Substance P and neprilysin in chronic pancreatitis.

BACKGROUND/AIMS: We aimed to analyze substance P (SP) and neprilysin (NEP), the membrane metallopeptidase that degrades SP, in chronic pancreatitis (CP). METHODS: SP and NEP mRNA levels were analyzed by qRT-PCR in tissue samples from 30 patients with CP and 8 organ donors. In addition, SP serum levels were determined before and after surgery in the same patients, by means of a competitive ELISA assay. Genetic and epigenetic analyses of the NEP gene were also performed. RESULTS: SP mRNA expression levels were higher in CP tissues compared to controls (p = 0.0152), while NEP mRNA showed no significant differences between CP and healthy subjects (p = 0.2102). In CP patients, SP serum levels correlated with those in tissue, and after surgical resection SP serum levels were reduced compared to the preoperative values. Failure of NEP to overexpress in CP tissues was associated with significant miR-128a overexpression (p = 0.02), rather than with mutations in the NEP coding region or the presence of hypermethylation sites in the NEP promoter region. CONCLUSION: Tissue and serum levels of SP were increased in CP, while NEP levels remained unaltered. In an SP/NEP-mediated pathway, it would appear that NEP fails to provide adequate surveillance of SP levels. Failure of NEP to overexpress could be associated with miRNA regulation.

Pancreatic insufficiency after different resections for benign tumours.

BACKGROUND: Pancreatic resections for benign diseases may lead to long-term endocrine/exocrine impairment. The aim of this study was to compare postoperative and long-term results after different pancreatic resections for benign disease. METHODS: Between 1990 and 1999, 62 patients underwent pancreaticoduodenectomy (PD), 36 atypical resection (AR) and 64 left pancreatectomy (LP) for benign tumours. Exocrine and endocrine pancreatic function was evaluated by 72-h faecal chymotrypsin and oral glucose tolerance test. RESULTS: The incidence of pancreatic fistula was significantly higher after AR than after LP (11 of 36 versus seven of 64; P = 0.028). The long-term incidence of endocrine pancreatic insufficiency was significantly lower after AR than after PD (P < 0.001). Exocrine insufficiency was more common after PD (P < 0.001) and LP (P = 0.009) than after AR. The probability of developing both endocrine and exocrine insufficiency was higher for PD and LP than for AR (32, 27 and 3 per cent respectively at 1 year; 58, 29 and 3 per cent at 5 years; P < 0.001). CONCLUSION: Different pancreatic resections are associated with different risks of developing long-term pancreatic insufficiency. AR represents the best option in terms of long-term endocrine and exocrine function, although it is associated with more postoperative complications.

Vanilloids in pancreatic cancer: potential for chemotherapy and pain management.

BACKGROUND: Success of chemotherapy and alleviation of pain are frequently less than optimal in pancreatic cancer patients, leading to increasing interest in new pharmacological substances, such as vanilloids. Our study addressed the question of whether vanilloids influence pancreatic cancer cell growth, and if vanilloids could be used for pain treatment via the vanilloid 1 receptor (VR1) in pancreatic cancer patients. METHODS: In vitro, the effect of resiniferatoxin (vanilloid analogue) on apoptosis and cell growth in pancreatic cancer cells--either alone, combined with 5-fluorouracil (5-FU), or combined with gemcitabine--was determined by annexin V staining, FACS analysis, and MTT assay, respectively. VR1 expression was evaluated on RNA and protein level by quantitative polymerase chain reaction and immunohistochemistry in human pancreatic cancer and chronic pancreatitis. Patient characteristics--especially pain levels--were registered in a prospective database and correlated with VR1 expression. RESULTS: Resiniferatoxin induced apoptosis by targeting mitochondrial respiration and decreased cell growth in pancreatic cancer cells without showing synergistic effects with 5-FU or gemcitabine. Expression of VR1 was significantly upregulated in human pancreatic cancer and chronic pancreatitis. VR1 expression was related to the intensity of pain reported by cancer patients but not to the intensity of pain reported by patients with chronic pancreatitis. CONCLUSIONS: Resiniferatoxin induced apoptosis in pancreatic cancer cells indicates that vanilloids may be useful in the treatment of human pancreatic cancer. Furthermore, vanilloid might be a novel and effective treatment option for neurogenic pain in patients with pancreatic cancer.

Role of unlabelled somatostatin analogues in the prevention of complications after elective pancreatic and peripancreatic surgery: a critical review.

Although studies on the use of the somatostatin analogues in the elective pancreatic surgery are mostly prospective, double blind and randomised, the results are contradictory and not univocally interpretable. Through the examination of all randomised perspective works published on this subject, a critical interpretation is attempted which may give relevant suggestions for further studies. A new clinical, randomised, double blind and multicentric prospective trial should take into proper consideration even the changes which have occurred in the care of the patients. Over the years a significant decrease of postoperative hospital stay and a deeper awareness of the medical expenses have been observed. Moreover, since the drug has a potential advantage on specific pancreatic complications, only these must be considered among the end points of the study and the population studied will be limited exclusively to patients who underwent resection of the pancreatic head or of the periampullar region because of neoplastic disease. Finally, the selection of the centres that enrol the patients must be considered, since the expertise of each operator or of the team, affects, as an independent variable, both morbidity and mortality.

[Intermediate resection and distal pancreatectomy for benign neoplasms of the pancreas: comparison of postoperative complications and costs]. / Resezione intermedia e pancreasectomia distale per neoplasie benigne del pancreas: confronto per complicanze postoperatorie e costi.

