in a decade, just before appearance of pegylated IFN trials in 2000, were included in this paper. Its purpose is to review the relationship between sustained biochemical response in active versus control group versus usual clinical variables as IFN regimens, cirrhosis, genotype and versus less frequently addressed variables as funding, methodological quality or location of principal author. Meta-analysis estimates of global treatment effect varied according to trial design: group 1=IFN versus placebo/no treatment, 32 RCTs, 2499 pts, OR 9.5 (6.3-14.2); group 2a=comparison of IFN schedules, 43 RCTs, 7454 pts, OR 1.6 (1.4-1.9); group 2b=IFN+other drugs versus standard IFN, 30 RCTs, 4737 pts, OR 2.0 (1.6-2.6). Fixed effects (arm-level) meta-regression on the complete data set (171 arms, 10,580 pts) revealed that sustained response was most likely in experimental arms of IFN+ribavirin or other drugs (OR 2.4), arms using yearly schedule (OR 2.0), trial principal author from Asia (OR 1.7), trial sample size >200 (OR 1.4) and arms enrolling less than 50% of cirrhotics (OR 1.3). Moreover, focus was on some significant interactions too, as the effect of trial's quality interacting to the recorded funding (more benefit if no-profit, less if for-profit) and the effect of trial funding interacting to the location of first author (more benefit if from Asia). Three main effects (experimental arm, cirrhosis, funding) and one interaction (funding*location of principal author) explained 31% of between study variability in a random-effect meta-regression. In a subgroup analysis on a data set including available information on HCV genotype (93 arms, around 7000 pts), meta-regression revealed that genotype 1 or 4 less than 50% per arm and specialistic journal were significant predictors of either biochemical (transaminases) or virological (HCV-RNA) sustained response, in a model including the same main effects identified in the complete data set analysis. Finally, although mostly captured by different IFN regimens along time, heterogeneity of effect in a large set of (not-pegylated) IFN trials was also explained by HCV genotype and variables of quality and reporting, such as trial's principal author from Asia.

Familial occurrence of inflammatory bowel disease in celiac disease.

BACKGROUND: The authors have previously reported a possible increased risk of the familial occurrence of Crohn's disease in patients with celiac disease. AIM: The aim of the current study was to evaluate in a case-control study the familial occurrence of inflammatory bowel disease (IBD) in first-degree relatives of patients with celiac disease. METHODS: One hundred eleven consecutive patients with biopsy-proven celiac disease were interviewed to ascertain whether IBD was present in first-degree relatives. The number of relatives, their ages, and possible IBD status were collected in a questionnaire. When a diagnosis of familial IBD was reported, the diagnosis was checked in the hospital records. Two hundred twenty-two controls matched for age and sex (111 from the general population and 111 from orthopedic wards) were also interviewed regarding the possible occurrence of IBD in first-degree relatives. The chi2 test was used to evaluate the difference in proportion of familial occurrence of IBD among individuals with celiac disease and controls. RESULTS: Among 600 first-degree relatives of patients with celiac disease, 10 cases of IBD were identified among first-degree relatives (7 cases of ulcerative colitis and 3 cases of Crohn's disease), whereas only 1 case of IBD was identified among the 1,196 first-degree relatives of control patients (p < 0.01). When ulcerative colitis and Crohn's disease were analyzed separately, only the prevalence of ulcerative colitis was statistically significant (p

Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis.

