Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

Application of clinical indexes in ulcerative colitis patients in regular follow-up visit: correlation with endoscopic 'mucosal healing' and implication for management. Preliminary results.

OBJECTIVE: Ulcerative Colitis (UC) is a chronic inflammatory disease of the colon of unknown etiology. Several clinical indexes have been proposed for UC disease activity evaluation, but none have been properly validated. Moreover, the reference parameter for the scores and their prognostic value is not clear. Mucosal healing has been recently proposed as an important end-point. Aim of the present study was to evaluate the correlation of four clinical indexes with objective diagnostic tools for UC evaluation, the discriminative ability in identifying patients with endoscopic mucosal healing, and to analyze the possible prognostic indication for disease course in 1 year of follow-up. PATIENTS AND METHODS: We analyzed data of 75 patients recorded in regular follow-up visit in IBD clinic at S. Andrea Hospital, Rome, between 2007-2011. We recorded clinical data and lab tests at the time of the visit, and endoscopic/histological reports performed within 1 month. Clinical indexes (Seo' activity index, Simple Clinical Colitis Activity Index, partial Mayo score and Endoscopic-Clinical Correlation Index) were calculated and correlation to endoscopic and histologic activity, and to C-reactive protein increment, was assessed by mean of Spearman's rank correlation. Discriminative ability of the indexes for patients with and without endoscopic mucosal healing was tested by calculation of area under ROC curve (AUC). Patients with low and high clinical scores were compared for number of flares and increment of therapy during 1 year of follow-up. RESULTS: Clinical indexes had a good correlation with endoscopic activity (mean r = 0.73 ± 0.06), a fair correlation with CRP-increment (mean r = 0.55 ± 0.01) and a poor one with histologic activity (mean r = 0.35 ± 0.01). The discriminatory ability of the indexes for endoscopic mucosal healing was good for all the indexes (mean AUC = 0.87 ± 0.05). Patients with high clinical score had more flares and required more frequently increase of therapy at 1 year of follow up compared with patients with low score. CONCLUSIONS: Clinical indexes have a good correlation with endoscopic activity and can discriminate patients with and without mucosal healing. Patients with low and high score have different risk of disease flare and of need to increase therapy at 1 year. Clinical indexes may represent a useful tool for disease assessment in clinical practice in UC outpatients with mild-moderate disease.

Cutaneous manifestations and gastrointestinal disorders: Report of two emblematic cases.

Gastrointestinal (GI) diseases, such as inflammatory bowel diseases (IBD), can manifest themselves with intestinal and extra-intestinal symptoms. Among the latter, cutaneous manifestations, such as pyoderma gangraenosum (PG) and metastatic Crohn's disease (MCD), represent a possible onset of IBD, with or without simultaneous bowel alterations. In such cases, intestinal and skin lesions are supported by the same immune-mediated mechanism. We hereby report two cases of patients with skin manifestations together with signs and symptoms suggestive of IBD. IBD and some skin lesions arise from the same immune-mediated mechanism. A multidisciplinary approach to these immune-mediated diseases is needed for an early and correct diagnosis, which in turn may lead to the use of the right drug avoiding useless treatment.

Eczema and food allergy in an Italian pediatric cohort: no association with TLR-2 and TLR-4 polymorphisms.

Recent studies have indicated that Toll-like receptor polymorphisms or their impaired signalling, specifically TLR-2 and TLR-4, were correlated with a higher risk for allergy. The purpose of this study is to evaluate the associations of TRL-2 and TRL-4 single nucleotide polymorphisms (SNP) and atopic traits in a cohort of 159 Italian allergic children (102 affected by eczema and 57 by IgE-mediated food allergy) and 147 healthy controls recruited in Rome, Italy. DNA was isolated from the peripheral blood and TLR-2 R753Q/TLR-4 D299G polymorphisms were determined by TaqMan MGB probes using Real-Time PCR technique. In the control group, the TLR-2 polymorphism R753Q had a prevalence of 2.5% while the frequency of the TLR-4 D299G was 12%. None of the 159 allergic patients showed the R753Q SNP. By contrast, 7/57 patients with food allergy (12%) and 6/102 subjects with eczema (6%) carried the TLR-4 mutation. In our cohort, no evidence of correlation between TLR-2 or TLR-4 polymorphism and eczema and food allergy incidence and/or severity was found. Further studies are needed to clarify the possible role of TLR-2 and TLR-4 polymorphism in allergic disease, in Italian children.

Probiotics in experimental and human inflammatory bowel disease: discussion points.

