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Background and Aims Intestinal ultrasound [IUS] is widely accepted as a reliable tool to monitor Crohn’s disease [CD]. Several IUS scores have been proposed, but none has been formally accepted by international organizations. Our aim here was to compare the available scores regarding their correlation with endoscopic activity. Methods Consenting CD patients undergoing ileocolonoscopy at our Unit between September 2021 and February 2023 were included. Endoscopic activity was defined as SES-CD ≥ 3 or Rutgeerts score ≥ i2b for operated patients. IUS was performed within 6 weeks of endoscopy and scored with IBUS-SAS, BUSS, Simple-US and SUS-CD scores. All correlations were performed using Spearman’s rank coefficient [rho = ρ]. Receiver operating characteristic [ROC] curves were compared with the Hanley and McNeil method. Results Of 73 CD patients, 45 [61.6%] presented endoscopic activity, of whom 22 were severe [30.1%]. All IUS scores showed a significant positive correlation with endoscopy [p Conclusions All IUS scores provided solid correlation with endoscopy and clinical symptoms. IBUS-SAS outperformed the others due to a more granular description that might help in stratifying different levels of disease activity. Therefore, the use of IBUS-SAS in centres with well-founded expertise in IUS can be suggested.

Inflammatory bowel disease (IBD) can affect young and reproductively active patients. Our aim was to analyze pregnancy outcomes in a large cohort of women with IBD.All women with at least one pregnancy were given a questionnaire regarding the outcome of their pregnancy. They were divided into IBD pregnancies and controls depending on whether pregnancy occurred within or over 10 years prior to the diagnosis of IBD.Three hundred questionnaires were analyzed for a total of 478 pregnancies that led to live-born babies. Age at conception was older in IBD women than in the controls. Active smoking was more frequent in the control group. The risk of intrauterine growth restriction (IUGR) was higher in IBD pregnancies (odds ratio [OR] 3.028, 95% confidence interval [CI] 1.245-7.370, P = 0.013). The week of gestation at delivery was lower in the IBD population. And the risk of cesarean section was higher in IBD pregnancies (OR 1.963, 95% CI 1.274-3.028, P = 0.002). Among women with IBD pregnancy, the risk of preterm birth was higher in patients with active disease at the time of conception (OR 4.088, 95% CI 1.112-15.025, P = 0.030), but lower in patients who continued regular therapy during pregnancy. Similarly, the risk of urgent cesarean section was reduced in the case of disease remission, while the risk of a planned cesarean delivery was higher in patients with perianal disease (OR 11.314, 95% CI 3.550-36.058, P 0.01).Our study shows a higher risk of IUGR, cesarean section, and poor blood pressure control in IBD pregnancies. We emphasize the importance of achieving disease remission before considering pregnancy.

Background Few data are currently available about SB5 in inflammatory bowel diseases (IBD). The aim of this study was to assess the effectiveness and safety of SB5 in a cohort of patients with IBD in stable remission switched from the adalimumab (ADA) originator and in a cohort of patients with IBD naïve to ADA. Methods We prospectively enrolled patients with IBD who started ADA treatment with SB5 (naïve cohort) and those who underwent a nonmedical switch from the ADA originator to SB5 (switching cohort). Clinical remission and safety were assessed at baseline and at 3, 6, and 12 months. In addition, in a small cohort of patients who were switched, we assessed the ADA serum trough levels and antidrug antibodies at baseline, 3, and 6 months. Results In the naïve cohort, the overall remission rate at 12 months was 60.42%, whereas in the switching cohort it was 89.02%. Fifty-three (36.3%) patients experienced an adverse event, and injection site pain was the most common; it was significantly more frequent in the switching cohort (P = 0.001). No differences were found in terms of ADA serum trough levels at baseline, 3, and 6 months after switching. No patient developed antidrug antibodies after the switch. Conclusions We found that SB5 seemed effective and safe in IBD, both in the naïve cohort and in the switching cohort. Further studies are needed to confirm these data in terms of mucosal healing.

Presenilin1 (PSEN1) gene is the most common known genetic cause of early-onset familial Alzheimer's disease. We describe an Italian family with the known p.Ala260Gly mutation in PSEN1 gene. The presence of an asymptomatic 64-year-old male carrying the mutation provides evidence of a possible incomplete penetrance leading to a wider range of age at onset. In order to evaluate whether or not epigenetic modifications could contribute to the phenotypic heterogeneity, we assessed global DNA methylation levels which resulted significantly higher in the three females than in their presymptomatic brother. The study suggests that DNA methylation can contribute to slowing down or possibly protecting from the manifestation of symptoms even in monogenic diseases, emphasizing the great complexity of familial Alzheimer's disease.

Vedolizumab is a gut-selective anti-integrin (α4β7) antibody for the treatment of inflammatory bowel disease with a well-known optimal safety profile. We aimed to compare its risk of infections with that of anti-TNF drugs and ustekinumab in patients with both ulcerative colitis and Crohn's disease.All Crohn's disease and ulcerative colitis patients undergoing biological treatment at our centre between 2013 and 2019 were retrospectively included. All infectious complications were registered, considering both inpatient and outpatient events. A comparison of the exposure-adjusted infection rates of vedolizumab, anti-TNF drugs and ustekinumab was carried out, with a specific focus on the rate of gut infections. All infection rates were expressed in events per patient-years (PYs).The overall exposure-adjusted infection rate was 11.5/100 PYs. The most common infections were respiratory tract infections, cutaneous infections, HSV infections/reactivations and gut infections. The rate of serious infections was 1.3/100 PYs. The infection rate of vedolizumab was 17.5/100 PYs, with Crohn's disease patients having a lower infection risk compared with ulcerative colitis patients (P = 0.035). Gut infections were observed in 3.0% of the whole patient population (1.5/100 PYs) and were more common in the vedolizumab group (P = 0.0001).Our study confirms the good safety profile of vedolizumab. Among patients treated with vedolizumab, those with ulcerative colitis have a higher risk of developing infectious complications. Patients treated with vedolizumab have a higher risk of gut infections compared with patients treated with anti-TNF drugs or ustekinumab. Presumably, this is due to the gut-selective mechanism of action of vedolizumab.

