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Objectives: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre.Method: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as definite' or possible' according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI).Results: Forty-one patients (15 females, 26 males) were included in this study: 26 with definite' IgG4-RD and 15 with possible' IgG4-RD. The median age at diagnosis was 62years. The median follow-up was 36 months (IQR 24-51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking.Conclusions: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases. ZB 0 ZR 0 ZS 0 Objectives: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre.Method: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as definite' or possible' according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI).Results: Forty-one patients (15 females, 26 males) were included in this study: 26 with definite' IgG4-RD and 15 with possible' IgG4-RD. The median age at diagnosis was 62years. The median follow-up was 36 months (IQR 24-51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking.Conclusions: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Every cancer can produce bone metastases. Metastatic tumors to the maxillo-facial bones are rare, mandible is the most frequent place of these bones. Often metastases represent the first symptom of malignant tumors.

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.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.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.A one-week course of treatment with nocturnal NIPPV improves exercise capacity in patients with severe kyphoscoliosis.

Nicolino Ambrosino1, Katia Foglio2, Gianni Balzano2, Pier Luigi Paggiaro1, Patrizia Lessi3, Steven Kesten3 On behalf of the Tiotropium Multicentric Italian Study Group1Cardio-Thoracic Department, University Hospital, Pisa, Italy; 2S Maugeri Foundation IRCCS, Italy; 3Boehringer Ingelheim, GmbH, Milan, ItalyBackground: Exercise training improves exercise tolerance in chronic obstructive pulmonary disease (COPD). Tiotropium 18 μg 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 μg 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

Background: Laparoscopic distal pancreatectomy (LDP) has been recently proposed as the procedure of choice for lesions of the pancreatic body and tail in experienced centres. The purpose of this study is to assess the potential advantages of LDP in a consecutive series of 100 patients. Methods: Propensity score matching was used to identify patients for comparison between LDP and control open group. Match criteria were: age, gender, ASA score, BMI, lesion site and size, and malignancy. All patients were treated according to an early feeding recovery policy. Primary endpoint was postoperative morbidity rate. Secondary endpoints were operative time, blood transfusion, length of hospital stay (LOS), hospital costs, and quality of life. Results: Thirty patients of the LDP group had pancreatic adenocarcinoma. Conversion to open surgery was necessary in 23 patients. Mean operative time was 29min shorter in the open group (p=0.002). No significant difference between groups was found in blood transfusion rate and postoperative morbidity rate. LDP was associated with an early postoperative rehabilitation and a shorter LOS in uneventful patients. Economic analysis showed € 775 extra cost per patient of the LDP group. General health perception and vitality were better in the LDP group onemonth after surgery. Conclusion: Laparoscopic distal pancreatectomy improved short-term postoperative recovery and quality of life in a consecutive series of both cancer and non-cancer patients. Despite the extra cost, thelaparoscopic approach should be considered the first option in patients undergoing distal pancreatectomy.

Background The possible benefit of frozen section (FS) analysis during (PD) for pancreatic ductal adenocarcinoma (PDAC) and of additional resection up to total pancreatectomy (TP) is debated. Aim of this work is to evaluate the prognostic role of positive FS analysis after PD for PDAC. Methods Multicentric retrospective analysis on prospective databases of three institutions. Based on FS analysis patients were classified as FS negative/FS positive. All positive FS patients underwent extended PD (EPD) or TP. Postoperative outcomes, disease-free (DFS) and disease-specific survival (DSS) were evaluated. Results Of 371 patients, 58 (16%) had positive FS. This resulted in 313 (84%) SPD (standard pancreatoduodenectomy), 22 (6%) EPD and 36 (10%) TP. Postoperative mortality was higher in patients undergoing TP (11% compared to 4.5% in EPD and 1% in SPD; p = 0.01). 26% of patients underwent neoadjuvant therapy, and it did not decrease the rate of positive FS. Systemic/local relapse rates were 59% and 41% in negative FS group, and 78% and 22% in positive FS group (p = 0.031). Median DFS and DSS were 20 and 37 months in negative FS group, and 12 and 23 months in positive FS patients (p = 0.001). Independent predictors of recurrence were G3, N1/N2 status and positive FS. R1 resection, G3, N1/N2 status, perineural invasion and positive FS were independent predictors of DSS. Conclusions Positive FS analysis is a poor prognostic factor after PD for PDAC. It is significantly associated with a high rate of R1 resection at final histology, PDAC recurrence and poor survival.