In recent years, novel insights have been made into the role of bacterial microflora in health and disease. Commensal flora manipulation by probiotic bacteria has been investigated in human and experimental inflammatory bowel disease (IBD). In particular, animal models of IBD offer the opportunity to address important issues regarding indication, therapeutic efficacy and mechanism of action of the probiotic bacteria. Despite the appealing results of many published studies, fundamental questions still remain unanswered. Further studies on appropriate animal models are needed in order to better clarify our knowledge about probiotic bacteria and their potential application as a valid therapeutic option in IBD patients.

Comparison of three different risk scoring systems in non-variceal upper gastrointestinal bleeding.

BACKGROUND AND AIMS: To prospectively validate in patients with non-variceal upper gastrointestinal bleeding three risk scoring systems (the Baylor College scoring system, the Rockall's risk scoring system and the Cedars-Sinai Medical Centre predictive index) previously proposed to be predictive of rebleeding/death after upper gastrointestinal bleeding. PATIENTS AND METHODS: We calculated values of the scores for 343 patients, who underwent endoscopy after non-variceal upper gastrointestinal haemorrhage during the years 1997-1999. We compared the observed outcomes with the ones expected upon the original series contributed by the authors. Discriminative ability was evaluated by calculating the area under the receiver operating characteristic curve. RESULTS AND CONCLUSIONS: Rockall's score accurately predicted rebleeding in low- and intermediate-risk categories (< 6), but not in high-risk patients. The rates of rebleeding were significantly higher than the ones predicted by the low-risk categories of either Cedars-Sinai index (< or = 2) or Baylor score (< or = 6). The predicted and the observed mortality was not significantly different throughout all the categories of Rockall's score, except for patients with a score of 4. All the scores had better discriminative ability for mortality than for rebleeding. The Rockall's score identifies a low-risk group of patients (Rockall's score < or = 2) for rebleeding and mortality.

Early and advanced gastric cancer during follow-up of apparently benign gastric ulcer: significance of the presence of epithelial dysplasia.

One hundred and forty-four patients with apparently benign gastric ulcer were endoscopically followed up in order to evaluate the outcome of the lesion. Particular attention was given to: (a) detect possible delay in diagnosing gastric cancer; (b) ascertain the frequency of association with epithelial dysplasia; (c) establish the role of markers, such as serum pepsinogen group I (PGI), and gastric juice CEA in predicting gastric ulcer evolution. Endoscopic and bioptic check-ups were carried out during the first year at 3, 6 and 12 months after endoscopic healing of the ulcer, and then at every symptomatic recurrence. Ten patients (6.9%) were found to present histological evidence of malignancy (within 3 months in six cases, between 6 and 12 months in three cases, and after 41 months in the rest). Four cases were early gastric cancers, and six had shown dysplastic changes of the mucosa at the edge or scar of the ulcer. Serum PGI levels were not significantly different in gastric cancer patients, while gastric juice CEA levels were sharply increased compared to those of gastric ulcer patients: nine out of ten patients had values above normal range. These data suggest that: (a) there may be some delay in diagnosing gastric carcinoma, and gastric ulcer patients should be controlled routinely more than once; (b) the presence of dysplasia indicates the need for prolonged follow-up, because of the high risk of association with or evolution into gastric cancer, and because of the higher number of early gastric cancer detections that this protocol allows; (c) further support in monitoring patients "at risk" may be afforded by gastric juice CEA determination.

Advanced gastric cancer and prognosis.

The morphological features of 158 gastric carcinomas were analyzed in an attempt to identify patterns best correlated with prognosis. To this end, the depth of infiltration, vascular invasion, intra- and perineoplastic lymphocytic infiltrate, lymph node metastases and number of metastatic lymph nodes were evaluated according to the several classifications for advanced gastric cancer. A good correlation between prognosis and histological features of malignancy were observed, as well as different five-year survival rates for Mulligan, Lauren and Ming histotypes. However, when the influence of each single morphological criteria of malignancy was examined, these differences disappeared for Mulligan and Lauren histotypes. On the other hand, the better prognosis for Ming expanding type carcinomas appeared unrelated to any individual feature of malignancy.

Prognostic correlations of operable carcinoma of the rectum.

Various histologic factors correlated to survival were studied in 124 patients radically operated on for rectal carcinoma in order to establish valid prognostic criteria. The total survival rate after five years was 63 percent, while in stage B1 it was 89 percent, in B2, 61 percent, and in C1, 47 percent (P less than 0.05). With regard to histotype, the survival was 83 percent in the papillary subtype of adenocarcinoma, while in the tubular subtype it was 62 percent, and 29 percent in the mucinous type (P = not significant). Vascular invasion negatively affected survival (41 percent); however, when there was no invasion, the prognosis was better (71 percent) (P less than 0.01). In evaluating histologic grading and lymphoglandular reactivity, the difference in survival rates was not statistically significant. The marked peri- and intratumoral lymphocytic infiltration gave a very good prognosis (92 percent) contrary to when reactivity was moderate (59 percent) or even absent (51 percent) (P less than 0.01). Finally, the expanding type tumor, with reference to Ming's classification of gastric carcinoma, had a much better prognosis (75 per cent) than the infiltrative type (40 percent) (P less than 0.01).

