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The natural course of progressive neuromuscular diseases can be complicated by respiratory muscle involvement. In muscular dystrophies such as Duchenne muscular dystrophy and myotonic dystrophy, respiratory muscle involvement is common. In others such as Becker, limb-girdle, and facioscapulo-humeral dystrophies, respiratory muscle involvement is infrequent and generally occurs in the more severe cases. Recently, it was reported that a mutation in the dysferlin gene and/or dysferlin deficiency causes proximal and distal forms of muscular dystrophy, which are known by the term dysferlinopathy. We describe a case of severe weakness of both limb-girdle and respiratory muscles in a patient who was carrier of the dysferlin gene mutation and who also had COPD. We suggest that the systemic inflammatory response of COPD and the dysferlin deficit interact and are responsible for both the skeletal and respiratory muscle impairment.

Background: Parenchyma-preserving resections (PPRs), including enucleation and middle pancreatectomy (MP), are accepted procedures for insulinomas, but their role in the treatment of nonfunctioning pancreatic endocrine tumors (NF-PETs) is debated. The aim of this study was to evaluate perioperative and long-term outcomes after PPRs for NF-PETs., Methods: All patients who underwent PPRs for NF-PETs between 1990 and 2005 were included. Patients with multiple endocrine neoplasia type 1 were excluded., Results: Overall, 50 patients (23 men, 27 women, median age 59 years) underwent 26 enucleations and 24 MP. A total of 58% of NF-PETs were incidentally discovered. Median size of the tumors was 13.5 mm with no preoperative suspicion of malignancy in all patients. Overall morbidity and pancreatic fistula rates were 58 and 50%, respectively. Reoperation rate was 4%, with no mortality. Postoperative complications were higher in the MP group. At pathology, there were 34 (68%) benign lesions, 13 (26%) neoplasms of uncertain behavior, and 3 (6%) well-differentiated carcinomas. Forty-one patients (82%) had tumors < or =2 cm in size. Only eight patients (16%) had at least one lymph node removed. After a median follow-up of 58 months, no patient died of disease. Overall, four patients (8%) experienced tumor recurrence after a mean of 68 months. The incidence of exocrine/endocrine insufficiency was 8%., Conclusions: PPRs are generally safe and effective procedures for treating small NF-PETs. However, better selection criteria must be identified, and lymph node sampling should be performed routinely to avoid understaging. Long-term follow-up evaluation (>5 years) is of paramount importance given the possible risk of late recurrence.

Purpose: The role and timing of chemotherapy and radiation for treating stage III pancreatic adenocarcinoma remains controversial., Methods: Treatment-naive patients with stage III non-resectable pancreatic adenocarcinoma were treated with PEFG/PEXG (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), gemcitabine) or PDXG (docetaxel substituting epirubicin) regimen for 6 months followed by radiotherapy (50-60 Gy) with concurrent F or X or G., Results: Ninety-one patients were registered between April 1997 and December 2007. Forty-three patients (47%) had a partial remission and 38 (42%) had a stable disease. Thirteen patients (14%) were radically resected yielding one pathologic complete remission. Median survival (OS) was 16.2 months. Median progression-free survival was 9.9 months. Pattern of failure consisted of isolated local failure (N = 26, 35%); both local and systemic failure (N = 14, 19%); isolated systemic failure (N = 35, 47%)., Conclusion: Combination chemotherapy with four-drug regimens followed by chemoradiation was a feasible strategy showing relevant results in stage III pancreatic adenocarcinoma.

Background: Radiologic assessment of tumor response in pancreatic cancer is complicated by desmoplastic reactions within or around the tumor. The objective of this study was to evaluate the correlation between a decline in carbohydrate antigen 19-9 (CA 19-9) and survival in patients with advanced pancreatic cancer who received upfront chemotherapy., Methods: CA 19-9 serum basal values were measured in 247 patients with advanced pancreatic cancer who were enrolled in 5 consecutive trials between 1997 and 2007. Survival curves were compared among patients who had a predefined CA 19-9 nadir variation (<50%. Group 1; 50% to 89%, Group 2; or >89%, Group 3). To eliminate guarantee-time bias, survival analysis was repeated using the landmark method., Results: In both univariate and multivariate analysis, the basal CA 19-9 value significantly predicted survival. The median survival was 15.5 months for 34 patients who had normal basal CA 19-9 values, 11.9 months for 108 patients who had basal values between 38 U/mL and 1,167 U/mL, and 8 months for 105 patients who had basal values >1,167 U/mL. At least 1 CA 19-9 follow-up value was available for 204 patients who had baseline values greater than normal. A significant difference in overall survival was observed in univariate and multivariate analyses between Groups 1 and 2, between Groups 1 and 3, and between Groups 2 and 3. The results were confirmed using the landmark method., Conclusions: In this study, baseline CA 19-9 was confirmed as an independent prognostic factor for survival, and it may be considered as a stratification factor in trials in patients with advanced pancreatic cancer. Biochemical response may be used as a complementary measure to radiologic response to provide a better assessment of chemotherapy activity and to drive treatment decisions in clinical practice., ((c) 2009 American Cancer Society.)

Background: Data on enhanced recovery programmes after pancreatic surgery are sparse. This retrospective cohort study, using historical controls, aimed to evaluate the impact of a fast-track programme after pancreaticoduodenectomy (PD)., Methods: Between 2004 and 2007, 252 patients undergoing PD were treated by a fast-track programme that included earlier postoperative feeding and mobilization. The patients were compared with an equally sized control group that received a traditional programme from 2000 to 2004. Outcome measures were morbidity, length of stay and readmission rate., Results: The rates of pancreatic fistula and other intra-abdominal complications were similar in the two groups. Delayed gastric emptying (DGE) was significantly reduced in the fast-track group (13.9 versus 24.6 per cent; P = 0.004). The independent effect of the fast-track protocol in reducing DGE was confirmed by the multiple regression analysis (adjusted odds ratio 0.477, P = 0.005). Length of stay was reduced with the fast-track protocol (median 13 versus 15 days; P < 0.001), without increasing the readmission rate (7.1 versus 6.3 per cent; P = 0.865)., Conclusion: A fast-track programme after PD improves gastric emptying and reduces postoperative stay., (Copyright (c) 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: Pancreas is a possible site of metastases from renal cell carcinoma (RCC). The aim of this study was to define the role of surgery in their treatment., Methods: We retrospectively analyzed 36 patients with pancreatic metastasis from RCC observed between January 1998 and February 2006. Patients were categorized into three risk groups according to the modified Memorial Sloan-Kettering prognostic factors model., Results: Resective surgery was performed in 23 patients, as follows: 11 distal pancreatectomy, 5 enucleation, 4 pancreatoduodenectomy, 2 total pancreatectomy, and 1 middle pancreatectomy. No perioperative mortality was observed; the morbidity rate was 47.8%. All patients who underwent resection belonged to the favorable risk group. Surgical resection was excluded in 13 cases because of locally advanced disease (2 cases) or extrapancreatic disease (11 cases); 5 of these patients were at favorable, 7 at intermediate, and 1 at poor risk. In patients undergoing surgery, the 5-year actuarial survival rate was 88%, and median disease-free survival was 44 months. Patients who did not undergo surgery had a 5-year survival rate of 47%, with a median survival time of 27 months (P = .02)., Conclusions: Patients with pancreatic metastases from RCC belonging to a favorable risk group are candidates for resection, even in the presence of another metastatic site or multifocal pancreatic disease.

