P. Soliani

Ex vivo characterization of tumor-derived melanoma antigen encoding gene-specific CD8 + cells in patients with hepatocellular carcinoma

BACKGROUND/AIMS Members of the melanoma antigen encoding gene family are expressed in tumors of different histological types but not in normal tissue. For this reason, they are attractive targets for cancer immunotherapy. METHODS In the present study, we analyzed the expression of MAGE-1 and -3 genes in the hepatocellular carcinoma (HCC) tissue as well as frequency, phenotype and function of circulating and tumor infiltrating CD8+ cells specific for HLA-A1 and -A2 restricted epitopes of MAGE-1 and -3. RESULTS Our study shows for the first time the presence of MAGE/tetramer+ CD8 cells in the tumor tissue of patients with HCC. These cells are able to recognize the MAGE-1 sequence 161-169 and the MAGE-3 sequence 271-279. In a patient with a particularly high frequency of MAGE-1 sequence 161-169-specific T cells, phenotypic and functional analysis was performed showing a phenotype of recently-primed CD8 cells (CD28+CD27+CD45RA-CCR7). CONCLUSIONS The observation of a spontaneous in vivo priming of a MAGE-specific T cell response in patients with HCC and the high frequency of MAGE antigens expression in this tumor, makes this antigen a potential candidate for a MAGE-specific immunotherapy in hepatocellular carcinoma.

Endoscopic treatment of colorectal benign-appearing lesions 3 cm or larger: Techniques and outcome

PURPOSE: Colonoscopic polypectomy is the preferred technique to remove the majority of polyps. The authors evaluate feasibility, safety, and the effectiveness of endoscopic treatment of colorectal benign-appearing polyps equal to or larger than 3 cm. METHODS: Ninety-seven patients with 104 giant polyps underwent polypectomy within a nine-year period. The majority of these procedures were performed on an outpatient basis, all on unsedated patients. Gross appearance, size, location, histologic characteristics, synchronous lesions, modality, and adequacy of removal of giant polyps were analyzed. The follow-up was achieved in 89 percent of patients during a period ranging from 6 to 96 months (median, 38). RESULTS: Of the 104 removed polyps, 75 (72 percent) were adenomatous, 2 (2 percent) were hyperplastic, and 27 (26 percent) were malignant polyps. Six patients had more than one giant polyp. Several additional smaller polyps were found in 52 patients and a synchronous cancer in 4. Twenty-one (20 percent) giant polyps were equal to or larger than 4 cm. Forty-nine were pedunculated, 20 were short-stalked, and 35 were sessile. Sixty-one polyps were excised in one piece, and forty-three were excised using a piecemeal technique. Only four complications (3.8 percent) were recorded; all cases were treated endoscopically. Fifty-eight (75 percent) adenomas and eighteen (67 percent) malignant polyps were completely excised. Surgery was performed in 7 of 27 patients (27 percent) with malignant polyps, where there was a doubtful, infiltrated margin or poorly differentiated cancer. Post-polypectomy surveillance permitted the detection and treatment of 25 metachronous or recurrent polyps and a metachronous cancer. CONCLUSIONS: This study shows that polypectomy of giant colorectal polyps, performed by an expert endoscopist, is feasible, effective, and safe, even on an outpatient basis. The authors confirm that malignant polyps with incomplete excision, lymphovascular invasion, and poor differentiation require bowel resection. Post-polypectomy surveillance is useful for all patients who have undergone colonoscopic resection of giant adenomatous or malignant polyps.

Radiofrequency Thermal Ablation for Hepatocellular Carcinoma Stimulates Autologous NK-Cell Response

BACKGROUND & AIMS Radiofrequency thermal ablation (RFA) is a minimally invasive technique used as standard local therapy of hepatocellular carcinoma and second-line treatment for metastatic liver tumors. Studies in preclinical models and in patients have shown that thermal destruction of tumor tissue can enhance anti-tumor cellular responses, but our knowledge of its impact on natural killer (NK) cells is still very limited. METHODS Thirty-seven patients undergoing RFA for hepatocellular carcinoma were studied for peripheral blood lymphocytes counts followed by phenotypic and functional characterization of NK-cell population. RESULTS Peripheral blood lymphocytes kinetics revealed an increased frequency and absolute number of NK cells expressing higher levels of activatory along with reduced levels of inhibitory NK receptors, and increased functional NK-cell activity. A prevalent expansion of the CD3(-)CD56(dim) NK subset was observed compared to the CD3(-)CD56(bright) counterpart. Interferon-gamma production, anti-K562 cell cytotoxicity, and antibody-dependent cell cytotoxicity, appeared consistently increased in terms of both absolute activity and killing efficiency at 4 weeks after RFA, as compared to baseline. Interestingly, when recurrence-free survival was assessed in 2 groups of patients separated according to higher vs lower enhancement of cytotoxicity and/or interferon-gamma production, a significant difference was observed, thus suggesting a potential predictive role of NK functional assays on efficacy of RFA. CONCLUSIONS RFA can lead to stimulation of NK cells with a more differentiated and proactivatory phenotypic profile with general increase of functional activities. This observation may be relevant for development of adjuvant immunotherapeutic strategies aimed at enhancing NK-cell responses against primary and metastatic liver tumors.