Background Acute severe ulcerative colitis (ASUC) is a potentially life-threatening disease, and the best option in cases of steroid-refractory disease is still debated. We compared the early- and long-term efficacy and safety of the 2 available "rescue therapies", infliximab (IFX) and cyclosporine (CYS), in this setting. Methods We retrospectively evaluated patients admitted for ASUC and treated with "rescue therapy". The primary endpoint was early colectomy-free survival (30 days) and colectomy-free survival until the end of follow up. The secondary endpoints were predictors of colectomy and long-term maintenance of the treatment strategy over time. Results Of 129 patients admitted, 68 received rescue therapy (47 with IFX), whereas 7 underwent early colectomy (10.3%). At 30 days, fewer patients treated with IFX showed a need for colectomy (8.5% vs. 14.3%) compared to those in the CYS group, though the difference was non-significant (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.10-4.69; P=0.47). No severe side effects due to IFX and CYS were observed. During a mean follow up of 40 months, 23 additional patients (37.7%) underwent colectomy, and the rate was significantly lower in the IFX group (25.6%) than in the CYS group (66.7%) (hazard ratio 0.25, 95%CI 0.10-0.61; P=0.003). Colectomy-free survival was significantly higher in the IFX group than in the CYS group (P=0.018) at 12 months. Conclusions In our setting, the early outcomes of IFX and CYS for ASUC were comparable. IFX was associated with significantly lower colectomy rates during the observation period and had a similar safety profile to CYS.

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Background and purpose CLOCK and PER2 genes have been implicated in sleep-wake cycle alterations and neurodegenerative diseases. Our aim was to evaluate the effect of CLOCK T3111C and PER2 C111G on cognitive functioning in subjective cognitive decline (SCD) patients and mild cognitive impairment (MCI) patients at the baseline of a longitudinal study, and the effect of these two polymorphisms on the progression to Alzheimer's disease (AD) of the two groups. Methods Sixty-eight subjects (41 SCD and 27 MCI) who underwent clinical evaluation, neuropsychological assessment, CLOCK and PER2 genotyping at baseline and neuropsychological follow-up every 2 years for a mean time of 10 years were included. Subjects who developed AD (SCD-c and MCI-c) and non-converters (SCD-nc, MCI-nc) were considered. Results CLOCK T3111C was detected in 47% of cases (21 SCD, 11 MCI) and PER2 C111G in 19% of cases (eight SCD and five MCI). PER2 G carriers presented lower premorbid intelligence score (P = 0.049), fewer years of education (P = 0.007) and a lower frequency of family history of AD (P = 0.04) than G non-carriers. MCI PER2 G carriers had worse performance in tests assessing memory, executive function, language and visuospatial abilities at baseline. During follow-up, two SCD and 15 MCI subjects progressed to AD: both of the SCD-c subjects presented the PER2 G allele, while none of the SCD PER2 G non-carriers converted to AD (P = 0.003). Conclusion PER2 seems to have a role in cognitive reserve and cognition in SCD and MCI patients. Nevertheless, further studies are needed to assess the role of PER2 C111G on the risk of progression to AD.

OBJECTIVE To evaluate the efficacy and safety of golimumab in biological naive and experienced patients with moderately to severely active ulcerative colitis (UC) treated at two Italian IBD centers. METHODS We retrospectively reviewed our prospectively maintained UC database from March 2015 to March 2017. Patients received golimumab 200 mg at week 0, 100 mg at week 2, then 50 mg or 100 mg every 4 weeks. Follow-up was recorded at 12 and 24 weeks and in March 2017, with a median follow-up of 64 weeks. The main outcomes evaluated were clinical remission (CR) and adverse event rates. RESULTS Of the 59 patients (44% naive and 56% experienced), CR rate was 47% at 12-week follow-up, 55% (among the 49 patients on treatment) at 24-week follow-up and 49% (among 35 patients on treatment) at the last follow-up visit. Median treatment duration was 52 weeks (interquartile range 30-64 weeks) among patients treated for >6 months. Overall, 10 (17%) patients experienced adverse events, of whom 50% discontinued treatment. The most frequent adverse events were infections. Biological naive and experienced patients did not differ in terms of CR and adverse event rates. CONCLUSIONS Our real-life experience showed that CR decreased over time and was achieved by almost one-third of the cohort at the last follow-up visit. Golimumab showed an overall favorable safety profile and the results were not different between biological naive and experienced patients. Future research is needed to confirm our results and to identify criteria to select patients most likely to respond.