Objective: The therapeutic arsenal for salvage therapy in pancreatic cancer is limited. PEFG (cisplatin, epirubicin, 5-fluorouracil [FU], gemcitabine) regimen is an effective upfront treatment in advanced pancreatic cancer. The activity and safety of this combination regimen were assessed by means of an observational study in a population of patients with progressive or recurrent pancreatic adenocarcinoma after gemcitabine-containing chemotherapy., Methods: Patients with age <76 years, Karnofsky performance status >50 were treated with either classic PEFG (until April 2004: cisplatin and epirubicin 40 mg/m day 1, gemcitabine 600 mg/m day 1 and 8, FU 200 mg/m/d continuous infusion day 1-28) or dose-intense PEFG (since May 2004: cisplatin and epirubicin 30 mg/m, gemcitabine 800 mg/m every 14 days; FU 200 mg/m/d continuous infusion day 1-28) until progressive disease or a maximum of 6 cycles of 28 days., Results: Forty-six patients (37 metastatic) received 69 cycles of classic PEFG (18 patients) or 104 cycles of dose-intense PEFG (28 patients) as second-line therapy. Prior treatment consisted of single agent gemcitabine (N = 17), gemcitabine-based chemotherapy (N = 4), or PEFG regimen (N = 25). Median previous progression-free survival was 7.6 months. Dose intensity (mg/m/wk) with classic PEFG was cisplatin and epirubicin 8.5; gemcitabine 230; FU 1035 and with dose-intense PEFG was cisplatin and epirubicin 11.5 (+36%); gemcitabine 259 (+13%); FU 1046 (+1%). Main grade >2 toxicity consisted of neutropenia in 26 patients (56%), thrombocytopenia in 10 (22%), anemia in 11 (24%), fatigue and stomatitis in 4 (9%), vomiting, diarrhea and hand-foot syndrome in 2 (4%). Partial response was observed in 11 patients (24%) (5 classic PEFG 28% + 6 dose-intense PEFG 21%). Median and 1-year survival was 8.3 months (8.0 vs. 9.0 months) and 26% (17% vs. 32%). Median and 6-months progression-free survival was 5.0 months (4.5 vs. 5.0 months) and 34% (33% vs. 38%)., Conclusions: PEFG regimen in gemcitabine refractory pancreatic cancer had an acceptable toxicity profile and interesting activity, and may constitute a treatment option in this setting.

Background: An inverse relationship between hospital volume and death following pancreatico duodenectomy (PD) has been reported from several countries. The aim of this study was to assess the volume-outcome effect of PD in Italy., Methods: The study group comprised 1576 patients who underwent PD in 2003. Hospitals were allocated to four volume groups: low volume, five PDs or fewer; medium volume, six to 13 PDs; high volume, 14 to 51 PDs; and very high volume, two hospitals that performed 89 and 104 PDs., Results: Some 221 hospitals performed at least one PD in 2003; hospital volume was low in 74.7 per cent, medium in 17.6 per cent, high in 6.8 per cent and very high in 0.9 per cent. The overall mortality rate was 8.1 per cent. Increasing hospital volume was associated with a significantly reduced mortality rate: 12.4 per cent (adjusted odds ratio (OR) 1.000) for low-volume, 7.8 per cent (OR 0.611) for medium-volume, 5.9 per cent (OR 0.466) for high-volume and 2.6 per cent (OR 0.208) for very high-volume hospitals. Length of postoperative stay was reduced in very high-volume hospitals (P < 0.001)., Conclusion: The outcome of PD in Italy is dependent on hospital volume and a policy of centralization may therefore be appropriate., (2007 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Bronchiectasis is a chronic and debilitating lung disease, characterised by irreversible dilatation of the bronchi as consequence of airway injury and remodelling due to recurrent or chronic airway inflammation and infection. The underlying aetiologies include autoimmune diseases, severe infections, genetic abnormalities and acquired disorders. The pathogenesis of bronchiectasis is poorly understood. Three distinct pathogenetic elements, namely infection, inflammation and enzymatic actions, which interact with each other, have been implicated in the pathophysiology of bronchiectasis. Some recent observations indicate that airway inflammation in bronchiectasis comes from a deregulated cytokine network independent of bacterial airway colonisation. In the present review, current knowledge about cellular and molecular inflammatory events in the dynamic process of host-pathogen interaction that are thought to play a relevant role in the pathogenic mechanisms of airway wall destruction leading to bronchiectasis are discussed.

Background: Exercise training improves exercise tolerance in chronic obstructive pulmonary disease (COPD). Tiotropium 18 microg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation, one of the pathophysiological factors contributing to exertional dyspnea in COPD patients., Aim: To determine whether tiotropium enhances the effects of exercise training in patients with COPD., Design: Multicenter, 25 week randomized, double-blind, placebo-controlled, parallel-group study., Setting: Twelve Italian Pulmonary Units practicing pulmonary rehabilitation., Patients and Intervention: Two hundred thirty four COPD patients (196 males; mean age: 67.4 +/- 7.6; forced expiratory volume at 1 second (FEV1): 41.4 +/- 13.0% predicted) were randomised to tiotropium 18 microg or placebo inhalation capsules taken once daily. Both groups underwent a 8 week pulmonary rehabilitation program (PR) consisting of 3 exercise training session per week., Measurements: Baseline, at the end of PR and after 12 weeks, patients completed pulmonary function testing, six minute walking test (6MWT), the Baseline and Transition Dyspnea Index (BDI and TDI), and the St. George's Respiratory Questionnaire (SGRQ)., Results: Relative to placebo, tiotropium had larger trough and post-study drug FEV1 responses on all test days. At the end of and 12 weeks following PR, patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo. Compared to the period immediately prior to PR, the mean improvement in 6MWT was only 29.7 meters (7.1%) for the combined cohort. Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo (p < 0.01). At 12 weeks after PR, TDI focal scores were 2.71 for tiotropium and 2.11 for placebo (p = 0.16). Reduction in all four SGRQ component scores, indicating an improvement in health-related quality of life, was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant. During the study period, there were fewer exacerbations and exacerbation days in the tiotropium group., Conclusion: Although significant improvements were observed with perceived dyspnea, compared to placebo, the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT.

Unlabelled: While the effectiveness of pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) is well established, its effectiveness in the most severe category of COPD, i.e. patients with chronic respiratory failure (CRF), is less well known., Objective: To verify the effects of PR in patients with CRF, and compare the level of improvement with PR in these patients to that of COPDs not affected by CRF., Methods: A multi-centre study was carried out on COPD patients with versus without CRF. The PR program included educational support, exercise training, and nutritional and psychological counselling. Lung function, arterial gases, walk test (6MWT), dyspnoea (MRC; BDI/TDI), and quality of life (MRF(28); SGRQ) were evaluated., Results: Thousand forty seven consecutive COPD inpatients (327 with CRF) were evaluated. In patients with CRF all parameters improved after PR (0.001). Mean changes: FEV(1), 112 ml; PaO(2), 3.0 mmHg; PaCO(2), 3.3 mmHg; 6MWT, 48 m; MRC, 0.85 units; MRF(28) total score, 11.5 units. These changes were similar to those observed in patients without CRF., Conclusions: This study, featuring the largest cohort so far reported in the literature, shows that PR is equally effective in the more severe COPD patients, i.e. those with CRF, and supports the prescription of PR also in these patients.