Background Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking. Methods Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007–2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test. Results Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien–Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14–39) versus 31 months (95% CI 19–42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18–53) versus 20 months (95% CI 15–24), P = 0.049], as compared with upfront resection. Conclusion In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement.

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.

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, ω-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.

Background: The prognostic role of resection margins in pancreatic ductal adenocarcinoma (PDAC) is debated. This study aimed to investigate the impact that global and individual resection margin status after pancreatic head resection for PDAC has on disease-free survival (DFS) and disease-specific survival (DSS). Methods: Surgical specimens of pancreaticoduodenectomy/total pancreatectomy performed for PDAC were examined with a standardized protocol. Surgical margin status (biliary, pancreatic neck, duodenal, anterior and posterior pancreatic, superior mesenteric vein groove and superior mesenteric artery margins) was classified as the presence of malignant cells (1) directly at the inked surface (R1 direct), (2) within less than 1 mm (R1 ≤ 1 mm), or (3) with a distance greater than 1 mm (R0). Patients with a positive neck margin at the final histology were excluded from the study. Results: Of the 362 patients included in the study, 179 patients (49.4 %) had an R0 resection, 123 patients (34 %) had an R1 ≤ 1 mm resection, and 60 patients (16.6 %) had an R1 direct resection. The independent predictors of DFS were R1 direct resection (hazard ratio [HR], 1.49), R1 ≤ 1 mm resection (HR, 1.38), involvement of one margin (HR, 1.36), and involvement of two margins or more (HR, 1.55). When surgical margins were analyzed separately, only R1 ≤ 1 mm superior mesenteric vein margin (HR, 1.58) and R1 direct posterior margin (HR, 1.69) were independently associated with DFS. Conclusions: Positive R status is an independent predictor of DFS (R1 direct and R1 ≤ 1 mm definitions) and of DSS (R1 direct). The presence of multiple positive margins is a risk factor for cancer recurrence and poor survival. Different surgical margins could have different prognostic roles.

Background There is an increased interest in venous vascular resection associated with pancreatic resection for pancreatic ductal adenocarcinoma as an upfront procedure or after neoadjuvant treatment. The aim of this study was to evaluate the impact of venous vascular resection for pancreatic ductal adenocarcinoma on postoperative and long-term outcomes. Methods The study is a retrospective analysis of patients who underwent pancreatectomy for pancreatic head pancreatic ductal adenocarcinoma with and without venous vascular resection between January 2010 and April 2018. The impact of venous vascular resection on postoperative and pathologic data was analyzed. Univariate and multivariate analyses of predictors of disease-free and disease-specific survival were analyzed for the entire cohort. A propensity-score matched cohort analysis was subsequently performed to remove selection bias and improve homogeneity. Results Four hundred and eighty-one patients were included, and 126 (26%) underwent a venous vascular resection. Patients undergoing venous vascular resection had higher morbidity (64% vs 54%; P = .026) with no differences in 90-day postoperative mortality (3.1 vs 2.8%; P = .5). Venous vascular resections were also significantly associated with R1 resections (52% vs 37%; P = .002) and perineural invasion (87% vs 77%; P = .017). Five-year disease-free survival in patients with and without venous vascular resection were 7% and 20% (P = .018), respectively. Independent predictors of worse disease-free survival included venous vascular resection, positive lymph node status, and perineural invasion. Independent predictors of worse disease-specific survival were perineural invasion and positive nodal status, while adjuvant treatment was a protective factor. Five-year disease-specific survival in patients with and without venous vascular resection were 19% and 35% (P = .42). Conclusion Pancreatectomy with venous vascular resection can be accomplished safely. Venous vascular resections are associated with poor prognostic factors and with a worse clinical outcome, being a significant predictor of cancer recurrence.

