Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103/µl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.

Prevalence of Whipple's disease in north-western Italy.

Whipple's disease (WD) is a rare systemic infection due, in genetically susceptible individuals, to Tropheryma whipplei, a heterogeneous Gram-positive actinobacteria. Although it has already been recognised that WD affects mainly middle-aged Caucasian men, the prevalence of WD is virtually unknown. The annual incidence of WD in the general population is said to be less than 1 per 1,000,000, but scientific evidence for these figures is still lacking. On the basis of the number of patients recorded with a diagnosis of Whipple's disease in the regional registers for rare diseases of Lombardia, Liguria and Piemonte-Valle d'Aosta regions, we studied the prevalence of WD in the north-western part of Italy. Forty-six patients with Whipple's disease were recorded in these regions (13 females; mean age at diagnosis 52.1 ± 11.1 years). Since 16,130,725 inhabitants live in these four regions, prevalence of WD in the general population is 3/10(6) and almost 30% of the patients are females. WD is certainly a rare disease but it also affects women in a considerable proportion of cases.

-295 T-to-C promoter region IL-16 gene polymorphism is associated with Whipple's disease.

Whipple's disease (WD) is a rare systemic condition caused, in genetically predisposed subjects, by Tropheryma whipplei, a common bacterium widespread in the environment. The relevance of genetic predisposition in WD is shown by the association with HLA alleles DRB1*13 and DQB1*06 and by the demonstration that, in patients with WD, the cytokine genetic profile is skewed toward a Th2 and Treg response. Since IL-16 is involved in hampering the development of a protective macrophagic response against Tropheryma whipplei, we investigated whether the genetic background of IL-16 is different between patients with WD and controls. The -295 T-to-C polymorphism of the promoter region of the IL-16 gene was studied in 90 patients with WD and 152 healthy controls. Levels of serum IL-16 protein were also tested. The frequency of the wild type T allele was significantly higher in patients with WD compared to the controls (155/180 vs. 235/304; p = 0.02 for the Chi(2) test), odds ratio 1.82 [95 % confidence interval (CI) 1.07-3.10]. The TT genotype was found in 65/90 patients with WD and 88/152 controls (p = 0.026). No relationship was found between serum levels of IL-16 and genotypes. Although the functional consequences of this genetic background on levels of IL-16 and on the course of the disease are still unknown, we found, for the first time, that the wild type T allele and the TT genotype of the -295 polymorphism are associated with WD.

A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

IgA anti-epidermal transglutaminase autoantibodies: a sensible and sensitive marker for diagnosis of dermatitis herpetiformis in adult patients.

BACKGROUND: Dermatitis herpetiformis (DH) is a rare gluten-sensitive blistering itchy skin disease, strictly related to coeliac disease (CD). Direct immunofluorescence, demonstrating IgA granular deposits localized either in the dermal papillae or along the dermo-epidermal junction, is currently the gold standard for diagnosis of DH. It has been shown that DH immunocomplexes contain epidermal transglutaminase (eTG) and that sera from patients with DH contain antibodies specifically directed against eTG. OBJECTIVES: We studied the usefulness of serum eTG antibodies in discriminating between DH, CD and other gastrointestinal and dermatologic diseases. METHODS: eTG antibodies were tested in 308 adult patients' sera: 44 patients with untreated dermatitis herpetiformis (UDH), 99 patients with untreated coeliac disease (UCD), 70 dermatological controls and 95 gastrointestinal controls. RESULTS: In UDH eTG antibody levels were significantly higher than in DH patients on gluten-free diet, UCD, gastrointestinal controls and dermatological controls. In UCD eTG antibodies strongly correlated with tissue transglutaminase (tTG) antibodies, whereas in UDH no significant correlation was observed. CONCLUSION: Serum IgA eTG antibody determination can efficiently distinguish UDH from other dermatological itchy diseases and is highly sensitive to gluten-free diet.

Cytokine genetic profile in Whipple's disease.