Background: PEFG regimen (cisplatin and epirubicin 40 mg/m2 day 1, gemcitabine 600 mg/m2 days 1 and 8, 5-fluorouracil (FU) 200 mg/m2/day continuous infusion) significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine in a previous phase III trial. This regimen was subsequently modified in a dose-finding study by increasing dose intensity of cisplatin and epirubicin (both at 30 mg/m2 every 14 days) and of gemcitabine (at 800 mg/m2 every 14 days). Results of a consecutive series treated by dose-intense PEFG regimen are herewith reported., Material and Methods: Dose-intense PEFG was administered to chemotherapy-naive patients with stages III-IV PA, < 75 years, performance status (PS) > 50, till progressive disease or for a maximum of 6 months., Results: Between January 2004 and June 2005, 49 (31 or 63% metastatic) patients, median age 62 years, median PS 80, were treated with dose-intense PEFG. Partial response and stable disease was observed in 24 (49%) and 16 (33%) patients, respectively; 31 patients were progression-free at 6 months (PFS-6 = 63%). Median survival was 10.5 months and 1-year overall survival (OS) was 48% (95% confidence interval: 33-61%). Main grade 3-4 toxicity was: neutropenia in 26% of patients, stomatitis and fatigue in 8%, anaemia, diarrhoea, nausea/vomit in 6%, febrile neutropenia and thrombocytopaenia in 4%, hand-foot syndrome in 2%., Conclusion: When compared with 84 patients treated by classical PEFG at the same institution, dose-intense PEFG was not inferior in terms of PFS-6 (63 versus 57%), 1-year OS (48 versus 42%) and response rate (49 versus 49%); it allowed to increase dose intensity for gemcitabine by 32%, for cisplatin and epirubicin by 36% (FU reduced by 3%), to significantly reduce grade 3-4 hematological toxicity (neutropenia: 26 versus 86%; P < 0.00001; thrombocytopaenia: 4 versus 58%; P < 0.00001) and to reduce by one-third the number of outpatient accesses. The new PEFG schedule appears more suitable for clinical use and should be preferred as a basis for further development of therapeutic strategies against pancreatic cancer.

The aim of this study was to assess the maximum tolerated dose (MTD) of an intensified PEFG regimen administered every 14 days to patients with Stage III or metastatic pancreatic adenocarcinoma. Twenty-nine patients received fixed doses of both epirubicin (30 mg/m2) and 5-fluorouracil (200 mg/m2/day on Days 1-14) and of escalating doses of cisplatin and gemcitabine. The MTD was cisplatin 30 mg/m2 and gemcitabine 800 mg/m2. With respect to classical PEFG, intensified regimen potentially improved the dose-intensity of both cisplatin and epirubicin by 50 percent and of gemcitabine by 33 percent, reduced Grade 3-4 haematological toxicity and the number of outpatient accesses.

Limited information on salvage treatment in patients affected by pancreatic cancer is available. At failure, about half of the patients present good performance status (PS) and are candidate for further treatment. Patients >18 years, PS >or=50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-containing chemotherapy, and progression-free survival (PFS) <12 months received a combination of raltitrexed (3 mg m(-2)) and oxaliplatin (130 mg m(-2)) every 3 weeks until progression, toxicity, or a maximum of six cycles. A total of 41 patients received 137 cycles of chemotherapy. Dose intensity for both drugs was 92% of the intended dose. Main grade >2 toxicity was: neutropenia in five patients (12%), thrombocytopenia, liver and vomiting in three (7%), fatigue in two (5%). In total, 10 patients (24%) yielded a partial response, 11 a stable disease. Progression-free survival at 6 months was 14.6%. Median survival was 5.2 months. Survival was significantly longer in patients with previous PFS >6 months and in patients without pancreatic localisation. A clinically relevant improvement of quality of life was observed in numerous domains. Raltitrexed-oxaliplatin regimen may constitute a treatment opportunity in gemcitabine-resistant metastatic pancreatic cancer. Previous PFS interval may allow the identification of patients who are more likely to benefit from salvage treatment.

The study of pancreatic diseases requires specific knowledge and experience. There are many reasons for the need of a specific approach: pancreatic diseases are rare, their clinical presentation is often misleading, diagnostic investigations pose many challenges and pancreatic surgery is very complex. Due to these characteristics, it is difficult for a physician who only occasionally deals with a pancreatic disease to correctly manage it. For example, it is not sufficient to make a diagnosis of "pancreatic tumor", because we have to precisely define its extension and its relationship with the surrounding vessels, to recognize rare histological types different from adenocarcinoma, to have a "pancreatic" surgical experience to lessen the risk of serious surgical complications. On the other hand, several reports have shown that pancreatic resections have lower mortality rates and better long-term outcomes if carried out in Centers with a high caseload of patients. These considerations support the creation of Pancreas Units, not mere high-volume Departments specialized in pancreatic diseases, but multidisciplinary teams (composed of surgeons, oncologists, gastroenterologists, pathologists, radiologists, radiotherapists and different types of researchers) devoted to all aspects (etiology, pathogenesis, diagnosis, treatment) of pancreatic diseases. We think that the adoption of a Pancreas Unit model could represent the right answer to the recent changes observed in Medicine and could offer a better approach to patients with pancreatic diseases.

The aim of the study was to identify factors related to the onset of pancreatic fistula and to define the characteristics of the fistula. The study group was composed of 123 patients who underwent left pancreatectomy since 1996. Pancreatic closure was accomplished by a hand-sewn technique (39 patients) or two kinds of mechanical staplers: Proximate (Ethicon Endo-Surgery, Cincinnati, OH) (46 patients) and Endo-GIA (United States Surgical, Norwalk, CT) (38 patients). Fistula was defined as output greater than 5 ml, with amylase x 5, after day 5. In case of fistula, the drain removal was scheduled at a daily output less than 5 ml. Mortality was 0%, morbidity was 48%, and pancreatic fistula rate was 34%. Fistula rate was 38% after hand-sewn closure, 26% after Proximate, and 39% after Endo-GIA (NS). None of the other factors (separate duct ligation, hand-sewn suture in addition to stapler, spleen preservation, use of pledgetted suture, sex, age, and indication for pancreatectomy) proved to be related to a reduction in the onset of fistula. All fistulas healed spontaneously. Mean fistula duration was 36 days; 92.8% of patients with fistula were discharged with drain. The policy of delayed drain removal allowed a low rate of fistula associated morbidity (16%) and of readmission (4.7%). In conclusion, fistula is an unsolved problem of left pancreatectomy. However, a careful drain management allows a good outcome in patients with fistula.