Quality of Life in Uncomplicated Symptomatic Diverticular Disease: Is It Another Good Reason for Treatment?

Background: Quality of life (QoL) is becoming a major issue in the evaluation of any therapeutic intervention. Aims: To assess the QoL in patients with uncomplicated symptomatic diverticular disease (DD) and to elucidate the influence of two different treatments either on symptoms or QoL. Materials and Methods: 58 outpatients affected by uncomplicated symptomatic DD, admitted in our Gastroenterological Unit from October 2003 to March 2004, were enrolled. Patients were randomly assigned to two different treatments consisting of rifaximin or mesalazine for 10 days every month for a period of 6 months. QoL was evaluated by means of an SF-36 questionnaire and clinical evaluation was registered by means of a global symptomatic score (GSS) at baseline and after 6 months. Results: At baseline, lower values in all SF-36 domains were confirmed in patients with DD. Both rifaximin and mesalazine groups showed a significant reduction of their mean GSS (p < 0.01 and p < 0.001, respectively) and improvement of SF-36 mean scores after therapy, even though treatment with mesalazine showed better results. Conclusions: DD has a negative impact on QoL. Cyclic treatment with poorly absorbable antibiotics or anti-inflammatory drugs relieves symptoms and improves QoL.

Immunological and Molecular Correlates of Disease Recurrence after Liver Resection for Hepatocellular Carcinoma

The definition of the risk of hepatocellular carcinoma (HCC) recurrence after resection represents a central issue to improve the clinical management of patients. In this study we examined the prognostic relevance of infiltrating immune cell subsets in the tumor (TIL) and in nontumorous (NT) liver (LIL), and the expression of immune-related and lineage-specific mRNAs in HCC and NT liver derived from 42 patients. The phenotype of infiltrating cells was analyzed by flow cytometry, and mRNA expression in liver tissue was examined by real-time reverse transcription (RT)-PCR. The tumor immune microenvironment was enriched in inhibitory and dysfunctional cell subsets. Enrichment in CD4+ T-cells and in particular CD4 and CD8+ memory subsets within TIL was predictive of better overall survival (OS) and time to recurrence (TTR). Increased programmed death ligand 1 (PDL1) mRNA content and higher prevalence of invariant NKT (iNKT) cells were associated with shorter OS and TTR, respectively. By combined evaluation of infiltrating cell subsets along with mRNA profiling of immune and tumor related genes, we identified the intratumoral frequency of memory T-cells and iNKT-cells as well as PDL1 expression as the best predictors of clinical outcome. HCC infiltrate is characterized by the expression of molecules with negative regulatory function that may favor tumor recurrence and poor survival.

Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells.

Cholangiocarcinoma is the second most common primary hepatic neoplasia and the only curative therapy is surgical resection or liver transplantation. Biphosphonates (BPs) are an emerging class of drugs widely used to treat bone diseases and also appear to possess direct antitumor activity. In two human cholangiocarcinoma cell lines (TFK-1 and EGI-1) we investigated, for the first time, the activity of zoledronic acid by determining proliferation, cell cycle analysis and apoptosis. The results obtained indicate that zoledronic acid induces cell-narrowing and growth inhibition, both reversed by 25 microM GGOH, and significantly affects the colony-forming ability of these cells. The inhibition by zoledronic acid of Rap1A prenylation was reversed in cell co-treated with GGOH. At 10-50 microM zoledronic acid exerted an S-phase cell cycle arrest which was confirmed by changes in the level of cyclins and of regulators p27(KIP1) and pRb. Interestingly, the expression level of cyclin A (putative S-phase marker) shows a dose-dependent increment in contrast to the decrement of cyclin D1 (putative G1 phase marker). However, neither hypodiploid cells nor cleaved PARP or caspase-3 was detected. The lack of TP53 or loss of its function, the large constitutive expressions of anti-apoptotic proteins Bcl-xL and HSP27 together with the low level of the pro-apoptotic Bax are the likely factors which protect cells from apoptosis. In conclusion, our study indicates that zoledronic acid induces S-phase arrest and cell-narrowing, both reversed by GGOH and, by changing the delicate balance between pro- and anti-apoptotic proteins, allows survival of cholangiocarcinoma cells.