The middle pancreatic resection for benign pathology of the pancreas has been proposed as an advantageous alternative to the distal pancreatectomy, even though the risk of complications is greater. The purpose of the present study is to compare the cost and intra and perioperative impact for the 2 procedures. All patients with benign neoplasia of the body and tail of the pancreas operated on from 1990-1999 were selected from our computer archives, 21 patients underwent an intermediate resection and 64 a distal pancreatectomy. Operative time, units transfused, perioperative complications, post-operative stay and cost were compared. Statistical analysis revealed that the 2 operations are not significantly different in the intra-operative period. Comparing serious complications, the percentage of pancreatic fistulas (33% vs. 11%; P < 0.03) and average hospital stay (21.2 +/- 11.7 days vs. 15.5 +/- 7.1 days; p = 0.009) are greater for the middle than distal resection, respectively. In cases with post-operative complications the hospital stay is even more significant (middle 31.8 +/- 10.3 days vs. 19.1 +/- 7.6 days; p = 0.0002). The economic margin of residual costs, calculated by using the difference of DRG (no 192) and average post-operative costs, is similar for the 2 procedures in cases with normal post-operative courses, (intermediate Euro 2890.02; distal Euro 3181.9), while in cases with complications (DRG no 191), the difference increases (intermediate Euro 8670.11; distal Euro 12788.94). The middle pancreatic resection in respect to the distal pancreatectomy presents a greater technical difficulty when you take into account the longer post-operative course, the increased difficulty in treating complications and the increased costs.

Beneficial effects of Batimastat (BB-94), a matrix metalloproteinase inhibitor, in rat experimental colitis.

BACKGROUND AND AIMS: Matrix metalloproteinases (MMPs) represent a group of enzymes that regulate cell-matrix composition playing a major role in the inflammatory response. In the present study we evaluated the ability of the MMP inhibitor Batimastat (BB-94) to modify the course of experimental colitis induced in the rat by trinitrobenzensulfonic acid (TNB). METHODS: Colitis was induced in 40 rats by intracolonic administration of TNB. Animals were divided into four groups of ten rats each: group 1 received only intracolonic TNB, group 2 received TNB+5 mg/kg intraperitoneal BB-94, group 3 TNB+10 mg/kg BB-94 and group 4 TNB+20 mg/kg BB-94. The MMP inhibitor was administered 30 min before induction of colitis and twice daily until death. Ten rats receiving only intracolonic 0.9% saline served as controls. Animals were killed after seven days; segments of colon were removed and used for histological score of inflammation and myeloperoxidase (MPO) activity. RESULTS: Rats receiving only intracolonic 0.9% saline showed no evidence of colitis. The inflammation score was 0.9, MPO activity 0.235 U/mg. Group 1 (TNB-treated rats) exhibited a high inflammation score (12.4) and MPO activity (0.715 U/mg). Conversely, BB-94-treated rats showed, compared to the TNB group, a significantly lower inflammation score and MPO activity in a dose-dependent fashion. Group 2: inflammatory score 10.1, MPO activity 0.474 (p < 0.05 vs. TNB); group 3: inflammatory score 8.3, MPO activity 0.287 (p < 0.01 vs. TNB); group 4: inflammatory score 5.0, MPO activity 0.256 (p < 0.01 vs. TNB). CONCLUSIONS: Treatment with BB-94 has dose-dependent beneficial effects on the inflammatory alterations in rat experimental colitis. Thus, the inhibition of MMPs may represent a novel therapeutic approach for treatment of intestinal inflammation.

Management of complications after pancreaticoduodenectomy in a high volume centre: results on 150 consecutive patients.

Pancreaticoduodenectomy (PD) is still a difficult procedure with significant morbidity. We report 150 consecutive PDs performed during a 3-year period. All the cases have been prospectively evaluated with regard to the surgical outcome. Mortality in this series was 3/150 (2%) with a re-operation rate of 5/150 (3.3%); surgical complications were experienced in 57/150 (38%). The most frequent complications were collections in 25/150 (16.6%) and pancreatic fistulas in 16/150 (10.7%). The majority of these complications were conservatively managed: only one abscess and one fistula due to an anastomotic dehiscence required re-operation. The complication most responsible for mortality was haemorrhage secondary to arterial pseudoaneurysms in patients with severe post-operative pancreatitis. The continued high morbidity of PDs is compensated by the ability to treat complications non-operatively, resulting in a surgical risk that should now be considered medium to low in high volume centres.

Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines.

New efforts in cancer therapy are being focused at various levels of signaling pathways. With phosphoinositide 3-kinase (PI3-K) potentially being necessary for a range of cancer-related functions, we have investigated the influence of selected inositol tris- to hexakisphosphates on cell growth and tumorigenicity. We show that micromolar concentrations of inositol 1,3,4,5,6-pentakisphosphate and inositol 1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P(4)] inhibit IGF-1-induced [(3)H]-thymidine incorporation in human breast cancer (MCF-7) cells and the ability to grow in liquid medium and form colonies in agarose semisolid medium by small cell lung cancer (SCLC) cells, a human cancer cell line containing a constitutively active PI3-K. In an ovarian cancer cell line that also contains a constitutively active PI3-K (SKOV-3 cells), Ins(1,4,5,6)P(4) again inhibited liquid medium growth. Furthermore, when applied extracellularly, inositol 1,3,4,5-tetrakisphosphate was shown indeed to enter SCLC cells. These effects appeared specifically related to PH domains known to bind to phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P(2)] and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)], indicating involvement of the PI3-K downstream target protein kinase B (PKB/Akt). This was further supported by inhibition of PKB/Akt PH domain membrane targeting in COS-7 cells by Ins(1,4,5,6)P(4). Thus, we propose that specific inositol polyphosphates inhibit PI3-K by competing with PtdIns(3,4, 5)P(3)-binding PH domains and that this occurs mainly at the level of the downstream PI3-K target, PKB/Akt.