Background: Patients with advanced pancreatic adenocarcinoma have a poor response, progression-free survival, and overall survival with standard treatment. We aimed to assess whether a four-drug regimen could improve 4 month progression-free survival compared with gemcitabine alone., Methods: In a randomised multicentre phase III trial, 52 patients were randomly assigned to 40 mg/m2 cisplatin and 40 mg/m2 epirubicin both given on day 1, 600 mg/m2 gemcitabine given intravenously over 1 h on days 1 and 8, and 200 mg/m2 fluorouracil a day given by continuous infusion on days 1-28 of a 4-week cycle (PEFG regimen), and 47 were assigned to 1000 mg/m2 gemcitabine given intravenously over 30 min once a week for 7 of 8 consecutive weeks in cycle 1 and for 3 of 4 weeks thereafter. The primary endpoint was 4-month progression-free survival. Secondary endpoints were overall survival, objective response, safety, and quality of life. Analyses were by intention to treat., Findings: 51 patients assigned PEFG and 46 assigned gemcitabine alone had disease progression. 49 patients in the PEFG group and 46 in the gemcitabine group died from progressive disease. More patients allocated PEFG than gemcitabine alone were alive without progressive disease at 4 months (60% [95% CI 46-72] vs 28% [17-42]; hazard ratio [HR] 0.46 [0.26-0.79]). 1-year overall survival in the PEFG group was 38.5% (25.3-51.7) and in the gemcitabine group was 21.3% (9.6-33.0; HR 0.68 [0.42-1.09]). More patients assigned PEFG showed disease response than did those assigned gemcitabine (38.5% [25.3-51.7] vs 8.5% [0.5-16.5]; odds ratio 6.60 [2.11-20.60], p=0.0008). More patients in the PEFG group had grade 3-4 neutropenia and thrombocytopenia than in the gemcitabine group (p<0.0001)., Interpretation: The PEFG regimen could be considered for treatment of advanced pancreatic adenocarcinoma.

Background: Postoperative management of patients with pancreatic adenocarcinoma (PA) is controversial., Methods: The aim of this pilot study was to assess the feasibility of postoperative combination chemotherapy followed by radiotherapy in patients aged 18-70 years with a histological diagnosis of PA, and Karnofsky performance status (KPS) > or =70. Cisplatin and epirubicin 40 mg/m2 on day 1, gemcitabine 600 mg/m2 on day 1 and 8, and 5-fluorouracil 200 mg/m2/day as protracted infusion (PEFG regimen) were delivered every 28 days for 4 cycles. Assuming a minimum one-year disease-free survival (DFS) of interest of 65% and a maximum of low interest of 45% (alpha 0.05; beta 0.10), the target enrollment was 51 patients, and the strategy would be considered to deserve further analysis if more than 29 patients were DF at one-year from surgery., Results: Fifty-one patients, KPS >80: 29, median tumor size 3.5 cm, stage II/III/IVA: 2/34/13, grade 3-4: 22, positive resection margins: 26, node positive: 46, received 179 cycles of chemotherapy. Main grade 3/4 toxicity consisted of neutropenia (51%), thrombocytopenia (18%), and anemia (4%). One-year DFS was 67 +/- 7%. Two-year overall survival was 53 +/- 7%., Conclusion: Postoperative management of PA with this multimodality strategy was well tolerated and yielded a promising outcome., (Copyright (c) 2005 S. Karger AG, Basel.)

There are a large number of stable pancreatic ductal carcinoma cell lines (PDCL) that are used by researchers worldwide. Detailed data about their differentiation status and genetic alterations are present in the literature, but a systematic correlation with cell biological behavior is often lacking. PDCL ( n=12) were clustered by source of tumor cell (ascites, primary tumor, metastasis), and the data of functional cell biology were correlated with the reported structural and genetic profiles. Major histocompatibility complex expression, chemosensitivity and aneuploidia appeared to be related to the source of PDCL, and proliferative capacity appeared to be related to the grade of differentiation. No correlation between genetic/structural features of PDCL and biological behavior was found. All the cell lines appeared generally insensitive to in vitro treatment with 5-fluorouracil and showed variable degrees of susceptibility to gemcitabine, raltitrexed and oxaliplatin. All the PDCL showed resistance to Fas-mediated apoptosis but were significantly sensitive to the pro-apoptotic effect of inflammatory cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha and interferon gamma]. PDCL were characterized for the secretion of several factors relevant to the tumor-immune cross talk. Vascular endothelial growth factor, CCL2, CCL5 and transforming growth factor beta were the factors most frequently released; less frequent was the secretion of CXCL8, CCL22, IL-6 and sporadically CXCL12, IL-10 and hepatocyte growth factor. The cytokines IL-1beta and TNFalpha were always undetectable. In conclusion, a clear correlation between structural/genetic features and function could not be detected, suggesting the weakness of a "morphological" classification for the in vitro studies of pancreatic cancer.

Dendritic cells (DC) initiate immunity by the activation of naive T cells and control immunity through their ability to induce unresponsiveness of lymphocytes by mechanisms that include deletion and induction of regulatory cells. An inadequate presentation to T cells by tumor-induced "regulatory" DC, among several mechanisms, can explain tolerance to tumor-associated Ags. In this study, we show that tumor-derived mucin profoundly affects the cytokine repertoire of monocyte-derived DC and switch them into IL-10(high)IL-12(low) regulatory APCs with a limited capacity to trigger protective Th1 responses. In fact, DC cocultured with pancreatic tumor cell lines in a Transwell system did not reach full maturation, had low immunostimulatory functions, did not produce IL-12, and released high levels of IL-10. The involvement of known tumor-derived immune-suppressive factors (e.g., vascular endothelial growth factor, TGF-beta, IL-6, and IL-10) was considered and excluded. We provide evidence that tumor-derived MUC1 mucins are responsible for the impaired DC maturation and function. DC obtained in the presence of tumor microenvironment preferentially polarized IL-4(+) response. Moreover, T cells primed by these regulatory DC became anergic and behaved as suppressor/regulatory cells. These findings identify mucin secretion as a novel mechanism of tumor escape from immune surveillance and provide the basis for the generation of potentially tolerogenic DC.

The aim of this study was to discover whether MCP-1/CCL2, a CC chemokine able to attract macrophages, is expressed in human pancreatic cancer and how it modulates cancer progression. All primary tumors were tested, and 6 of 14 pancreatic cancer cell lines were constitutively secreted CCL2. Analysis of the regulation demonstrated that the expression of CCL2 was significantly elevated and in a synergistic manner by IFN-gamma, tumor necrosis factor alpha, and interleukin 1beta. By immunohistochemistry and in situ hybridization, CCL2 production was confirmed in neoplastic ducts from surgical specimens. Serum levels of CCL2 in pancreatic cancer patients were significantly higher than in normal healthy subjects (P < 0.0001). Patients with high circulating levels of CCL2 had significantly higher survival rate than low CCL2 producers. Serum CCL2 levels positively correlated with tumor macrophage infiltration and inversely correlated with tumor proliferative activity (Ki67 expression). A direct effect of CCL2 on tumor cells is to be excluded, either because primary tumors as well as cell lines have no detectable CCL2 receptor (CCR2) and because addition of CCL2 on tumor cells in vitro did not modify cell cycle progression or apoptosis. In vitro, a model of tumor microenvironment showed a direct antiproliferative and proapoptotic activity of monocytes toward pancreatic cancer cell, which is mediated at least in part by interleukin 1beta. Moreover, other proinflammatory cytokines such as tumor necrosis factor alpha and IFN-gamma appeared able to induce apoptosis and to reduce the proliferative rate of pancreatic cancer. On the whole, the results presented in our investigation suggest that CCL2 could be a relevant negative regulator of pancreatic cancer progression.