Background and aim We aimed to evaluate the outcome of patients with acute severe ulcerative colitis previously exposed to immunosuppressive (IMS) therapy. Methods We retrospectively collected data from 86 consecutive patients from 2008. Early outcome was evaluated as response to steroids, rescue therapy, and colectomy rate, whereas colectomy free-survival was determined along the follow-up. Results The overall response rates to steroids and rescue therapy was 33.7% and 90.5%, respectively, while early colectomy rate was 22.1%. Patients previously treated with IMS (n = 47) showed a trend towards lower response to steroids (25.5% vs 43.6%; p = 0.10), and a high-risk of early colectomy (29.8% vs 12.8%; p = 0.07), but a similar response to rescue therapy (87.5% vs 94.4%, p = 0.62) when compared with IMS-naive patients (n = 39). The overall cumulative probability to avoid the surgery was 67.5% and 56.6% at 12 and 60 months, respectively, regardless of previous exposure to IMS (p = 0.30). At multivariate analysis the risk of early colectomy was increased by previous IMS (OR 5.16, p = 0.017), anaemia (OR 4.26, p = 0.02), and diagnosis above 40 years (OR 5.31, p = 0.011). Conclusions Patients previously treated with IMS showed a non-significant trend towards a worse response with steroid therapy, a satisfactory response rate to rescue therapy, and a similar probability of avoiding colectomy during the follow-up vs IMS-naive patients.

Laparoscopic rectal surgery has demonstrated its superiority over the open approach, however it still has some technical limitations that lead to the development of robotic platforms. Nevertheless the literature on this topic is rapidly expanding there is still no consensus about benefits of robotic rectal cancer surgery over the laparoscopic one. For this reason a review of all the literature examining robotic surgery for rectal cancer was performed. Two reviewers independently conducted a search of electronic databases (PubMed and EMBASE) using the key words "rectum", "rectal", "cancer", "laparoscopy", "robot". After the initial screen of 266 articles, 43 papers were selected for review. A total of 3013 patients were included in the review. The most commonly performed intervention was low anterior resection (1450 patients, 48.1%), followed by anterior resections (997 patients, 33%), ultra-low anterior resections (393 patients, 13%) and abdominoperineal resections (173 patients, 5.7%). Robotic rectal surgery seems to offer potential advantages especially in low anterior resections with lower conversions rates and better preservation of the autonomic function. Quality of mesorectum and status of and circumferential resection margins are similar to those obtained with conventional laparoscopy even if robotic rectal surgery is undoubtedly associated with longer operative times. This review demonstrated that robotic rectal surgery is both safe and feasible but there is no evidence of its superiority over laparoscopy in terms of postoperative, clinical outcomes and incidence of complications. In conclusion robotic rectal surgery seems to overcome some of technical limitations of conventional laparoscopic surgery especially for tumors requiring low and ultra-low anterior resections but this technical improvement seems not to provide, until now, any significant clinical advantages to the patients.

Background There is no consensus on the leading causes of death among inflammatory bowel diseases (IBD) patients. Aim We present the results of an extended follow-up of the population-based Florence IBD cohort, including 689 ulcerative colitis and 231 Crohn's disease patients. Methods The causes of death of cohort members were determined through linkage with the local mortality registry. We calculated standardized mortality ratios (SMR) and 95% confidence intervals (95%CI) by applying gender-, age- and calendar time–death rates to person-years at risk. Results Ulcerative colitis patients had overall mortality comparable to the general population (SMR 0.99, 95%CI 0.85–1.14), though being at increased risk of dying from Hodgkin's disease (SMR 11.74, 95%CI 2.94–46.94), rectal cancer (SMR 3.69, 95%CI 1.66–8.22) and Alzheimer's disease (2.40, 95%CI 1.00–5.76). Crohn's disease patients had an increased overall mortality (SMR 1.79, 95%CI 1.39–2.27) and were at higher risk of dying from cancer (SMR 2.57, 95%CI 1.28–5.13) and non-cancer diseases of the respiratory system (SMR 2.51, 95%CI 1.05–6.04), brain cancer (SMR 6.26, 95%CI 1.57–25.02) and non-cancer diseases of the genitourinary system (SMR 4.38, 95%CI 1.10–17.52). Conclusions IBD patients should be offered counselling on risk reduction strategies, as much of their mortality excess is potentially avoidable.

BACKGROUND The disease course and colectomy rate of ulcerative colitis (UC) vary largely in population-based and referral center cohorts. We retrospectively evaluated our cohort to determine the disease course and risk factors for colectomy. METHODS A cohort of 1723 ulcerative colitis patients (986 males; mean age, 34.8 ± 15.4 yrs) were identified and followed since 1960s for a mean of 11 ± 9 years (range, 1-49 yrs). RESULTS The disease extension was classified as E1, E2, and E3 on diagnosis at 19.7%, 54.2%, and 26.1% of patients, respectively. At the final follow-up, the disease extension increased in 20% of the cases. Extraintestinal manifestations (EIMs) were reported by 11% of the patients, whereas systemic corticosteroids (CS), IM or anti-TNFα agents were used by 68.6%, 20.4%, and 6.4% of patients, respectively. The crude colectomy rate was 7% (120 pts), with a 1.2% rate (n = 21) at 1 year from diagnosis (95% CI, 0.7-1.7) and a Kaplan-Meyer estimation of up to 18.2% after 30 years of follow-up. The 1-year colectomy rate showed no significant difference through the decades, whereas the 5-year and 10-year absolute value of colectomy was halved in the last 2 decades compared with the period from 1960 to 1990 (P = 0.01), with a general trend of a reduced colectomy rate at survival curves (P = 0.056). CONCLUSIONS The colectomy rate was low in our cohort and further reduced in the last 2 decades. However, despite the availability of anti-TNFα agents, no further significant reduction of colectomies was observed in the last decade.