Background: Defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma (PDAC) receiving primary chemotherapy is an unmet need. The role of time to CA19-9 nadir and of nadir magnitude was explored in this study. Patients and methods: The databases of our institution’s prospective trials were queried to speculate on the time to maximum chemotherapy response. Patients with pathologically proven, metastatic (N = 356) or non-metastatic non-resected (N = 163) PDAC and elevated baseline (> 34UI/mL) CA19-9 were analyzed. Survival curves were estimated using the Kaplan–Meier method and compared by means of the log-rank test for analyses including at least 45 patients. Multivariable Cox proportional hazards model was used to estimate clinical features for their association with OS. All probability values were from two-sided tests. Results: Time to CA19-9 nadir was ≥ 4months in 184 of 346 (53%) metastatic and 121 of 163 (74%) non-metastatic patients (p = 0.002). The likelihood of a later nadir was higher with taxane-based chemotherapy as compared to taxane-free combinations (73% versus 56%; p = 0.02). Both metastatic and non-metastatic patients had significantly longer survival when nadir occurred later. Patients with a larger CA19-9 nadir magnitude had significantly longer survival. Metastatic patients with CA19-9 reduced by < 50%, 50–89%, or > 89% and had a median survival of 7.4, 9.8, and 14.7months, respectively (p ≤ 0.001 for all comparisons). The corresponding figures for non-metastatic patients were 10.6; 17.0; and 18.7months, respectively (p ≤ 0.02 for < 50% versus 50–89% or > 89%; p = 0.14 for 50–89% versus > 89%). Multivariable analyses showed that time to CA19-9 nadir but not CA19-9 nadir magnitude was independently predictive of survival. Conclusion: The present study suggests that a 4–6months program might be a more suitable candidate for prospective assessment in comparison to shorter pre-defined period in patients who are candidates to surgery after primary chemotherapy.

Background: Pancreatic neuroendocrine neoplasms (PanNEN) are ideal entities for minimally invasive surgery. The advantage of the laparoscopic approach in terms of complications, length of stay (LOS) and cosmetic results has been previously demonstrated. However, scarce data are available on long-term oncological outcomes. Aim of this study was to compare short-term postoperative outcomes, pathological findings and long-term oncological results of minimally invasive distal pancreatectomy (MIDP) and open distal pancreatectomy (ODP) for PanNEN. Methods: Patients who underwent ODP or MIDP for nonfunctioning PanNEN (NF-PanNEN) were retrospectively analyzed. Inverse probability of treatment weighting using propensity score was performed to compare the outcomes of MIDP and ODP. Results: Overall, 124 patients were included in the study: 84 underwent OPD, whereas 40 were submitted to MIDP. The rate of high-grade postoperative complications was significantly lower in the MIDP group (p = 0.005, grade of complication with highest estimated probability 0 vs 2) and the postoperative LOS was significantly shorter after MIDP (p < 0.001, estimated days 8 versus 10). The number of examined lymph nodes (ELN) in the ODP group was significantly higher (p = 0.0036, estimated number of ELN 13 vs 10). Similar disease-free survival and overall survival were reported for the two groups (p = 0.234 and p = 0.666, respectively). Conclusions: Although MIDP for PanNEN seems to be associated with a lower number of ELN, long-term survival is not influenced by the type of surgical approach. MIDP is advantageous in terms of postoperative complications and LOS, but prospective studies are needed to confirm the overall oncological quality of resection in this group of neoplasms.

International audience; OBJECTIVE: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. METHODS: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. RESULTS: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200?mL (60-400) vs 300?mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P \textless 0.001] were lower after MIDP. Clavien-Dindo grade >=3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P \textgreater 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P \textless 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P \textless 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929). CONCLUSIONS: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

Duodeno-jejunal (DJ) and gastro-jejunal (GJ) anastomosis leakage represents a rare but life-threatening complication after pancreaticoduodenectomy or total pancreatectomy. The aim of this study was to assess its incidence, clinical presentation, and outcomes, and to identify perioperative risk factors for DJ/GJ leak. Prospectively collected perioperative data were reviewed, and a case–control study was performed. Patients who presented with a DJ/GJ leak (cases) were matched in a 1:5 ratio with patients who did not develop it. Match criteria included age, diagnosis, type of surgery, and anastomosis. Perioperative factors and outcomes were compared between groups. From January 2008 to present, 13 cases were observed and compared to 60 controls. Concerning pre-operative variables, cases showed lower pre-operative serum hemoglobin (p=0.021) and increased pre-operative radiotherapy (p=0.037). Cases experienced more severe post-operative complications than Controls, according to the CD classification (p&nbsp

AIMS: To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis. METHODS: Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan-Meier and by Cox regression. RESULTS: Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival. CONCLUSIONS: Insulin resistance is associated with the aggressiveness of PDAC.