Background: Patients with severe kyphoscoliosis, with or without stable respiratory failure, frequently experience oxyhaemoglobin desaturation during sleep, exercise, or both. Nasal Intermittent Positive Pressure Ventilation (NIPPV) applied during sleep has been demonstrated to be able to control nocturnal desaturations and also improve diurnal respiratory failure, if this is present, in this group of patients. The aim of this study was to evaluate the effect of a seven-day treatment with nocturnal NIPPV on exercise tolerance in a group of 6 patients with severe kyphoscoliosis and significant nocturnal and exercise-induced oxyhaemoglobin desaturation., Methods: NIPPV was applied each night for a week by means of a volume cycled pressure ventilator set in assisted/controlled mode. In each patient lung function, daytime arterial blood gas analysis, overnight non invasive recording of arterial saturation, and 6-minutes walking test were carried out initially and at the end of the NIPPV course., Results: During nocturnal NIPPV, as compared to baseline, the percent of night time spent below 90% of oxyhaemoglobin saturation significantly fell from 20 +/- 12.8 to 2.3 +/- 1.9 (Student t-test: p = 0.017). The 6-minute walking distance significantly increased from 244.7 +/- 132.2 to 340 +/- 122.3 m (p = 0.0097). Spirometry, daytime arterial blood gas analysis, and exercise-induced oxyhaemoglobin desaturation were unaffected by treatment., Conclusion: A one-week course of treatment with nocturnal NIPPV improves exercise capacity in patients with severe kyphoscoliosis.

Objective: Using a prospective randomized study to assess postoperative morbidity and pancreatic function after pancreaticoduodenectomy with pancreaticojejunostomy and duct occlusion without pancreaticojejunostomy., Summary Background Data: Postoperative complications after pancreaticoduodenectomy are largely due to leakage of the pancreaticoenterostomy. Pancreatic duct occlusion without anastomosis of the pancreatic remnant may prevent these complications., Methods: A prospective randomized study was performed in a nonselected series of 169 patients with suspected pancreatic and periampullary cancer. In 86 patients the pancreatic duct was occluded without anastomosis to pancreatic remnant, and in 83 patients a pancreaticojejunostomy was performed after pancreaticoduodenectomy. Postoperative complications were the endpoint of the study. All relevant data concerning patient demographics and postoperative morbidity and mortality as well as endocrine and exocrine function were analyzed. At 3 and 12 months after surgery, evaluation of weight loss, stools, and the use of antidiabetics and pancreatic enzyme was repeated., Results: Patient characteristics were comparable in both groups. There were no differences in median blood loss, duration of operation, and hospital stay. No significant difference was noted in postoperative complications, mortality, and exocrine insufficiency. The incidence of diabetes mellitus was significantly higher in patients with duct occlusion., Conclusions: Duct occlusion without pancreaticojejunostomy does not reduce postoperative complications but significantly increases the risk of endocrine pancreatic insufficiency after duct occlusion.

Leukotriene receptor antagonists (LTRAs), such as montelukast and zafirlukast, have been demonstrated in a number of studies to possess bronchodilating and anti-inflammatory properties, that make these drugs ideal candidates for the treatment of asthma. The last 1998-updating of the GINA Guidelines for the diagnosis and therapy of asthma recommends the use of LTRAs in the treatment of moderate and mild asthma. In patients with moderate asthma not completely controlled with moderate doses of inhaled corticosteroids, the addition of a LTRA is indicated in alternative to either the increase of the inhaled corticosteroid dose or the addition of an inhaled long-acting beta2-agonist. Both in vitro and in vivo evidences indicate that LTRAs possess an anti-inflammatory activity that is presumably complementary to that presented by corticosteroids. Moreover, clinical studies show that the addition of an LTRA, montelukast, is able to improve clinical and functional indexes in patients with asthma not controlled with inhaled corticosteroids, and to allow a reduction in corticosteroid dosage in patients with asthma well controlled by inhaled corticosteroids. In patients with mild persistent asthma monotherapy with an LTRA is indicated in alternative to a low-dose inhaled corticosteroid, an inhaled cromone, or an oral slow-release theophylline. Previous clinical studies in patients with mild to moderate asthma had demonstrated that monotherapy with LTRAs is able to improve airway function, asthma symptoms, use of as-needed medications, exacerbation rate, and quality of life, without evidence of tolerance with prolonged use. Recently, in a subgroup analysis of patients with mild persistent asthma, a 6-week treatment with oral montelukast or inhaled beclomethasone gave similar improvements in "rescue-free" days, days with well controlled asthma, FEV1, blood eosinophils, beta-agonist use, and nocturnal awakes due to asthma.

Purpose: To assess the impact on local control and survival of intraoperative radiotherapy (IORT) in resectable pancreatic adenocarcinoma., Methods and Materials: The outcome of 127 patients surgically treated with curative intent combined with IORT was compared with the therapeutic results of 76 patients treated with surgery as exclusive treatment., Results: Operative mortality and morbidity were similar in IORT and no-IORT patients. In 49 patients with locally limited disease (Stage I-II; LLD), IORT (n = 30) reduced the local failure rate and significantly prolonged time to local failure (TTLF), time to failure (TTF), and overall survival (OS) with respect to surgery alone (n = 19). The multivariate analyses, stratifying patients by age, tumor grade, resection margins, chemotherapy, and external-beam radiotherapy use, confirmed the independent impact of IORT on outcome. In patients with locally advanced disease (Stage III-IVA; LAD), IORT had an impact on local failure rate and on TTLF when combined with beam energies of greater than 6 MeV, whereas no effect on TTF and OS was observed., Conclusion: IORT did not increase operative mortality and morbidity and achieved a significant improvement in local control and outcome in patients with LLD. In patients with LAD, beam energies greater than 6 MeV prolonged TTLF.

Purpose: To evaluate the efficacy and toxicity of a cisplatin, epirubicin, gemcitabine, and fluorouracil (PEF-G) schedule on stage IV pancreatic adenocarcinoma., Patients and Methods: Patients < or = 70 years, with no prior chemotherapy and with bidimensionally measurable stage IV pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or Karnofsky performance status between 50 and 70. Treatment consisted of 40 mg/m2 each of cisplatin and epirubicin day 1, gemcitabine 600 mg/m2 on days 1 and 8 every 4 weeks, and fluorouracil 200 mg/m2/d as a protracted venous infusion., Results: Between April 1997 and April 1999, 49 patients from a single institution were eligible for the study. Altogether, 203 cycles (median, four cycles) of PEF-G were delivered. The objective response rate was 58% in 43 assessable patients and 51% in the intent-to-treat population. Fourteen patients had stable disease. Grade 3 or 4 World Health Organization neutropenia occurred in 51% of cycles, thrombocytopenia in 28%, anemia in 7%, stomatitis in 5%, and diarrhea, and nausea, and vomiting in 2%. The median duration of response was 8.5 months. The median time to tumor progression was 7.5 months. The median survival was 11 months in the assessable population and 10 months in the intent-to-treat population. Clinical benefit was achieved in 22 (78%) of 28 assessable patients., Conclusion: PEF-G is a well-tolerated and safe regimen; it obtained a very high rate of durable responses and deserves further evaluation in a phase III trial.