Objective The study aimed to evaluate the long-term efficacy and safety of vedolizumab in a real-life cohort of patients with inflammatory bowel diseases enrolled at a tertiary referral center. Methods Data were retrospectively collected from August 2016 to November 2018. The primary outcomes were clinical response and remission at 14, 24, and 52 weeks, and steroid-free remission rate (SFRR) at 52 weeks. Endoscopic response and remission rates at 52 weeks were the secondary outcomes. Results Altogether 49 patients (22 with ulcerating colitis [UC] and 27 with Crohn's Disease [CD]) were enrolled. The clinical response rate gradually dropped from 85% and 50% in CD and UC, respectively, at week 14 to 59% and 25% at week 52, with significantly a higher response in CD at week 14. The endoscopic response at week 52 was 55% in CD and 25% in UC (P = 0.21). CD group had a higher SFRR than UC group (41% vs 20%) at 52 weeks, although the difference was not statistically significant. Similar clinical and endoscopic rates were observed in biologic-naive and -experienced patients. We reported no discontinuation due to adverse drug reactions, and only mild to moderate events. Conclusions In our cohort the clinical response in the induction phase was similar to those of registered trials, despite surprising better results for CD. During the maintenance phase we observed an higher drop out than in the reported literatures. Of note, its good safety profile makes vedolizumab a reliable choice in patients with contraindications to anti-tumor necrosis factor agents.

Background and purpose Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. Methods We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. Results We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (similar to 80% of patients), urinary urgency (similar to 30%) and pyramidal signs (similar to 70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. Conclusions The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

To evaluate the efficacy and safety of golimumab in biological naive and experienced patients with moderately to severely active ulcerative colitis (UC) treated at two Italian IBD centers.We retrospectively reviewed our prospectively maintained UC database from March 2015 to March 2017. Patients received golimumab 200 mg at week 0, 100 mg at week 2, then 50 mg or 100 mg every 4 weeks. Follow-up was recorded at 12 and 24 weeks and in March 2017, with a median follow-up of 64 weeks. The main outcomes evaluated were clinical remission (CR) and adverse event rates.Of the 59 patients (44% naive and 56% experienced), CR rate was 47% at 12-week follow-up, 55% (among the 49 patients on treatment) at 24-week follow-up and 49% (among 35 patients on treatment) at the last follow-up visit. Median treatment duration was 52 weeks (interquartile range 30-64 weeks) among patients treated for6 months. Overall, 10 (17%) patients experienced adverse events, of whom 50% discontinued treatment. The most frequent adverse events were infections. Biological naive and experienced patients did not differ in terms of CR and adverse event rates.Our real-life experience showed that CR decreased over time and was achieved by almost one-third of the cohort at the last follow-up visit. Golimumab showed an overall favorable safety profile and the results were not different between biological naive and experienced patients. Future research is needed to confirm our results and to identify criteria to select patients most likely to respond.

Background Hypersensitivity reactions (HRs) and loss of response (LOR) to infliximab (IFX) are related to drug immunogenicity characterized by antidrug antibodies (ADAs). Objective To analyze the timing of ADA appearance and its relationship with drug levels and clinical outcomes in IFX-treated patients with different diseases. Methods Samples were longitudinally collected before each infusion from 91 IFX-treated patients and were assayed for ADA and drug levels by enzyme-linked immunosorbent assay and for IgE by ImmunoCAP system. Clinical data regarding efficacy and safety of therapy were also monitored. Results The ADA onset occured quite early, irrespective of the type of disease, during the first year and more frequently and earlier during the second cycle of therapy. Patients with HR were more frequently ADA-positive and with higher ADA titers compared with other patient groups. ADA onset tends to precede HRs and LOR; all HRs that occur after a period of drug interruption are preceded by ADA development. Before ADA detection, a progressive decline in IFX levels until a complete disappearance was observed. The ADA titer was maintained for years both in patients with ongoing therapy and in those who interrupted it. IgE ADAs are more frequently developed in patients with higher ADA levels and earlier ADA onset, but their rate of negativization is faster. Conclusion The present data suggest that most IFX-exposed patients develop ADAs within the first year of treatment irrespective of disease type. The clinical outcome to the treatment is preceded by ADA development, which in turn is associated with the reduction in drug serum levels. Both ADA evaluation and therapeutic drug monitoring may have a relevant impact on clinical practice, giving new insights to predict LOR and HRs.

Introduction: Corticosteroids are still the mainstay of treatment in patients with active ulcerative colitis (UC) refractory to mesalamine (5-aminosalicylic acid, 5-ASA), but their benefits are offset by the frequent occurrence of adverse events. In recent years, new corticosteroid molecules have been developed combining an oral controlled-release formulation, high affinity for the corticosteroid receptor and a rapid first-pass liver metabolism.Areas covered: Oral beclomethasone (BOH) is an example of these oral locally acting steroids used in inflammatory bowel diseases and this review will focus on its efficacy in UC. Beclomethasone dipropionate (BDP) is a prodrug that is activated and metabolised locally, available as topical and oral formulation. BDP enema is equally effective as first-generation corticosteroids enemas but has a better safety profile. Topical combination of BDP and 5-ASA is by far the most effective topical therapy in UC. Oral BDP showed similar efficacy compared to systemic corticost...