Whipple's disease (WD) is a very rare chronic systemic condition characterised by a Th2/T regulatory (Treg) dysregulated immune response versus Tropheryma whipplei, a bacterium widely diffuse in the environment. To investigate whether this Th2/Treg polarised response has a genetic background, we investigated the Th1, Th2, Th17 and Treg cytokine genetic profile of 133 patients with WD. Thanks to the European Consortium on WD (QLG1-CT-2002-01049), the polymorphism of 13 cytokine genes was analysed in 111 German and 22 Italian patients using the polymerase chain reaction with sequence-specific primers (PCR-SSP) technique. The frequencies of the genotypes, haplotypes and functional phenotypes were compared with those obtained in 201 German and 140 Italian controls. Clinical heterogeneity was also considered. Functionally, WD patients may be considered as low producers of TGF-ß1, having an increased frequency of the genotype TGF-ß1+869C/C,+915C/C [12.3 % vs. 3.81 %, odds ratio (OR) = 4.131, p = 0.0002] and high secretors of IL-4, carrying the genotype IL-4-590T/T (5.34 % vs. 1.17 %, OR = 5.09, p = 0.0096). No significant association was found between cytokine polymorphism and clinical variability. Analogously to the recent cellular findings of a Th2/Treg polarised response, we showed that the cytokine genetic profile of WD patients is skewed toward a Th2 and Treg response. This was similar in both German and Italian populations. However, the significant deviations versus the controls are poorer than that expected on the basis of these recent cellular findings.

COVID-19 in celiac disease: a multicentric retrospective cohort study.

OBJECTIVE: Celiac disease (CD) is an autoimmune disorder, characterized by increased susceptibility to bacterial and viral infections. Therefore, the CD patients could be exposed to an increased risk of contracting SARS-CoV-2, a virus for which the WHO declared a pandemic status in March 2020. This study aims to investigate the incidence of SARS-CoV-2 infection in CD patients, to assess the impact of CD on the risk of contracting this virus. PATIENTS AND METHODS: This retrospective multicentric cohort study evaluated 542 celiac patients, who answered a questionnaire concerning both the underlying disease (adherence to the gluten-free diet, residual symptoms) and the possible SARS-CoV-2 infection (swab outcome, presence and characteristics of symptoms and type of treatment received), referring to the period between 20th January 2020 and 27th October 2020. RESULTS: Five patients (0.92%) tested positive; of these, 2 were asymptomatic and 3 developed symptoms of COVID-19. The incidence of SARS-CoV-2 infection in CD patients was not significantly different from the general population. The ratio of positive/diagnostic swabs tends to be higher in CD patients than in the general population (IR: 0.15; 0.06; p=0.06), whereas the number of subjects who performed the swab in this group is significantly lower (IR: 0.06; 0.15; p<0.001). CONCLUSIONS: Although CD patients are more susceptible to infections, the incidence of SARS-CoV-2 infection in our sample was not significantly different from the general population. However, the positive/diagnostic swabs ratio seems to be higher, probably also due to the lower number of patients tested.

Isolation and characterization of circulating tissue transglutaminase-specific T cells in coeliac disease.

Tissue transglutaminase (TG2) was identified as the humoral autoantigen in coeliac disease, but whether it can also serve as T cell autoantigen is still unknown. We aimed, therefore, to firstly explore the presence of TG2-specific T cells in peripheral blood of ten adult patients (four active, i.e. carrying both serological and histological features of the disease; four treated, i.e. with proven mucosal recovery and disappearance of specific antibodies after an adequate period of gluten free diet; and two potential coeliacs, i.e. carrying the serological stigmata of the disease, but not the intestinal lesions), and four healthy controls (two carrying the HLA-DQ2 haplotype of susceptibility to the disease), and secondly to carry out a detailed in vitro characterization of the isolated antigen-specific T cells. T cell lines were first established by means of weekly stimulation with human recombinant TG2 followed by generation of T cell clones through distribution of T cells on plates at one cell/well limiting dilution and further rounds of stimulation. Antigen specificity and HLA-DQ2 restriction were both assessed by evaluating the proliferative response to TG2 in the absence and presence of human sera blocking HLA-DQ2 molecules, after exclusion of impurities in the antigen preparation. Immune phenotyping of T cell clones was performed by flow cytometry, and the expression of IL-1â, IL-4, IL-6, IL-10, IL-12, TGF-beta, IFN-gamma and TNF-alpha was determined by ELISA assay on the supernatants of these clones. A total of 91 T cell clones were isolated from the three HLA-DQ2-positive, active patients, but none from the other patients and controls. The immune phenotyping showed that the majority of them (85.7 percent) were CD3/CD4+ and only a small percentage (14.3 percent) were CD3/CD8+, all carried the TCR alphabeta, and had a memory phenotype. The cytokine profile showed high levels of IFN-gamma and IL-6 that, together with the absence of IL-4, placed these T cell clones in the T helper type 1-like category. Further in vitro analysis was carried out on 32/91 CD4+ clones and showed a specific and dose-dependent proliferative response towards TG2 and an HLA-DQ2 restriction. Finally, when incubating duodenal mucosal specimens of treated patients with the supernatant of TG2-specific T cell clones, characteristic disease lesions were found, indicating a role for TG2-specific cellular immune response in the pathogenesis of coeliac disease.

Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease.

BACKGROUND AND AIMS: Interleukin 17 (IL17) is now known to be involved in a number of chronic inflammatory disorders. However, the mechanisms regulating its production in inflammatory bowel disease (IBD) are still unclear. METHODS: Endoscopic biopsies or surgical specimens were taken from inflamed and uninflamed colonic mucosa of 72 patients with IBD (38 with Crohn's disease and 34 with ulcerative colitis), and normal colon of 38 control subjects. IL17 and interferon gamma (IFNgamma) were detected by ELISA in the supernatants of biopsies cultured ex vivo, and anti-CD3/CD28-stimulated lamina propria mononuclear cells (LPMCs) incubated with IL12, IL23, IL1beta plus IL6, transforming growth factor beta1 (TGFbeta1), or anti-IL21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells. RESULTS: IL17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFNgamma. Anti-CD3/CD28-stimulated IBD LPMCs produced higher IL17 amounts compared to controls. The percentages of Th17 and Th1/Th17 cells were increased in patients with IBD. IL23 and IL1beta plus IL6 had no effect on IBD LPMC production of IL17; however, IL12 markedly increased IFNgamma production and decreased IL17 production. TGFbeta1 dose-dependently decreased IFNgamma, but had no significant inhibitory effect on IL17 production. Blocking IL21 significantly downregulated IL17 production. CONCLUSIONS: Our findings support a role for IL12, TGFbeta and IL21 in modulating IL17/IFNgamma production in IBD. The abundant IL17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFNgamma antibodies in clinical trials of Crohn's disease.

Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures.

BACKGROUND AND AIMS: In addition to its crucial role in dampening tissue-damaging immune responses in the gut, transforming growth factor beta (TGFbeta) is a potent profibrogenic agent inducing collagen synthesis and regulating the balance between matrix-degrading matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). TGFbeta signalling was investigated by analysis of Smad proteins and MMPs/TIMPs in the mucosa overlying strictures in patients with Crohn's disease (CD). METHODS: Specimens were collected from macroscopically normal mucosa overlying strictured and non-strictured gut of patients with fibrostenosing CD. Isolated myofibroblasts were cultured with anti-TGFbeta blocking antibody or TGF beta 1. TGFbeta transcripts were analysed by quantitative reverse transcription-PCR (RT-PCR). Smad proteins and MMPs were determined by immunoblotting. MMP-12 activity was measured by a real-time MMP-12 activity assay. An in vitro wound-healing scratch assay was used to assess myofibroblast migration. RESULTS: TGFbeta transcripts, phosphorylated Smad2-Smad3 (pSmad2-3) and TIMP-1 proteins were higher in mucosa overlying strictures than in mucosa overlying non-strictured areas. In contrast, mucosa overlying strictured gut had lower expression of Smad7, MMP-12 and MMP-3. Myofibroblasts from mucosa overlying strictured gut showed higher TGFbeta transcripts, a greater pSmad2-3 response to TGFbeta, increased TIMP-1, lower Smad7, increased collagen production and reduced migration ability compared with myofibroblasts from mucosa overlying non-strictured gut. TGFbeta blockade increased myofibroblast MMP-12 production and migration, more obviously in myofibroblasts isolated from mucosa overlying non-strictured compared with strictured gut. CONCLUSIONS: Changes in TGF-beta signalling and MMP production were identified in the mucosa overlying strictures in CD which may give a window into the process of fibrosis.

mTOR sustains inflammatory response in celiac disease.