Background: We studied dendritic cell (DC) function in patients affected by pancreatic carcinoma, and the possibility of obtaining DC adequate for immunological treatment modalities., Methods: Leucocytes were isolated from buffy coats obtained by autotransfusion of six patients undergoing pancreatico-duodenectomy. The leucocytes were cryopreserved and, after thawing, were purified by density gradient and/or plastic adhesion. They were then cultured in vitro in cytokine-enriched medium (granulocyte/macrophage-colony-stimulating factor + interleukin-4) with different sources of serum: 10% fetal calf serum (FCS), 2% autologous human serum or 2% pooled human AB serum., Results: The DC obtained were identical to those from healthy donors in terms of phenotype, antigen uptake capacity, capacity for antigen presentation and their capacity to mature after exposure to stimuli like CD40L. DC differentiated in human serum demonstrated more mature behaviour than did DC cultured in FCS but, after exposure to CD40L, this difference disappeared. In one patient soluble factors in serum were able to inhibit the capacity of DC to stimulate T cells., Conclusion: It's possible to obtain DC from autotransfusion of patients with pancreatic carcinoma: these cells do not show evident quantitative or qualitative alterations, are able to present soluble antigen even when cultured in the presence of human serum and may be used in immunological tumour treatments.

Patients undergoing pancreaticoduodenectomy (PD) often require postoperative artificial nutrition. This trial was undertaken to evaluate whether the route of administration and the composition of the postoperative nutritional support could affect the immunometabolic response and outcome. A prospective, randomized trial was carried out in 212 subjects who underwent PD. Patients were randomized to receive a standard enteral formula (standard group, n = 73) or an enteral formula enriched with arginine, omega-3 fatty acids, and RNA (immunonutrition group, n = 71), or total parenteral nutrition (parenteral group, n = 68). Postoperative feeding started 6 hours after surgery. The three regimens were isocaloric and isonitrogenous. Assessed parameters were phagocytosis ability of polymorphonuclear cells, plasma interleukin-2 receptors, C-reactive protein, retinol binding protein, tolerance of enteral feeding, rate of postoperative complications, and length of hospital stay (LOS). Full nutritional goal (25 kcal/kg) was achieved in 87% of enterally fed patients versus 95% in the parenteral group. Subjects receiving immunonutrition had a significantly better recovery of the immunometabolic parameters on postoperative day 8 compared to the other two groups. The rate of postoperative complications was lower in the immunonutrition group (33.8%) than in either the standard (43.8%) or parenteral group (58.8%) (p = 0.005 immunonutrition vs. parenteral). Also, the mean LOS was shorter in the immunonutrition group than in the standard and parenteral groups (15.1 vs. 17.0 vs. 18.8 days, respectively; p < 0.05). Early postoperative enteral feeding may safely and effectively replace parenteral nutrition in patients undergoing PD. Immunonutrition ameliorates the immunometabolic response and improves outcome compared to parenteral feeding.

Sputum induction has recently been proposed as the only direct noninvasive method for measuring airway inflammatory indices. The reference values and the distribution of cells in induced sputum in a control population have not yet been well defined. We therefore evaluated data from a large number of healthy volunteers. One hundred fourteen healthy, nonatopic, nonsmoking volunteers without airway hyperreactivity were enrolled (age: 38 +/- 13 yr [mean +/- SD]; FEV(1): 105 +/- 10% predicted; provocative dose of methacholine inducing a 20% decrease FEV(1) > 3,200 microgram). Ninety-six subjects (84%) produced adequate analysis samples. The subjects had a normal age distribution. Their induced sputum was rich in macrophages (69.2 +/- 13%) and neutrophils (27.3 +/- 13%), and poor in eosinophils (0.6 +/- 0.8%), lymphocytes (1.0 +/- 1.2%), and epithelial cells (1.5 +/- 1.8%). Only macrophages and neutrophils showed a normal distribution; total and differential counts of other cells did not. We propose that these data be used in comparison of the induced sputum cells of normal subjects and those of patients with airway inflammation.

The aim of this study was to compare the immediate and long-term bronchodilator effect as well as the patient acceptability of a 2-week, multidrug, inhalation treatment delivered by a metered dose inhaler (MDI) versus a jet nebulizer in a group of elderly patients with chronic obstructive pulmonary disease (COPD) or asthma and an at least partially reversible airflow obstruction. Twenty elderly outpatients (17 men; mean +/- SD age, 67 +/- 2 years; mean +/- SD baseline forced expiratory volume in 1 second [FEV1], 46.5 +/- 14% of predicted value) with COPD or asthma participated in the study, which was of an open, randomized, crossover design. After a 1-day baseline evaluation, including patient history, clinical examination, and spirometry, participants were randomly assigned to receive a multidrug inhalation treatment (a combination of salbutamol, ipratropium, and flunisolide) with either an MDI or a jet nebulizer. Two weeks later, they were shifted to treatment with the alternative system for a further 2 weeks. FEV1 was measured on the first and fourteenth days of each treatment period, on each occasion both before and 30 minutes after the morning inhalation. At the end of the study, patients were asked to express a personal preference for one of the two inhalation treatments with regard to effectiveness and acceptability by filling out a simple questionnaire. Both the MDI and jet nebulizer had a significant immediate bronchodilator effect on the first and fourteenth days of treatment, with no differences between treatments. No long-term bronchodilator effect was seen with either aerosol delivery system. Patient preferences were clearly in favor of the jet nebulizer with regard to effectiveness and in favor of the MDI with regard to acceptability. In conclusion, in elderly patients with COPD or asthma and partially reversible airflow obstruction, a maintenance multidrug bronchodilator/anti-inflammatory inhalation treatment produced a statistically significant and clinically relevant bronchodilator effect without substantial differences between the two delivery systems. Most patients considered the MDI to be more acceptable and the jet nebulizer to be more effective. These preferences should be taken into consideration when prescribing a maintenance aerosol inhalation treatment.

The number and significance of airway eosinophils in stable COPD is controversial. Aims of this study were to evaluate airway inflammation in patients with stable COPD compared with other groups, and to examine the correlations between inflammatory markers and functional indices of airway obstruction. Cellular analysis and evaluation of eosinophil cationic protein (ECP) levels in induced sputum were made in 46 subjects (10 patients with clinically stable COPD, 15 patients with asthma, 11 asymptomatic smokers, and 10 healthy control subjects). As expected, eosinophils were significantly (p < 0.01) higher in patients with asthma (22.2%) than in other groups (COPD, 0.7%; smokers, 0.2%; control subjects, 0.2%), and neutrophils were significantly (p < 0.01) higher in patients with COPD (77.5%) than in the other groups (asthma, 26.7%; smokers, 33.1%; control subjects, 35.9%). However, eosinophils were also increased in patients with COPD, as compared with healthy controls (p < 0.05). Sputum ECP levels were significantly and similarly higher in both asthma and COPD groups than in the other two groups (p < 0.01). In patients with COPD and asymptomatic smokers, considered as a whole, good correlations were found between eosinophils and ECP, on the one hand, and between FEV(1) and the FEV(1)/FVC ratio, on the other. Our data suggest that eosinophils may be involved in the airway inflammation of COPD.

During 1990 to 1997 a series of 39 patients underwent a classic pancreaticoduodenectomy and 74 a pylorus-preserving pancreaticoduodenectomy for pancreatic adenocarcinoma. The two groups had similar tumor characteristics and received comparable adjuvant treatments. No significant differences were found between the two groups in terms of mortality, morbidity, gastric emptying, food intake resumption, and hospital stay. Postoperative survival was not affected by the preservation of the pylorus, determined by both univariate and multivariate analyses. Postoperative nutritional outcome was similar in the two groups, although patients receiving adjuvant chemotherapy had a better nutritional recovery if the whole stomach was preserved. In our opinion pylorus-preserving pancreatoduodenectomy is the treatment of choice of pancreatic head cancer.