Background Robotic surgery has been developed with the aim of improving surgical quality and overcoming the limitations of conventional laparoscopy in the performance of complex mini-invasive procedures. The present study was designed to compare robotic and laparoscopic distal gastrectomy in the treatment of gastric cancer. Methods Between June 2008 and September 2015, 41 laparoscopic and 30 robotic distal gastrectomies were performed by a single surgeon at the same institution. Clinicopathological characteristics of the patients, surgical performance, postoperative morbidity/mortality and pathologic data were prospectively collected and compared between the laparoscopic and robotic groups by the Chi-square test and the Mann-Whitney test, as indicated. Results There were no significant differences in patient characteristics between the two groups. Mean tumor size was larger in the laparoscopic than in the robotic patients (5.3 ± 0.5 cm and 3.0 ± 0.4 cm, respectively; P = 0.02). However, tumor stage distribution was similar between the two groups. The mean number of dissected lymph nodes was higher in the robotic than in the laparoscopic patients (39.1 ± 3.7 and 30.5 ± 2.0, respectively; P = 0.02). The mean operative time was 262.6 ± 8.6 min in the laparoscopic group and 312.6 ± 15.7 min in the robotic group (P < 0.001). The incidences of surgery-related and surgery-unrelated complications were similar in the laparoscopic and in the robotic patients. There were no significant differences in short-term clinical outcomes between the two groups. Conclusions Within the limitation of a small-sized, non-randomized analysis, our study confirms that robotic distal gastrectomy is a feasible and safe surgical procedure. When compared with conventional laparoscopy, robotic surgery shows evident benefits in the performance of lymphadenectomy with a higher number of retrieved and examined lymph nodes.

Piaceri I, Del Mastio M, Tedde A, Bagnoli S, Latorraca S, Massaro F, Paganini M, Corrado A, Sorbi S, Nacmias B. Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder. The majority of cases are sporadic ALS (SALS), with 5–10% being familial ALS (FALS), and are inherited mostly as autosomal dominant. Mutations in Cu/Zn superoxide dismutase (SOD1) and the TAR DNA-binding protein (TARDBP) gene are the most commonly known cause of ALS. We analyzed these genes in 61 Italian ALS patients using high-resolution melting analysis to confirm the role of SOD1 and TARDBP in the physiopathology of ALS. The screenings showed a single mutation in SOD1 (Asp109Tyr) and three in TARBDP (Ala382Thr, Gly295Ser, Gly294Val) in five unrelated ALS patients. This report enlarges the spectrum of clinical phenotypes associated with genetic mutations in SOD1 and TARDBP genes confirming the variability of phenotypes associated with the same mutation and emphasizes the importance of genetic analysis. The different genotype–phenotype correlations suggest the implication of other factors possibly influencing clinical manifestation of the disease, such as an epigenetic or epistatic effect with other genes not yet identified.

Intracellular adhesion molecules and matrix metalloproteinases (MMPs) are up-regulated in intestinal mucosa of patients with inflammatory bowel diseases (IBD), i.e. ulcerative colitis (UC) or Crohn's disease (CD). Our aim was to verify whether the vitamin D analogue ZK 156979 (ZK) down-regulates adhesion molecules, and decreases MMPs production by PBMC of IBD patients. ICAM-1 and LFA-1 levels increase, when PBMC were incubated with PHA or LPS or TNF-alpha, and decrease when these substances were used in combination with ZK. MMPs activity increases incubating the cells with PHA or LPS or TNF-alpha. MMP-9 decreases when ZK was used in association, while MMP-2 decreases only when ZK was used in combination with anti-TNF-alpha. Our results suggest that the down-regulation of ICAM-1 and LFA-1 on PBMC and the inhibition of MMP-9 activity by ZK could provide a potential role of this low calcemic vitamin D derivative in future strategies in IBD therapy.

Background Lymphocytes are crucial in the pathogenesis of inflammatory bowel disease (IBD) and are an important target for drug development. Our aim was to verify whether 2 vitamin D derivatives, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and EB 1089, could induce cell apoptosis and affect cell-cell interaction by regulating adhesion molecule levels. Methods Peripheral blood mononuclear cell (PBMC) proliferation was studied by [3H]thymidine incorporation and apoptosis was determined using an enzyme-linked immunosorbent assay (ELISA) kit. (Poly(ADP-ribose)polymerase (PARP) cleavage, caspase-3, and ICAM-1 protein levels were determined by Western blot analysis. Results Our results indicate that 1,25(OH)2D3 or EB 1089 or anti-TNF-alpha (infliximab) induce apoptosis in PBMC obtained from healthy subjects. In IBD patients apoptosis is induced by vitamin D derivatives and by anti-TNF-alpha only in CD patients. Caspase-3 activation and PARP cleavage are registered when PBMC were treated with vitamin D derivatives. ICAM-1 levels remarkably increase when PBMC was incubated with lipopolysaccharide (LPS) or TNF-alpha. The treatment with the vitamin D derivatives, alone or in combination with LPS or TNF-alpha, significantly decreases ICAM-1 levels both in healthy subjects and IBD patients. In HUVEC cocultured with PBMC, previously incubated with LPS or TNF-alpha associated with 1,25(OH)2D3, ICAM-1 levels decrease both in healthy subjects and IBD patients. Conclusions 1,25(OH)2D3 and EB 1089 inhibit PBMC proliferation, induce apoptosis in PBMC of healthy subjects and IBD patients, and affect ICAM-1 expression on PBMC and on HUVEC cocultured with PBMC, suggesting that the ICAM-1 downregulation could provide a new target for controlling the recruitment of leukocytes at the sites of inflammation in IBD.