Colostomy plug devices : a possible new approach to the problem of incontinence

The authors report their experience in the use of the Conseal™(Coloplast S.p.A., Bologna, Italy) Colostomy Plug, a new device for the regulation of continence in patients with colostomies. The devices were tested on 57 patients divided into two groups: Group A (36 patients) ht with a two-piece Conseal™system and Group B (21 patients) fit with a one-piece Conseal™system. All patients had the same colostomy type, and all were trained for self-irrigation. The objectives of this randomized, prospective study were to determine compliance with the different systems, to identify the advantages, and to verify the possible different applications among the population of irrigated patients. The following results were obtained. Regarding compliance: Group As results were excellent in 22.2 percent and good in 52.7 percent of patients. Group B had better compliance than Group A (excellent in 66.6 percent and good in 19 percent of patients). Regarding controlled evacuation, continence time, and silent gas emission: in Group A, the device permitted controlled evacuations (23.8 percent of patients practicing daily washouts) with silent and odorless gas emission (100 percent of cases). In Group B, the results concerning improvement in continence were good (33.3 percent of patients) and excellent concerning the emission of flatus. Regarding the potential use of both systems in different groups of self-irrigated patients: the study has revealed the Conseal™Uni-system as being ideal for patients with a well-constructed stoma, slight gas distention, and a better psychologic adaptability to largersized systems. In all other cases, the alternative two-piece system is more suitable, owing to the better safety it offers.

The Node Ratio as Prognostic Factor after Curative Resection for Gastric Cancer

IntroductionThe depth of the tumor invasion and nodal involvement are the two main prognostic factors in gastric cancer. Staging systems differ among countries and new tools are needed to interpret and compare results and to reduce stage migration. The node ratio (NR) has been proposed as a new prognostic factor.Materials and MethodsWe retrospectively reviewed 282 patients who underwent curative resection for gastric cancer at Parma University Hospital between 2000 and 2007. TNM stage, NR, overall survival, survival according to nodal status, and survival according to the total number of nodes retrieved were calculated.ResultsAt univariate analysis, the TNM stage, number of metastatic nodes, NR, and depth of tumor invasion, but not the number of nodes retrieved, were significant prognosis factors. Patients with more than 15 nodes retrieved in the specimen survived significantly longer (p < 0.04). This was confirmed for all N or NR classes within N groups. There was a correlation between the number of nodes retrieved and N but not with the NR category. NR was an independent prognostic factor at Cox regression.ConclusionNR is a reliable and sensitive tool to differentiate patients with similar characteristics, probably more so than the TNM system. NR is not strictly related to the number of nodes retrieved and this may potentially decrease the stage migration phenomenon. More trials are needed to validate this factor.

Dunbar's syndrome and superior mesenteric artery's syndrome: a rare association.

Celiac artery compression syndrome (CACS) and superior mesenteric artery syndrome (SMAS) are 2 rare diseases, widely described in literature. Their association has not been specifically investigated; in fact, few cases have been reported. For this reason we reviewed our experience from January 1974 to June 2004. We report 59 patients affected by CACS and 28 by SMAS. Coexistence of both syndromes in 8 patients was observed. These 8 patients were successfully treated with duodenojejunal bypass and decompression of the celiac trunk. In this paper, we analyze the pathogenesis, clinical presentation, diagnosis, and treatment of these syndromes, emphasizing their common aspects. The misdiagnosis of this association may justify in some cases the controversial results reported regarding the surgical treatment of these syndrome.

Choledocholithiasis caused by migration of a surgical clip after video laparoscopic cholecystectomy.

We present a case of a 67-year-old woman, in which a clip in the common bile duct (CBD) was the nidus of stone formation. The ultrasonographic examination reported a CBD with an abnormally large diameter and an endoscopic retrograde sphincterotomy showed a stone in the ampulla. The stone was extracted through the Vaters Papilla and the patient was discharged after 24 hours.