Background: According to international guidelines, artificial nutrition may be indicated after pancreaticoduodenectomy (PD). This clinical study was designed to evaluate whether the route of administration and the composition of the postoperative nutritional support could affect outcome., Methods: One hundred patients who underwent PD for cancer of the pancreatic head were prospectively studied. Patients were randomized to receive a standard enteral formula (SEN; n = 35) or immunonutrition with an enteral formula enriched with arginine, omega-3 fatty acids, and RNA (IEN group; n = 33), or total parenteral nutrition (TPN; n = 32). Postoperative feeding was started within 12 h after surgery. The three regimens were isoenergetic and isonitrogenous. Tolerance of enteral feeding, rate and severity of postoperative complications, and length of hospital stay (LOS) were evaluated., Results: Full nutritional goal (25 kcal/kg) was achieved in 84% of enterally fed patients versus 96% in the parenteral group (p = NS). The rate of postoperative complications was lower in the IEN group (33%) than in the SEN (40%) and TPN groups (59%). The severity of infectious complications (sepsis score) was lower in the IEN (5.5) than the SEN (7.9) and TPN groups (10.4; p < 0.05). LOS was shorter in the IEN than in the SEN and TPN groups (16.3 vs. 17.8 vs. 19.3 days, respectively; p < 0.05)., Conclusions: In patients undergoing PD the established nutritional goal can be obtained by enteral feeding. Immunonutrition seems to improve outcome.

Various techniques are used to collect specimens from the nasal mucosa for morphologic and biochemical analysis. The purpose of this study was to devise a method that overcomes some of the disadvantages (e.g., invasive procedure, samples not suitable for cytologic and biochemical analysis, lack of standardization, and poor reproducibility) of these techniques. The new method requires subjects, with neck extended, to inhale an ultrasonic nebulization of a hypertonic (3% NaCl) solution (UNHS) for 5 min. They then blow their nose into a Petri dish, one nostril at a time with the other one blocked. The secretions are dispersed with 0.1% dithiothreitol in phosphate buffer solution for 20 min. Total cell count (TCC) is evaluated, and the cellular suspension is divided into two aliquots: one is centrifuged and the supernatants are collected for eosinophil cationic protein (ECP) measurements; the other is cytocentrifuged and the slides, stained with Diff-Quik, are used for differential cell count. The results obtained with the UNHS and nasal lavage (NL) methods were compared. Eleven nonatopic healthy subjects and 19 allergic rhinitic patients were studied. Total cell count (x10(5)) was significantly higher with UNHS than with NL (13.0+/-12.3 vs 1.9+/-1.6; P<0.01) The differential cell count was similar with the two procedures. ECP levels (microg/l) were higher with UNHS than with NL (39.1+/-38.2 vs 16.7+/-41.2; P<0.01). For evaluation of reproducibility, four healthy and six rhinitic subjects underwent UNHS on two occasions within 5 days, and the results of two samples (sample 1 vs sample 2) were analyzed. Reproducibility was good as to TCC, differential cell count, and ECP.

Background: Pancreatic cancer resection is considered a high-risk procedure in patients aged 70 years or older., Methods: Some 398 patients with pancreatic adenocarcinoma, observed between 1990 and 1995, were reviewed. Operative outcome and survival of 33 patients aged 70 years or more were compared with findings in 85 younger patients who underwent resection., Results: Resectability was not significantly different between the elderly and younger patients; neither were mortality or overall morbidity. However, patients aged 70 years or more had more relaparotomies (P < 0.01) and more haemorrhagic complications (P < 0.001). Nutritional recovery after resection was satisfying even for elderly patients (body-weight gain and increase in serum albumin concentrations, P < 0.05). Univariate analysis showed a moderately poorer survival in the elderly (P = 0.09). Multivariate analysis demonstrated that tumour diameter, grading and Union Internacional Contra la Cancrum stage were independent prognostic factors, whereas age was not., Conclusion: Patients aged 70 years or more can benefit from pancreatic cancer resection similarly to younger patients.

Background and Methods: The cranio-facial morphology has been evaluated on the basis of cephalometric studies in nine patients with Turner's syndrome. The aim of this study is to identify the growth model and the typical malocclusions of this syndrome. This study has been completed with an evaluation of mesio-distal dimension of permanent teeth., Results: According to the literature, the results show: a flattening of the basal skull; a cross-bite coming from a transversal dimension reduction of the upper maxilla. A Class II malocclusion was found in two patients. All the patients showed a mandibular retrusion associated to maxillary retrusion in eight cases. The growth direction was normal in all the patients., Conclusions: A reduction of the mesio-distal diameter in all of the permanent teeth, was also found. This last measure was evaluated using the study casts.

The aim of the study was the definition of the clinical features and survival of 27 resected cases of distal bile duct carcinoma. This neoplasm accounted for 14% of all periampullary malignancies treated by pancreaticoduodenectomy between 1990 and 1996. Jaundice was present in 96% of patients, but was the first symptom only in 78%. Preoperative investigations allowed to recognize distal bile duct cancer in a minority of patients (41%). Operative mortality and morbidity were 3.7 and 44%, respectively. Most patients (88%) were assigned to UICC stage IV-A. Postoperative survival was not significantly better than survival of 101 patients undergoing pancreaticoduodenectomy for pancreatic ductal carcinoma; median survival was 22 months, with a 13% 5-year survival rate. Determinants of a better prognosis were UICC stage

Objective: To assess the effects of short-term transdermal E2 administration on nitric oxide (NO) plasma levels in postmenopausal women., Design: Randomized, placebo-controlled trial., Setting: Healthy volunteers in an academic research environment., Patient(s): Twenty-eight healthy postmenopausal women., Intervention(s): Transdermal administration of E2 (100 microg/d) or placebo on days 1 and 4 of a 1-week treatment regimen., Main Outcome Measure(s): Serum concentrations of E2 and plasma concentrations of NO stable oxidation products were assessed on day 1, before placement of the patch, and subsequently on days 2, 3, and 6., Result(s): The mean concentration of NO metabolites on days 2, 3, and 6 was significantly greater in the E2 group (40.08+/-15.42 micromol/L, 38.05+/-18.82 micromol/L, and 42.03+/-16.81 micromol/L on days 2, 3, and 6, respectively) compared with both baseline levels (23.07+/-5.79 micromol/L) and the placebo group (23.51+/-4.06 micromol/L, 21.64+/-4.72 micromol/L, and 21.81+/-4.46 micromol/L on days 2, 3, and 6, respectively)., Conclusion(s): During a 1-week treatment regimen with transdermal E2, plasma levels of NO in postmenopausal women were significantly higher than baseline levels on days 2, 3, and 6. This suggests that the effect of estrogens on NO synthesis is rapid and that it is maintained with repeated administration.

We have isolated a novel cDNA (SEL1L) that shows sequence similarities to SEL-1, a gene identified as an extragenic suppressor of the lin-12 hypomorphic mutant from Caenorhabditis elegans (7, 8). SEL1L exhibits a tissue-specific pattern of expression: a single poly(A)+ RNA species of 7.5 kb is abundantly expressed only in the pancreas of healthy individuals, whereas low to undetectable levels are observed in other adult and in some fetal tissues. Somatic hybrid panel and fluorescence in situ hybridization positioned this gene in the q31 band of human chromosome 14. The tissue-specific expression of this gene induced us to study its role in human pancreatic carcinomas. Our analysis revealed that 17% of adenocarcinomas of the pancreas did not express SEL1L to a detectable level; however, no gross genomic alterations were apparent in the few hundred kilobases of the relevant region.