Celiac disease (CD) is an enteropathy triggered by the ingestion of gluten proteins in genetically predisposed individuals and characterized by excessive activation of effector immune cells and enhanced production of inflammatory cytokines. However, factors/mechanisms that amplify the ongoing mucosal inflammation in CD are not fully understood. In this study, we assessed whether mammalian target of Rapamycin (mTOR), a pathway that combines intra- and extra-cellular signals and acts as a central regulator for the metabolism, growth, and function of immune and non-immune cells, sustains CD-associated immune response. Our findings indicate that expression of phosphorylated (p)/active form of mTOR is increased in protein lysates of duodenal biopsy samples taken from patients with active CD (ACD) as compared to normal controls. In ACD, activation of mTOR occurs mainly in the epithelial compartment and associates with enhanced expression of p-4EBP, a downstream target of mTOR complex (mTORC)1, while expression of p-Rictor, a component of mTORC2, is not increased. Stimulation of mucosal explants of inactive CD patients with pepsin-trypsin-digested (PT)-gliadin or IFN-γ/IL-21, two cytokines produced in CD by gluten-specific T cells, increases p-4EBP expression. Consistently, blockade of such cytokines in cultures of ACD mucosal explants reduces p-4EBP. Finally, we show that inhibition of mTORC1 with rapamycin in ACD mucosal explants reduces p-4EBP and production of IL-15, a master cytokine produced by epithelial cells in this disorder. Our data suggest that ACD inflammation is marked by activation of mTORC1 in the epithelial compartment.

Complete long-term response to radiotherapy of gastric early-stage marginal zone lymphoma resistant to both anti-Helicobacter pylori antibiotics and chemotherapy.

BACKGROUND: The optimal approach to patients with gastric lymphoma of extranodal mucosa-associated lymphoid tissue (MALT) that resist to anti-Helicobacter pylori (HP) eradication therapy is still to be defined. PATIENTS AND METHODS: From January 1997 to December 2004, we observed 24 patients affected with newly diagnosed early-stage and HP-positive gastric lymphoma of the MALT type. Five of them resisted to oral anti-HP antibiotic regimens and to subsequent one (two patients) or two (three patients) chemotherapy regimens. Age ranged between 51 and 77 years (median 70); three were females. Translocation (11;18) was ascertained in one subject. They were admitted to local radiation therapy with a total dose of 30 Gy. RESULTS: All such resistant patients achieved complete remission after radiotherapy. No relapses were observed after 21, 45, 48, 52, and 67 months of uninterrupted follow-up. Early toxicity was very low and consisted of mild nausea. Late toxicity or secondary malignancy was not recorded so far. CONCLUSIONS: Radiotherapy proved to be effective and safe for early-stage HP-positive gastric extranodal lymphoma of MALT type that is resistant to anti-HP eradication antibiotics and to following chemotherapy. Radiotherapy might be suggested as principal salvage therapy after resistance to HP eradication, instead of chemotherapy.

Blockade of transforming growth factor beta upregulates T-box transcription factor T-bet, and increases T helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa.

BACKGROUND AND AIMS: The role of transforming growth factor beta (TGFbeta) in inhibiting T cell function in the normal gut has been studied in animal models. However, the impact of TGFbeta inhibition on T cells in the normal human gut remains poorly understood. The effect of TGFbeta blockade in normal intestinal biopsies grown ex vivo and lamina propria mononuclear cells (LPMCs) on T-bet, a T-box transcription factor required for T helper cell type (Th)1 differentiation, interferon gamma (IFN gamma) production, T cell apoptosis and matrix metalloproteinase (MMP)-3 production has therefore been tested. METHODS: TGFbeta transcripts were determined by quantitative reverse transcription-PCR in laser-captured gut epithelium and lamina propria. Biopsies and LPMCs were cultured with anti-TGFbeta neutralising antibody. After 24 h culture, T-bet was determined by immunoblotting, and T cell apoptosis was assessed by flow cytometry. IFN gamma, tumour necrosis factor alpha (TNFalpha), interleukin (IL) 2, IL6, IL8, IL10, IL12p70 and IL17 were measured by ELISA. MMP-3 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were assessed by immunoblotting. RESULTS: A higher number of TGFbeta transcripts was found in the lamina propria than in the epithelium in normal gut. T-bet expression was significantly higher in biopsies and LPMCs cultured with anti-TGFbeta antibody than in those cultured with control antibody. TGFbeta blockade downregulated T cell apoptosis, and induced a significant increase in IFN gamma, TNFalpha, IL2, IL6, IL8 and IL17 production. A higher expression of MMP-3, but not TIMP-1, was observed in the tissue and supernatant of biopsies treated with anti-TGFbeta antibody. CONCLUSIONS: The findings support a crucial role for TGFbeta in dampening T cell-mediated tissue-damaging responses in the human gut.

Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma.

BACKGROUND: A large amount of evidence suggests a possible role of interleukin-6 (IL-6) in the pathogenesis of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We studied both IL-6 and A(1)FP in patients with HCC, non-neoplastic liver disease or in healthy controls. RESULTS: IL-6 titers were four-fold higher in cancer than in cirrhotic patients and 25-fold higher than in healthy controls. As for alpha1-fetoprotein (A(1)FP) titers, the highest levels were observed in cancer patients. Receiver operating characteristic (ROC) curves analysis demonstrated that IL-6 is significantly more discriminant than A(1)FP, with 'optimal' cut-off values of 7.9 pg/ml (sensitivity = 0.83, specificity = 0.83, efficiency = 0.83). The ROC curves used to distinguish HCC from cirrhotic patients only, showed higher discriminant power of IL-6 versus A(1)FP titers, with a new cut-off value of 12 pg/ml (sensitivity = 0.73, specificity = 0.87, efficiency = 0.8). Discriminant analysis on HCC and non-HCC subjects yielded sensitivity, specificity and efficiency rates of 77%, 93% and 88%, respectively. The overall efficiency of the two tests combined was 82%. CONCLUSIONS: IL-6 could be considered a promising tumor marker for HCC. In particular, the diagnostic value of the test is significantly increased when combined with A(1)FP.

The incidence of coeliac disease in adult first degree relatives.

BACKGROUND AND AIMS: Although prevalence of coeliac disease among first degree relatives of coeliac patients is well-known, only four studies are available about its incidence. We investigated whether first degree relatives found to be negative at a first serological screening can subsequently develop coeliac disease. PATIENTS AND METHODS: In the last 6 years, endomysial antibodies were tested in 158 adult first degree relatives referred to our coeliac out-patient clinic. After at least a year, negative subjects were offered a second testing. Sixty-three accepted. RESULTS: 130/158 first degree relatives tested negative initially. Although one of them had developed coeliac disease after the first testing, at the second testing none of the 63 endomysial antibody negative first degree relatives proved positive. Incidence of coeliac disease among first degree relatives was 1/64 in 51 months, 0.437% year (95%CI 0.05-2.62). An analysis of the sample size showed that 10,000 first degree relatives must be followed up to significantly reduce the CI. CONCLUSIONS: Although we confirmed the high prevalence of coeliac disease among first degree relatives (28/158, 17.7%), we found that the low incidence suggests that further studies are required to understand whether endomysial antibody negative first degree relatives need to be followed up.

Disability, and not diabetes, is a strong predictor of mortality in oldest old patients hospitalized with pneumonia.

BACKGROUND: Pneumonia causes more deaths than any other infectious disease, especially in older patients with multiple chronic diseases. Recent studies identified a low functional status as prognostic factor for mortality in elderly patients with pneumonia while contrasting data are available about the role of diabetes. The aim of this study was to evaluate the in-hospital, 3-month and 1-year mortality in elderly subjects affected by pneumonia enrolled in the RePoSi register. METHODS: We retrospectively analyzed the data collected on hospitalized elderly patients in the frame of the REPOSI project. We analyzed the socio-demographic, laboratory and clinical characteristics of subjects with pneumonia. Multivariate logistic analysis was used to explore the relationship between variables and mortality. RESULTS: Among 4714 patients 284 had pneumonia. 52.8% were males and the mean age was 80 years old. 19.8% of these patients had a Barthel Index ≤40 (p ˂ 0.0001), as well as 43.2% had a short blessed test ≥10 (p ˂ 0.0117). In these subjects a significant CIRS for the evaluation of severity and comorbidity indexes (p ˂ 0.0001) were present. Although a higher fasting glucose level was identified in people with pneumonia, in the multivariate logistic analysis diabetes was not independently associated with in-hospital, 3-month and 1-year mortality, whereas patients with lower Barthel Index had a higher mortality risk (odds ratio being 9.45, 6.84, 19.55 in hospital, at 3 and 12 months). CONCLUSION: Elderly hospitalized patients affected by pneumonia with a clinically significant disability had a higher mortality risk while diabetes does not represent an important determinant of short and long-term outcome.

UFT as maintenance therapy in patients with advanced colorectal cancer responsive to the FOLFOX4 regimen.