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders with a 9 - 23% prevalence estimated in the general population. Patients can be subdivided into those who tend to have predominant diarrhea (IBS-D) or predominant constipation (IBS-C). Total annual productivity loss related to IBS in US is estimated at $205 million, with a significant impairment of health-related quality of life. A gold standard for the treatment of IBS is not established. Symptoms might improve with the use of few drugs and behavioral therapy, however, data concerning efficacy, safety and tolerability are limited. Therefore, development and validation of new therapies targeting at the molecular level are widely awaited.We will specifically describe in this review Phase II and Phase III trials, with specific focus on treatment of IBS-D patients. Unfortunately, it is difficult to draw definite conclusions from Phase II and Phase III trials, because of the known high placebo effect.Drugs active on opioid receptor subtypes and neurokinin (NK) receptors seem to be the most promising, but substantial progress of information in this field is still needed. The achievement of more insights on the pathogenesis of IBS could surely better drive and target the therapy, but still strong efforts are awaited.

Intravenously administered infliximab, a monoclonal antibody directed against tumor necrosis factor-alpha, has been proven to be efficacious in the treatment of fistulas in patients with Crohn's disease. It has recently been suggested that local injections of infliximab might be beneficial as well. The aim of this study was to assess whether infliximab could play an effective role in the local treatment of perianal fistulas in Crohn's disease.Local infliximab injections were administered to 11 patients suffering from Crohn's disease complicated by perianal disease. Eligible subjects included Crohn's disease patients with single or multiple draining fistulas, regardless of status of luminal disease at baseline. Patients, however, were excluded from the study if they had perianal or rectal complications, such as abscesses or proctitis or if they had previously been treated with infliximab. Twenty-milligram doses of infliximab were injected along the fistula tract and around both orifices at baseline and then every 4 weeks for up to 16 weeks or until complete cessation of drainage. No further doses were administered to patients who did not respond after three injections. Efficacy was measured in terms of response (a reduction in fistula drainage of 50% or more) and remission (complete cessation of fistula drainage for at least 4 weeks). Time to loss of response and health-related quality of life were also evaluated.Overall, 8/11 patients (72.7%) responded to the therapy and 4/11 (36.4%) reached remission, whereas 3/11 patients (27.2%) showed no response. Response or remission was very much dependent on the location of the fistulas, and time to loss of response was generally longer for patients who reached remission compared to patients in response. Changes in health-related quality of life, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), also reflected response or remission, with more marked improvements associated with remission. After a mean 10.5 months' follow-up (range 7-18 months), 6/11 patients (54.5%) are in response and 4/11 patients (36.4%) are in remission. No adverse events have been observed in this cohort of patients.Local injections of infliximab along the fistula tract seem to be an effective and safe treatment of perianal fistulas in Crohn's disease. However, further controlled clinical investigations are warranted.

Infliximab treatment demonstrated clinical and endoscopic benefits in active refractory and fistulizing Crohn's disease. The aim of this research was to investigate the proliferative response of peripheral blood mononuclear cells (PBMC) obtained from patients with active and fistulizing Crohn's disease treated with infliximab therapy. PBMC proliferation and VDR protein levels were also studied when 1,25(OH)2D3 or its analogues (EB 1089, KH 1060) were added to cells cultures. At day 5 of culture, the proliferation of PBMC obtained from patients responsive to the therapy showed a remarkable decrease (about 60%) at T6 (after two infusions) with respect to T0 (before the first infusion). On the contrary, in the unresponsive patient, the proliferative response was four times higher at T6 in comparison with T0. Vitamin D derivatives induced a decrease in cell proliferation higher in responsive patients than in the unresponsive one. Increased VDR levels during therapy were registered only in the unresponsive patient. Our results indicate that PBMC proliferation and VDR expression may be useful indicators to predict the response of patients with Crohn's disease to the infliximab therapy.

Background Some recent studies have suggested that laparoscopic surgery for colorectal cancer may provide a potential survival advantage when compared with open surgery. This study aimed to compare cancer-related survivals of patients who underwent laparoscopic or open resection of colon cancer in the same, high volume tertiary center. Methods Patients who had undergone elective open or laparoscopic surgery for colon cancer between January 2002 and December 2010 were analyzed. A clinical database was prospectively compiled. Survival analysis was calculated by using the Kaplan-Meier method. Results A total of 460 resections were performed. There were no significant differences between the laparoscopic (n = 227) and the open group (n = 233) apart from tumor stage: stage I tumors were more frequent in the laparoscopic group whereas stage II tumors were more frequent in the open group. The mean number of harvested lymph nodes was significantly higher in the laparoscopic than in the open group (20.0 ± 0.7 vs 14.2 ± 0.5, P

Peroxisome proliferator-activated receptor gamma (PPARγ) is member of a family of nuclear receptors that interacts with nuclear proteins acting as coactivators and corepressors. The colon is a major tissue which expresses PPARγin epithelial cells and, to a lesser degree, in macrophages and lymphocytes and plays a role in the regulation of intestinal inflammation. Indeed, both natural and synthetic PPARγligands have beneficial effects in different models of experimental colitis, with possible implication in the therapy of inflammatory bowel disease (IBD). This paper will specifically focus on potential role of PPARγin the predisposition and physiopathology of IBD and will analyze its possible role in medical therapy.