Objective: To study the effect of the route of delivery and formulation of postoperative nutritional support on host defense, protein metabolism, infectious complications, and outcome., Design: Prospective, randomized, clinical trial., Setting: Department of Surgery at a university hospital., Patients: Two hundred sixty candidates for pancreaticoduodenectomy or gastrectomy for cancer., Interventions: Patients were randomly allocated into 3 groups during surgery. Starting 6 hours after operation, the first group received a standard enteral formula (standard group; n = 87); the second, the same enteral formula enriched with arginine, omega-3 fatty acids, and RNA (immunonutrition group; n = 87); and the third, total parenteral nutrition (parenteral group; n = 86). The 3 regimens were isocaloric and isonitrogenous. The nutritional goal was 105 kJ/kg per day., Main Outcome Measures: Immune response by phagocytosis ability of polymorphonuclear cells, interleukin (IL)-2 receptor levels, and delayed hypersensitivity response; protein synthesis by IL-6 and prealbumin; tolerance of enteral feeding; incidence of postoperative complications; and length of hospital stay., Results: The immunonutrition group had a significantly better recovery of the immune parameters on postoperative day 8 compared with the other groups. Linear regression analysis showed an inverse correlation between IL-6 and preambulin levels (r = 0.766) only in the immunonutrition group. Only 11 patients (6.3%) in both enteral groups did not reach the nutritional goal. Postoperative infection rate was 14.9% (13/87) in the immunonutrition group, 22.9% (20/87) in the standard group, and 27.9% (24/86) in the parenteral group (P = .06). Mean +/- SD length of hospital stay was 16.1 +/- 6.2, 19.2 +/- 7.9, and 21.6 +/- 8.9 days in the immunonutrition, standard, and parenteral groups, respectively (P = .01 vs standard group; P = .004 vs parenteral group)., Conclusions: Early postoperative enteral feeding is a valid alternative to parenteral feeding in patients undergoing major surgery. Immunonutrition enhances the host response, induces a switch from acute-phase to constitutive proteins, and improves outcome.

Local recurrence is the most frequent site of failure after resection for pancreatic cancer. We reported our experience in term of tolerance, local control and survival obtained by the association of resection and intraoperative radiation therapy (IORT). Between January 1985 and July 1996 152 resection for pancreatic cancer were performed at the authors' institution. For 77 patients, IORT was added to resection (group 1), whereas the other 75 patients underwent resection alone (group 2), because of either the unavailability of the linear accelerator or the patient's refusal. In group 1, radiation doses from 12.5 to 20 Gy, with electron beam energies between 6 and 12 MeV, were delivered. Extension of the disease, percentage of radical resection and postoperative chemotherapy were similar in the two groups of patients. Operative mortality and overall early postoperative complications were respectively 1.3% and 31.2% in group 1 and 4% and 32% in group 2. The median survival was 17 months in group 1 and 15 months in group 2 and the median disease free survival was 12 months in group 1 and 8 months in group 2. A local recurrence was detected in 31% of patients in group 1 and in 49.3% of patients in group 2 (p < 0.1). The results suggest a better local control in patients with pancreatic cancer undergoing adjuvant IORT.

Pancreatico-jejunal anastomosis still represents the main source of postoperative complications after pancreatoduodenectomy. In this study our experience on the occlusion of the residual pancreatic stump instead of pancreatico-jejunal anastomosis is reviewed. Between March 1981 and December 1995 we performed 223 pancreatoduodenectomies using Neoprene injection into the Wirsung duct for pancreatic carcinoma of the head (123 cases), ampullary carcinoma (36 cases), distal bile duct cancer (23 cases), islet cells carcinoma (17 cases), chronic pancreatitis (11 cases), duodenal carcinoma (5 cases), miscellaneous diseases (8 cases). Neoprene is a fluid, synthetic glue which polymerized and hardens when in contact with the pancreatic juice, inducing a fibrosis tissue which spares the endocrine component. We observed a 4.9% operative mortality (11 patients): 5 abdominal sepsis, 1 DIC, 1 aortoiliac thrombosis, 1 pulmonary embolism, 1 stroke, 1 hepatic failure, 1 cardiac failure. Overall morbidity was 44.8% (100 patients): in 25 cases (11.2%) a major complication requiring reintervention occurred. In 38 patients (17%) pancreatic fistula was detected: median duration was 43 days, with a mean output of 5.3 ml/day; in all cases a spontaneous solution of the fistula was observed. In conclusion, intraductal injection of Neoprene after pancreatoduodenectomy is a safe procedure, it represents an useful alternative to pancreatico-jejunal anastomosis.

Conclusion: A different stage grouping of TNM factors can improve the predictivity of the UICC TNM classification for pancreatic cancer. Nevertheless, the Japanese Pancreas Society (JPS) classification maintains a higher prognostic value., Background: The use of a reliable staging classification facilitates the evaluation of anticancer treatments and the correct management of patients. The aim of the present study was to evaluate the prognostic value of three modified UICC TNM classifications, obtained by different stage grouping of the UICC TNM factors, comparing their predictivity to the standard UICC and the JPS classifications., Methods: Clinical material consisted of 228 patients who underwent resection for pancreatic cancer. The reliability of the classifications was analyzed by the following methods: univariate analysis of stage survival curves; multivariate analysis of each classification after adjusting for grading and radicality; and correlation between the patients' distribution in the stages of each classification and in survival classes., Results: The following modified UICC classification allowed a better differentiation of stage II and III survival (P = 0.08) than standard UICC (P = 0.74): stage I: T1N0M0; stage II: T1N1M0/T2N0M0: stage III: T2N1M0/T3 any NM0; stage IV: M1. The JPS classification better discriminated between the different stages (P < 0.001). All classifications had an independent prognostic value by multivariate analysis. The correlation between stages and survival classes was higher for the JPS classification than either UICC TNM classification or the modified UICC classifications.

In the 1985-1994 period, 101 patients underwent resection for ductal pancreatic adenocarcinoma. In 27 patients, the resection was not associated with adjuvant therapies, whereas in 74 patients, it was. Intraoperative radiation therapy (IORT) was performed in 54 patients. Operative mortality and morbidity were similar in patients undergoing IORT (1.8 and 29.6%) to those undergoing resection alone (2.1 and 27.6%). Median survival of the IORT group was 17 vs 14 mo of the non-IORT group (irrespective of postoperative treatments) (ns); the local recurrence rates were 38 and 54%, respectively. The group of 74 patients undergoing adjuvant therapies had a greater survival than 27 patients with no adjuvant treatment, both at the univariate (p < 0.01) and the multivariate analyses (p < 0.05) (covariates tumor stage and radicality). The subgroup of patients undergoing only radiotherapy (RT) and/or chemotherapy (CT) did not show significantly better survival than patients with no additional therapies, whereas the group of patients undergoing IORT + CT + RT showed a significantly better survival (p < 0.05). In conclusion, adjuvant therapies seem to improve survival in patients undergoing resection for pancreatic cancer.

The purpose of the present study is to investigate the factors contributing to skeletal relapse after surgical correction of mandibular prognathism. Postoperative follow-up after mandibular setback is carried out to clarify the timing and causes of the relapse. The subjects are mandibular prognathism patients. The etiology of relapse is discussed.