Deborah Bonamini

Mutations in the SPINK1 gene in idiopathic pancreatitis Italian patients

Idiopathic chronic and acute recurrent pancreatitis (IP) have been associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Mutations in the serine protease inhibitor Kazal 1 (SPINK1) have been described in some idiopathic chronic patients and it has been suggested that mutations in this gene could be responsible for a loss of trypsin inhibitor function. In this study, the 5′UTR region, and the four exons and exon–intron boundaries of the SPINK1 gene in 32 IP patients have been analyzed. Three IP patients (9.3%) and one control/100 carried the N34S mutation of the SPINK1 gene (Fishers exact test, P=0.044). No other mutation that could be associated with an altered function of the SPINK1 protein was observed. The N34S mutation was present in two patients who carried the CFTR-IVS8 5T variant and in one who carried the L997F variant in the CFTR gene. The association of SPINK1 with CFTR gene mutations in IP patients is statistically significant (3/32 IP cases and 0/100 control individuals carrying mutations in both genes; Fishers exact test P=0.01).

CD45 and multiple sclerosis: the exon 4 C77G polymorphism (additional studies and meta-analysis) and new markers

We re-evaluated the association with multiple sclerosis (MS) of the C77G splicing regulatory variation in the CD45 gene and screened for new mutations the three alternatively spliced exons (#4, 5 and 6). No association with C77G was detected in two groups of patients (total=448) and controls (total=559) from Northern and Southern Italy. When excluding the first published study indicating a positive association, a meta-analysis of the five further studies conducted to date (including the present one) led to a non-significant combined odds ratio (OR) of 1.11. None of the four newly identified nucleotide substitutions, namely C77T (Pro59Pro) in exon 4, G69C (Asp121His) in exon 5, T127A (Ile187Asn) and A138G (Thr191Ala) in exon 6, was significantly associated to MS.

Myelin oligodendrocyte glycoprotein polymorphisms and multiple sclerosis.

A detailed analysis of the coding sequences of myelin oligodendrocyte glycoprotei (MOG) gene was performed in multiple sclerosis (MS) patients and in control individuals and three new polymorphisms are described: T636C, nt 571+77C-->T (IVS 4), and nt 710-44A-->G (IVS 6). Screening studies demonstrated that T636C was present in three MS patients and in no control individual and that polymorphisms nt 571+77C-->T (IVS 4), and nt 710-44A-->G (IVS 6), were present with no significant frequency differences in MS patients and control individuals. No mutations were found after sequencing the coding sequences of the extracellular domain of MOG gene in 20 MS patients and 20 control individuals. Screening studies were also performed for known polymorphisms: G15A, Val142Leu, nt 571+68A-->G (IVS 4), and 571+92C-->G (IVS 4). Polymorphism Val 142 Leu, which is linked to nt 571+68A-->G (IVS 4), resulted under-represented in MS patients.

Cationic trypsinogen and pancreatic secretory trypsin inhibitor gene mutations in neonatal hypertrypsinaemia

Neonatal hypertrypsinaemia with normal sweat chloride detected during CF screening may be related to trypsin activation. We have looked for mutations of the cationic trypsinogen (PRSS1) and pancreatic secretory trypsin inhibitor (PSTI) genes in 50 hypertrypsinaemic neonates with known CFTR genotypes and negative sweat test. No mutations were found in either gene. Two silent polymorphisms were detected in the PRSS1 gene. A polymorphism in the promoter region and an intronic polymorphism of the PSTI gene were found. No difference was observed in the frequency of PRSS1 or PSTI polymorphisms in neonates carrying or not carrying CF mutations. These results do not provide an indication for an increased frequency of mutations in the PRSS1 and PSTI genes in this group of neonates with transient hypertrypsinaemia.