BACKGROUND: In advanced colorectal cancer (ACC), FOLFOX4 has been accepted as a standard chemotherapeutic regimen. Due to the neurotoxicity induced by oxaliplatin, which occurs in about 50% of patients during the 6-month FOLFOX4 regimen, and the frequent need for hospitalization, alternative regimens may be required. We aimed to determine whether a 'maintenance' therapy with oral UFT (uracil-tegafur) in patients responding to FOLFOX4 is able to maintain the response and improve the quality of life (QoL) as a result of the outpatient regimen and lower psychological distress. METHODS: Untreated patients with ACC who did not progress after 6 months of FOLFOX4 received oral UFT until disease progression or unacceptable toxicity. The aim of the study was to maintain the response obtained with the FOLFOX4 regimen for at least 6 months. The secondary objective was to evaluate QoL during the two different treatment regimens utilizing the 36-item Short Form Health Survey (SF-36). RESULTS: From January 2003 to August 2004, out of the enrolled 30 patients [22 males and 8 females; 2 patients with a complete response (CR), 14 patients with a partial response (PR) and 6 patients in stable disease (SD) after 6 months of FOLFOX4] 22 continued therapy with UFT until progression without significant toxicity; the remaining 8 patients (27%) had progressive disease (PD) during or at the end of FOLFOX4 and were treated with other regimen. After 6 months of UFT, 4 patients (13%) had CR, 6 patients (20%) PR and 4 patients (13%) SD; 16 patients (53%) progressed. Median follow-up was 31 months [interquartile range (IQR): 20-31 months]; 14 patients died of PD. The median time to progression was 13.9 (IQR: 7.7-20.1) months and the median survival time was 31 months (IQR: 20-31 months). Evaluation of QoL demonstrated a trend towards better QoL during UFT treatment. CONCLUSIONS: These results support the feasibility of maintaining good response and improving QoL (measured by SF-36) with an oral fluoropyrimidine after combination chemotherapy in ACC patients; moreover, since UFT can be used orally, patient compliance is increased and the duration of hospitalization can be decreased.

Visceral hypersensitivity and intolerance symptoms in lactose malabsorption.

Lactose malabsorption is not always associated with intolerance symptoms. The factors responsible for symptom onset are not yet completely known. As differences in visceral sensitivity may play a role in the pathogenesis of functional symptoms, we evaluated whether an alteration of visceral sensitivity is present in subjects with lactose intolerance. Thirty subjects, recruited regardless of whether they were aware of their capacity to absorb lactose, underwent an evaluation of intestinal hydrogen production capacity by lactulose breath test, followed by an evaluation of lactose absorption by hydrogen breath test after lactose administration and subsequently an evaluation of recto-sigmoid sensitivity threshold during fasting and after lactulose administration, to ascertain whether fermentation modifies intestinal sensitivity. The role of differences in gastrointestinal transit was excluded by gastric emptying and mouth-to-caecum transit time by (13)C-octanoic and lactulose breath tests. Lactulose administration induced a significant reduction of discomfort threshold in subjects with lactose intolerance but not in malabsorbers without intolerance symptoms or in subjects with normal lactose absorption. Perception threshold showed no changes after lactulose administration. Severity of symptoms in intolerant subjects was significantly correlated with the reduction of discomfort thresholds. Visceral hypersensitivity should be considered in the induction of intolerance symptoms in subjects with lactose malabsorption.

New agents in medical oncology and the risk of venous thromboembolism.

Over the past several years the medical approach to cancer patients has made important steps forward both in the field of novel, selective, antiproliferative agents and more effective supportive therapies. A greater understanding of the molecular pathways regulating cell proliferation and metastasis has led to the identification of a range of targets specifically inhibited by these new drugs. The clinical development of these compounds (the so called "targeted therapies") has shown distinctive adverse effects with respect to standard chemotherapeutic agents but the potential increasing risk of venous thromboembolism remains unvaried. In fact, the incidence of this potentially life-threatening complication in patients receiving standard chemotherapy ranges from about 11% to 20% and even more depending on the type of drug administered and on the possible association with other anti-neoplastic and supportive therapies. In this paper we reviewed all the available evidences concerning the increasing risk of venous thromboembolism in cancer patients during treatment with new agents currently used in medical oncology together with data concerning the clinical value of a concomitant prophylactic anticoagulation. At present, additional information concerning safety in terms of thromboembolic risk of novel biological and molecular therapies should be collected from specifically designed original basic science studies and clinical trials in order to optimize their use in current oncology practice.