Background Analytical morphometric assessment has recently been proposed to improve preoperative risk stratification. However, the relationship between body composition and outcomes following pancreaticoduodenectomy is still unclear. The aim of this study was to assess the impact of body composition on outcomes in patients undergoing pancreaticoduodenectomy for cancer. Methods Body composition parameters including total abdominal muscle area (TAMA) and visceral fat area (VFA) were assessed by preoperative staging CT in patients undergoing pancreaticoduodenectomy for cancer. Perioperative variables and postoperative outcomes (mortality or postoperative pancreatic fistula) were collected prospectively in the institutional pancreatic surgery database. Optimal stratification was used to determine the best cut-off values for anthropometric measures. Multivariable analysis was performed to identify independent predictors of 60-day mortality and pancreatic fistula. Results Of 202 included patients, 132 (65·3 per cent) were classified as sarcopenic. There were 12 postoperative deaths (5·9 per cent), major complications developed in 40 patients (19·8 per cent) and pancreatic fistula in 48 (23·8 per cent). In multivariable analysis, a VFA/TAMA ratio exceeding 3·2 and American Society of Anesthesiologists grade III were the strongest predictors of mortality (odds ratio (OR) 6·76 and 6·10 respectively; both P < 0·001). Among patients who developed major complications, survivors had a significantly lower VFA/TAMA ratio than non-survivors (P = 0·017). VFA was an independent predictor of pancreatic fistula (optimal cut-off 167 cm2: OR 4·05; P < 0·001). Conclusion Sarcopenia is common among patients undergoing pancreaticoduodenectomy. The combination of visceral obesity and sarcopenia was the best predictor of postoperative death, whereas VFA was an independent predictor of pancreatic fistula.

Summary Background Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. Methods This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18–75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m 2 , nab-paclitaxel 150 mg/m 2 , and gemcitabine 800 mg/m 2 on days 1 and 15 and oral capecitabine 1250 mg/m 2 on days 1–28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. Findings Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58–86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31–63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. Interpretation Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. Funding Celgene.

Introduction The aim of this study is to analyze the evolution of pancreatectomy with venous resection in 10 referral Italian centers in the last 25 years. Methods A multicenter database of 425 patients submitted to pancreatectomy with venous resection between 1991 and 2015 was retrospectively analyzed. Patients were classified in 5 periods: 1 (1991–1995); 2 (1996–2000); 3 (2001–2005); 4 (2006–2010); 5 (2011–2015). Indications and outcomes were compared according to the period of surgery. Results Nineteen patients were operated in period 1, 28 in period 2, 91 in period 3, 140 in period 4, and 147 in period 5. Use of neoadjuvant therapy increased from 0% in period 1 and 2–12.1% in period 5. Postoperative complications ranged from 46.3% to 67.8%, and mortality from 5.3% to 9.2%. Median survival progressively increased, from 6 months in period 1–16 months in period 2, 24 months in period 3 and 4 and 35 months in period 5 (p = 0.004). Period, venous and nodal invasion were significant prognostic factors for survival. Conclusion Management and outcomes of pancreatectomy with venous resection have evolved in the last 25 years in Italy. Improvement in patients' multidisciplinary management has lead to significant improvement of median survival.