BACKGROUND & AIMS: Emergency sclerotherapy is used as a first-line therapy for variceal bleeding in cirrhosis, although pharmacologic treatment stops bleeding in most patients. We performed a meta-analysis comparing emergency sclerotherapy with pharmacologic treatment. METHODS: MEDLINE (1968-2002), EMBASE (1986-2002), and the Cochrane Library (2002;4) were searched to retrieve randomized controlled trials comparing sclerotherapy with vasopressin (+/- nitroglycerin), terlipressin, somatostatin, or octreotide for variceal bleeding in cirrhosis. Outcome measures were failure to control bleeding, rebleeding, blood transfusions, adverse events, and mortality. RESULTS: Fifteen trials were identified. Sclerotherapy was not superior to terlipressin, somatostatin, or octreotide for any outcome and to vasopressin for rebleeding, blood transfusions, death, and adverse events; it was superior to vasopressin for the control of bleeding in a single trial flawed by a potential detection bias. Sclerotherapy was associated with significantly more adverse events than somatostatin. In a predefined sensitivity analysis, combining all of the trials irrespective of the control treatment, risk differences (sclerotherapy minus control) and confidence intervals (CIs) were as follows: failure to control bleeding, -0.03 (-0.06 to 0.01); mortality, -0.035 (-0.07 to 0.008); adverse events, 0.08 (0.02 to 0.14). Mortality risk difference was -0.01 (-0.07 to 0.04) in good-quality trials and -0.08 (-0.14 to -0.02) in poor-quality trials. CONCLUSIONS: Available evidence does not support emergency sclerotherapy as the first-line treatment of variceal bleeding in cirrhosis when compared with vasoactive drugs, which control bleeding in 83% of patients. Therefore, endoscopic therapy might be added only in pharmacologic treatment failures.

Disseminated non-Hodgkin's lymphoma and chronic hepatitis C: a case report.

Hepatitis C virus (HCV) infection is occasionally associated to B-cell type non-Hodgkin's lymphoma. Evidence showing a possible etiological link between HCV and lymphoma has been reported from areas of high HCV prevalence. We describe the case of a 68-year-old woman with B-cell non-Hodgkin's lymphoma mainly involving the skin. Typical manifestations of disease were cutaneous nodules, red-violet in color, scattered on the entire body and adherent to the subcutaneous tissue. A 3-cm nodule excised from the leg was found at histology to consist of centroblastic-like B cells, which stained positively for CD45, CD20 and CD79a. Although the patient was treated with different chemotherapy schedules, she died 1 year later with a diagnosis of disseminated lymphoma. Our report suggests that HCV, a trigger for clonal B-cell proliferation, predisposing to immunological disorders, such as mixed cryoglobulinemia and B-cell malignancies, may also account for the "rare" extranodal high-grade non-Hodgkin's lymphoma. Further observations suggest that treating HCV infection with antiviral therapy could help to prevent the development of B-cell non-Hodgkin's lymphoma.

Familial clustering of (mostly) HCV-related cirrhosis. A case-control study.

BACKGROUND: Increased prevalence of cirrhosis in cirrhotics' families in previous studies. AIMS: To compare the prevalence of cirrhosis in cirrhotics' families with that in families of patients with non-hepatic diseases. METHODS: Case-control study including 500 index cases with cirrhosis and 500 pair-matched controls with chronic non-hepatic diseases, interviewed about cirrhosis in first-degree relatives and spouses using standardized forms. RESULTS: Ninety-three index cases (88% anti-hepatitis C virus (HCV)-positive) and 13 controls had one or more cirrhotics among first-degree relatives and/or spouses (odds ratio (OR) 7.38, 95% confidence interval (CI) 4.21-12.9); cirrhosis was found in 123/4485 first-degree relatives of the index cases and in 16/4086 of controls (OR 7.17 95% CI 4.25-12.09), in 14/467 spouses of the index cases and in 1/416 spouses of controls (OR 12.8, 95% CI 1.67-97.96). The percentage of secondary cases in the families of 440 anti-HCV-positive and 60 anti-HCV-negative index cases was similar (18.8 and 21.6%, respectively). Almost all the secondary cases in families of anti-HCV-positive index cases and none in families of anti-HCV-negative index cases were anti-HCV-positive. CONCLUSIONS: Cirrhosis is significantly more frequent among first-degree relatives and spouses of patients with cirrhosis, mostly HCV-related, than among first-degree relatives and spouses of controls.