Objective: To investigate the presence of lower limb entheseal abnormalities in IBD patients without clinical signs and symptoms of SpA and their correlation with IBD clinical variables. Methods: A total of 81 IBD patients [55 Crohn's disease (CD) and 26 ulcerative colitis (UC), 43 females and 38 males, mean age 41.3 (12.4) years, BMI 24 (2)] with low active (12) and inactive (67) disease were consecutively studied with US (LOGIQ5 General Electric 10-MHz linear array transducer) of lower limb entheses and compared with 40 healthy controls matched for sex, age and BMI. Quadriceps, patellar, Achilleon and plantar fascia entheses were scored according to the 0-36 Glasgow Ultrasound Enthesitis Scoring System (GUESS) and power Doppler (PD). Correlations of GUESS and PD with IBD features [duration, type (CD/UC) and activity (disease activity index for CD/Truelove score for UC)] were investigated. The intra- and inter-reader agreements for US were estimated in all images detected in patients and controls. Results: Of the 81 patients, 71 (92.6%) presented almost one tendon alteration with mean GUESS 5.1 (3.5): 81.5% thickness (higher than controls P0.9 intra-class correlation variability). Conclusions: US entheseal abnormalities are present in IBD patients without clinical signs and symptoms of SpA. US enthesopathy is independent of activity, duration and type of gut disease. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved

TO THE EDITOR: Jess et al. have presented the results of a meta-analysis based on the results of population-based studies evaluating the risk of colorectal (CRC) and small bowel (SB) cancer in patients affected with Crohn's Disease (CD) (1). While the paper is quite interesting and well written, we would like to point out that the authors did not identify all the papers on this issue, even according to their strict criteria. We have recently published such a paper in a major journal (2), reporting the follow-up results of a population-based cohort of ulcerative colitis and CD patients residing in the metropolitan area of Florence, central Italy. This cohort included all patients identified in the area in the period 1978–1992 and the follow-up is still ongoing with a very low proportion of patients lost; we have recently updated our mortality results (3,4).

Crohn's disease (CD) is an inflammatory disease characterized by the activation of the immune system in the gut. Since tumor necrosis factor (TNF-alpha) plays an important role in the initiation and perpetuation of intestinal inflammation in CD, we investigated whether TX 527 [19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)], a Vitamin D analogue, could affect peripheral blood mononuclear cells (PBMC) proliferation and exert an immunosuppressive effect on TNF-alpha production in CD patients, and whether this immunosuppressive action could be mediated by NF-kappaB down-regulation. TX 527 significantly decreased cell proliferation and TNF-alpha levels. On activation, NF-kappaB, rapidly released from its cytoplasmatic inhibitor (IKB-alpha), transmigrates into the nucleus and binds to DNA response elements in gene promoter regions. The activation of NF-kappaB, stimulated by TNF-alpha, and its nuclear translocation together with the degradation of IKB-alpha were blocked by TX 527. At the same time, NF-kappaB protein levels present in cytoplasmic extracts decreased in the presence of TNF-alpha and increased when PBMC were incubated with TX 527. The results of our studies indicate that TX 527 inhibits TNF-alpha mediated effects on PBMC and the activation of NF-kappaB and that its action is mediated by Vitamin D receptor (VDR), which is activated when the cells are stimulated with TX 527.

Background The active form of vitamin D, 1,25(OH) 2 D 3 , exerts important effects on proliferation and differentiation of many cell types, and immunoregulatory activities in particular on T cell-mediated immunity. Aim The aim of this study was to investigate whether KH 1060, a vitamin D analogue, could decrease tumor necrosis factor-alpha (TNF-α) levels in patients with inflammatory bowel disease (IBD). Methods PBMC proliferation was determined by [ 3 H]thymidine incorporation. TNF-α levels were measured by ELISA kit; VDR, Bcl-2 and Bax protein levels with Western blot analysis. Results KH 1060 inhibited PBMC proliferation and decreased TNF-α levels in IBD patients and this effect was synergistic with anti-TNF-α. VDR protein levels were significantly increased by PBMC treatment with KH 1060 or anti-TNF-α or their combination in ulcerative colitis (UC) patients, and decreased in Crohn's disease (CD) patients, treating the cells with KH 1060. In UC patients an increase in Bcl-2 and Bax levels was observed incubating, PBMC with KH 1060 or anti-TNF-α or their combination. In CD patients a slight decrease in Bcl-2 levels was registered when anti-TNF alone or in association with KH 1060 was used. Bax protein levels were slightly increased in the presence of KH 1060 alone or in combination with anti-TNF. Conclusion This study shows that KH 1060 acts as an immunomodulator on PBMC, acting as TNF-α inhibitor. This finding provides strong evidence that vitamin D status could be an important regulator of immunity IBD.

Background and aims: Two divergent patterns of mortality for smoking related diseases in ulcerative colitis and Crohn’s disease patients were suggested in a previous population based study in Florence, Italy. Long term follow up (median 15 years) was completed to re-evaluate mortality in this Mediterranean cohort. Patients and methods: Overall, 920 patients with inflammatory bowel disease were followed until December 2001 or death, with seven patients (0.8%) lost to follow up. A total of 14 040 person years were available for analysis; 118 deaths were observed (81/689 in ulcerative colitis and 37/231 in Crohn’s disease). Expected deaths were estimated using age, sex, and calendar specific national and local mortality rates; standardised mortality ratios (SMR) and 95% confidence interval (CI) were calculated. Results: Among Crohn’s disease patients, mortality was strongly increased for gastrointestinal diseases (SMR 4.49 (95% CI 1.80–9.25)), all cancers (SMR 2.10 (95% CI 1.22–3.36)), and lung cancer (SMR 4.00 (95% CI 1.60–8.24)), leading to a significant 50% excess total mortality. Ulcerative colitis patients showed a significantly reduced total mortality because of lower cardiovascular (SMR 0.67 (95% CI 0.45–0.95)) and lung cancer (SMR 0.32 (95% CI 0.07–0.95)) mortality. No significant excess for colorectal cancer mortality was evident in this extended follow up. Conclusions: These clearly divergent patterns of mortality correlate with documented differences in smoking habits between Crohn’s disease and ulcerative colitis patients. Family doctors and gastroenterologists should consider stopping cigarette smoking a specific priority for Crohn’s disease patients; the latter should be offered free participation in structured programmes for smoking cessation, with the aim of reducing smoking related excess mortality. Overall, no evidence of an increased mortality for large bowel cancer emerged in this series.