Pancreaticoduodenectomy in patients ≥ 75 years of age: Are there any differences with other age ranges in oncological and surgical outcomes? Results from a tertiary referral center

AIM To compare surgical and oncological outcomes after pancreaticoduodenectomy (PD) in patients ≥ 75 years of age with two younger cohorts of patients. METHODS The prospectively maintained Institutional database of pancreatic resection was queried for patients aged ≥ 75 years (late elderly, LE) submitted to PD for any disease from January 2010 to June 2015. We compared clinical, demographic and pathological features and survival outcomes of LE patients with 2 exact matched cohorts of younger patients [≥ 40 to 64 years of age (adults, A) and ≥ 65 to 74 years of age (young elderly, YE)] submitted to PD, according to selected variables. RESULTS The final LE population, as well as the control groups, were made of 96 subjects. Up to 71% of patients was operated on for a periampullary malignancy and pancreatic cancer (PDAC) accounted for 79% of them. Intraoperative data (estimated blood loss and duration of surgery) did not differ among the groups. The overall complication rate was 65.6%, 61.5% and 58.3% for LE, YE and A patients, respectively, P = NS). Reoperation and cardiovascular complications were significantly more frequent in LE than in YE and A groups (P = 0.003 and P = 0.019, respectively). When considering either all malignancies and PDAC only, the three groups did not differ in survival. Considering all benign diseases, the estimated mean survival was 58 and 78 mo for ≥ and < 75 years of age (YE + A groups), respectively (P = 0.012). CONCLUSION Age is not a contraindication for PD. A careful selection of LE patients allows to obtain good surgical and oncological results.

Screening/surveillance programs for pancreatic cancer in familial high-risk individuals: A systematic review and proportion meta-analysis of screening results

BACKGROUND/OBJECTIVES Screening/surveillance programs for pancreatic cancer (PC) in familial high-risk individuals (FPC-HRI) have been widely reported, but their merits remain unclear. The data reported so far are heterogeneous-especially in terms of screening yield. We performed a systematic review and meta-analysis of currently available data coming from screening/surveillance programs to evaluate the proportion of screening goal achievement (SGA), overall surgery and unnecessary surgery. METHODS We searched MEDLINE, Embase, PubMed and the Cochrane Library database from January 2000 to December 2016to identify studies reporting results of screening/surveillance programs including cohorts of FPC-HRI. The main outcome measures were weighted proportion of SGA, overall surgery, and unnecessary surgery among the FPC-HRI cohort, using a random effects model. SGA was defined as any diagnosis of resectable PC, PanIN3, or high-grade dysplasia intraductal papillary mucinous neoplasm (HGD-IPMN). Unnecessary surgery was defined as any other final pathology. RESULTS In a meta-analysis of 16 studies reporting on 1551 FPC-HRI cases, 30 subjects (1.82%), received a diagnosis of PC, PanIN3 or HGD-IPMNs. The pooled proportion of SGA was 1.4%(95% CI 0.8-2, p < 0.001, I2 = 0%). The pooled proportion of overall surgery was 6%(95% CI 4.1-7.9, p < 0.001, I2 = 60.91%). The pooled proportion of unnecessary surgery was 68.1%(95% CI 59.5-76.7, p < 0.001, I2 = 4.05%); 105 subjects (6.3%) received surgery, and the overall number of diagnoses from non-malignant specimens was 156 (1.5 lesion/subject). CONCLUSIONS The weighted proportion of SGA of screening/surveillance programs published thus far is excellent. However, the probability of receiving surgery during the screening/surveillance program is non-negligible, and unnecessary surgery is a potential negative outcome.

Vanishing Pancreatic Cysts during Follow-Up: Another Step Towards De-Emphasizing Cyst Size as a Major Clinical Predictor of Malignancy

Introduction: In the management of pancreatic cystic neoplasms (PCN), size plays a crucial role as the expression of disease progression. While many evidences regarding the natural history of growing pancreatic cysts exist, almost no data are available regarding cysts with a reduction in size. Methods: Radiological and clinical data from patients of the dedicated pancreatic cysts outpatient clinic of the Department of General and Pancreatic Surgery, University of Verona Hospital were retrospectively reviewed. Patients diagnosed with PCNs reducing in size during follow-up were reviewed. Results: From a total of 3,146 patients, we identified 12 (0.38%) vanishing/reducing cysts without a history of pancreatitis. Most of them were presumed IPMN (66.6%). The median follow-up was 69 months and the median cyst’s size 30 mm (range 10–49). Most of the patients (75%) experienced a reduction in cyst size (median reduction of 8 mm, range 6–22) after a median time of 12 months (range 6–63), 3 patients experienced a complete disappearance of the cyst. Conclusion: Cyst size reduction during follow-up is a rare phenomenon of unknown explanation. It adds to the debate regarding the role of size as a clinical predictor whenever a definite diagnosis of a PCN cannot be reached.