Hormone receptors and breast cancer: correlations with clinical and histologic features.

The possible relationships between hormone receptor status and several clinical (age, gynecologic history, clinical stage) and morphologic aspects (histologic grade, vascular invasion, lymphocytic infiltration, necrosis, fibrosis, elastosis and lymph node metastasis) were evaluated. A highly significant correlation between estrogen receptor levels, patient age, menses regularity and postmenopausal status was found. The histologic features most significantly related to tumor receptor status were histologic grade, lymphocytic infiltrate, necrosis and elastosis. Since these same histologic aspects appear to influence prognosis in breast cancer, the prognostic significance attributed to tumor receptor levels is substantiated. Therefore the importance of this assay is confirmed, not only for its diagnostic and therapeutic purposes, but also for its prognostic value.

Gastric cancer: problems in histogenesis.

Intestinal metaplasia in the mucosa adjacent to a gastric carcinoma suggests that some carcinomas of the stomach might arise from metaplastic mucosa, as well as the existence of a gastric cancer with morphological features resembling intestinal mucosa. In this study, the extent of intestinal metaplasia of adjacent mucosa, the type of intestinal metaplasia (complete or incomplete), the degree of tumour differentiation, the type and quantity of mucins secreted by neoplastic cells and morphological features of the tumours were evaluated in 59 cases of gastric carcinoma. An analysis of the findings suggests that a carcinoma may arise in the stomach with features of association with incomplete metaplasia and histochemical and histological patterns which mimic carcinomas of the large intestine.

Gastric epithelial dysplasia and sulphomucin-type intestinal metaplasia.

The HID-AB histologic staining technique, which distinguishes sulphomucin from sialomucin types of intestinal metaplasia, was employed in endoscopic gastric mucosal biopsies to evaluate their frequency of association with epithelial dysplasia. Sulphomucin-type intestinal metaplasia was found in 33% of the cases under observation; moderate or severe dysplasia was only associated with this type of intestinal metaplasia. Its precancerous significance can be ascertained only by means of prospective studies.

Is mild gastric epithelial dysplasia an indication for follow-up?

We evaluated the changes over 1-55 months in mild gastric epithelial dysplasia (a relatively frequent, but not widely studied histological lesion) in 20 patients (11 with benign gastric ulcer, eight with chronic gastritis, and one after Billroth 2 operation), in order to ascertain whether to follow-up such patients in the future. Regression of the lesion was documented in 13 (65%), and no change in six (30%). Progression from mild to moderate dysplasia occurred in only one patient (5%). As mild dysplasia regresses or remains unchanged in most patients, at least over the short-term, specific follow-up is probably unnecessary. Nevertheless, a rational program of monitoring the associated precancerous conditions is in order.

Gastric cancer: problems in histological diagnosis.

The reproducibility of the most recent histological classifications for gastric cancer was studied. A comparison of the results obtained independently by both authors using the criteria of Lauren, Ming, Mulligan and WHO, showed that highest reproducibility was achieved with the WHO classification. However, an acceptable accuracy in diagnosis for the other three classifications was obtained. This study confirms the validity of the WHO criterion for initial diagnosis, while the other classifications should be kept for further specific investigations, such as epidemiological or prognostic studies.

Precancerous significance of colonic type intestinal metaplasia.

Numerous epidemiologic, morphologic and experimental studies have demonstrated the precancerous significance of intestinal metaplasia. We report here the results of a histochemical study of intestinal metaplasia in which 2 types were observed: one with sialomucin-secreting cells typical of the small intestine, and the other with sulphomucin-secreting cells typical of colonic mucosa. The correlation between colonic type intestinal metaplasia and gastric cancer is explored, since a significant precancerous value for this type of intestinal metaplasia is suggested.

Is the solitary papilloma of the bronchus always a benign tumor?

99 pulmonary resections for benign tumors were performed during the period 1967-1978. 4 patients showed bronchial papilloma. Solitary papilloma of the bronchus is one of the rarest benign tumors; the differences of multiple papillomatosis and inflammatory polyp are stressed. Malignant change was observed in 3 of the 4 cases. The 4 patients presented a 2- to 5-year history of hemoptysis episodes and radiographic aspects characterized by intermittent atelectasis. Radical surgery is the only satisfactory therapy; endoscopic removal of the neoplasm is often incomplete and unsatisfactory.