The hMLH1 gene lies in the linkage susceptibility region to inflammatory bowel disease (IBD) on 3p21. A single nucleotide polymorphism, 655A>G, in exon 8 of the gene causes an I219V change in the MLH1 protein. To test whether hMLH1 may confer susceptibility to ulcerative colitis (UC), we investigated an association between the 655A>G polymorphism and the disease. DNA-based technologies were used to analyze the 655A>G polymorphism in 201 UC patients and 126 healthy ethnically matched controls. The comparison of the allelic frequencies of the 655A>G polymorphism in UC patients and healthy controls did not show significant differences. However, genotype frequencies at the hMLH1 655 position were found to be significantly different when patients with and without refractory UC were compared. This was mainly attributable to a higher level of homozygosity for the G allele in refractory UC patients. Almost 5 times as many (4.9 times) refractory UC patients carried the GG genotype compared with nonrefractory patients (P < 0.0001). The present study provides evidence that the hMLH1 gene is involved in genetic susceptibility to refractory UC. If confirmed by other studies, the GG genotype at position 655 of the hMLH1 gene may represent a useful predictive factor for the clinical management of UC patients.

This FDG-PET study with SPM99 compared 46 patients with sporadic Alzheimer disease (SAD) to 40 patients with familial AD (FAD) and to 35 matched controls. AD groups had equivalent metabolic (METglu) reductions in several cortical and limbic areas with respect to the controls. Patients with FAD showed decreased METglu in the posterior cingulate, parahippocampal, and occipital cortex as compared to the patients with SAD (p < 0.001). Genetic factors lead to phenotypic differences in AD.

Background & Aims: All patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) residing in Florence, Italy, in 1978–1992 were identified and included in a population-based study of cancer risk evaluation. Methods: A total of 920 patients were followed up (median, 11 years), and 64 newly diagnosed malignancies were identified by linkage to the local cancer registry. Expected cases were calculated on the basis of age- and sex-specific cancer incidence rates to estimate relative risks in comparison with the general population. Results: Overall, cancer incidence rates were not increased. A significant excess risk of Hodgkin's disease was observed among patients with UC (standardized incidence ratio, 9.3; 95% confidence interval [CI], 2.5–23.8). Respiratory tract cancers were significantly reduced to one fourth of the expected rate in patients with UC, but tended to be increased among patients with CD, who had a 50% higher risk of cancer at all sites. Only a nonsignificant, modestly increased risk of colorectal cancer was observed. Conclusions: A strongly increased risk of Hodgkin's disease was evident in this first cancer follow-up of a representative series of patients with UC in a Mediterranean country. Two divergent risk patterns of respiratory tract cancers, possibly explained by differences in smoking habits, emerged in the 2 inflammatory bowel diseases. GASTROENTEROLOGY 2000;119:647-653

The etiopathogenesis of eating disorders (ED) is complex and poorly understood. The hypothalamic-pituitary-adrenal (HPA) axis, involved in the biological response to stress, could influence the onset and the course of ED.) Several variants in the Glucocorticoid receptor (GR) gene have been related to different metabolic parameters suggesting a possible role in ED. We studied if genetic variants of GR could represent potential risk factors for the development of Anorexia Nervosa (AN) and Bulimia Nervosa (BN).We investigated the distribution of several single nucleotide polymorphisms (SNPs) of the GR including N363S (rs6195), Er22/23EK (rs6189-6190), A/G SNP in exon 9beta (rs6198) and the intronic BclI polymorphism (rs41423247), in 118 Italian patients affected by AN and in 108 patients with BN. Moreover we studied 116 normal individuals and 177 obese subjects. The distributions of genotypes and allele frequency of the SNPs in all studied groups followed Hardy-Weinberg equilibrium and did not significantly differ from that of controls. A trend towards association was observed in case-control association analysis (p=0.07) for rs6198. A correlation of metabolic parameters to the GR genotypes was performed.We report the analysis of different GR SNPs for the first time in Italian patients with AN and BN. We failed to detect an allelic association between the studied SNPs in the GR gene and AN and BN.None of the variants seems to influence these pathologies, not supporting a role for the GR gene as genetic risk factors for ED.

The genetics of neurodegenerative diseases has an important role to clarify the pathogenetic mechanism, the diagnosis and finally the therapeutic and ethical implications. Moreover, the genetic approach to the study of the main clinical forms of dementia (Alzheimer’s disease-AD and Frontotemporal Dementia-FTD) suggests clinical guidelines for helping families to navigate through these complexities. AD and FTD are multifactorial, genetically complex diseases involving many candidate genes. Mutations in three genes (i.e. Amyloid Precursor Protein, APP; presenilin 1, PSEN1; presenilin 2, PSEN2) have been linked to 50% of all familial forms of AD (FAD). Genome wide association studies (GWAS) have involved an increasing number of genes with a possible role in the disease pathogenesis. Up to now, the genetics of familial forms of FTD is related to 7 genes: the microtubule-associated protein tau (MAPT) progranulin (GRN), the valosin-containing protein (VCP), chromatin-modifying 2B (CHMP2B), the TARDNA binding protein 43 encoding gene (TARBDP), fused in sarcoma (FUS) and the last hexanucleotide expansion repeats in the open reading frame of chromosome 9 (C9orf72). Pre-test counseling and the identification of genetic defects are important in both patients and asymptomatic at risk family members.