Objective. [18F]Fluorodeoxyglucose (18F-FDG) PET/CT is increasingly used to assess organ involvement and response to treatment in IgG4-related disease (IgG4-RD), but clear correlations between 18F-FDG uptake and disease activity have not been established yet. We aimed to correlate the intensity and distribution of 18F-FDG uptake with validated clinical, serological and immunological parameters of IgG4-RD activity. Methods. Twenty patients with active IgG4-RD underwent a baseline 18F-FDG PET/CT. Ten patients repeated 18F-FDG PET/CT after immunosuppressive treatments. 18F-FDG tissue uptake was measured using the standardized uptake value corrected for the partial volume effect (PVC-SUV) and the total lesion glycolysis (TLG) with (TLGtot+ln) and without (TLGtot-ln) lymph nodes. Disease activity was assessed by means of clinical parameters [IgG4-RD Responder Index (RI)], serological (ESR and CRP) and immunological (serum IgG4 and circulating plasmablasts) biomarkers. The enhanced liver fibrosis score was exploited as a biomarker for fibroblast activation. Results. Thirteen (65%) patients had two or more organs affected by IgG4-RD. All patients had active IgG4-RD as defined by a median IgG4-RD RI value of 9 (range 6-15; normal < 3). Serum IgG4 and plasmablasts were elevated in 85% of patients. Circulating plasmablasts positively correlated with PVCSUV (P = 0.027), inversely correlated with TLGtot-ln (P = 0.023) and did not correlate with TLGtot+ln (P > 0.05). No statistically significant correlation was found between PVC-SUV or TLG and IgG4-RD RI, ESR, CRP, serum IgG4 or enhanced liver fibrosis score (P > 0.05). Clinical response to immunosuppressive therapies was associated with a consensual reduction of circulating plasmablasts, PVC-SUV, TLGtot+ln and TLGtot-ln values (P < 0.05 for all comparisons). Conclusions. 18F-FDG uptake of IgG4-RD lesions reflects immunological perturbations of the B cell compartment rather than fibroblast activation and extracellular matrix deposition. Conventional biomarkers of disease activity, namely IgG4-RD RI, ESR, CRP and serum IgG4 levels, do not appear to correlate with the radiometabolic activity of IgG4-RD lesions. In light of our results PET/CT represents a reliable instrument for assessing IgG4-RD activity, although lymph-node uptake deserves careful interpretation

Background Enhanced recovery (ER) pathways have improved outcomes across multiple surgical specialties, but reports concerning their application in distal pancreatectomy (DP) are lacking. The aim of this study was to assess compliance with an ER protocol and its impact on short-term outcomes in patients undergoing DP. Methods Prospectively collected data were reviewed. One hundred consecutive patients undergoing DP were treated within an ER pathway comprising 18 care elements. Each patient was matched 1:1 with a patient treated with usual perioperative care. Match criteria were age, BMI, ASA score, lesion site, and type of disease. Results Adherence to ER items ranged from 15% for intraoperative restrictive fluids to 100% for intraoperative warming, antibiotic and anti-thrombotic prophylaxis. Patients in ER group experienced earlier recovery of gastrointestinal function (2 vs. 3 days, pÂ

Patients with borderline (BL) or locally advanced (LA) pancreatic adenocarcinoma are usually treated with primary chemotherapy (CT), followed by resection when feasible. Scanty data are available about the criteria to candidate patients to resection after CT.Between 2002 and 2016 overall 223 patients diagnosed with BL or LA pancreatic adenocarcinoma were primarily treated with Gemcitabine combination (4-drugs or nab-paclitaxel-gemcitabine) for 3-6 months followed by surgery and/or chemoradiation. Resection was carried out when radical resection could be predicted by imaging studies and intraoperative findings. The prognostic value of both pre-treatment factors and treatment response was retrospectively evaluated, searching for criteria that could improve the selection of patients for surgery.Median survival (MS) for the whole population was 18.3 months. Surgical resection was carried out in 61 patients; MS in resected patients was significantly longer (30.0 months) as compared with 162 non-resected patients (16.5 months) (P 0.00001). According to response criteria, 48% had a radiological partial response, 47% a stable disease and 5% a disease progression); CA19.9 response (reduction 50%) was obtained in 77.8% of patients. Among resected patients, neither pre-treatment factors, including BL/LA distinction, nor radiological response, were able to prognosticate survival differences. Survival of resected patients having no CA19.9 response was significantly lower as compared with responders (MS 15.0 versus 31.5 months, P = 0.04), and was similar to non-responders patients that did not undergo resection (MS 10.9 months, P= 0.25). Multivariate analysis carried out on the overall population, showed that Karnofsky performance status, T3-T4 status, resection and CA19.9 response were independent prognostic factors, while radiological response, BL/LA distinction and baseline CA19.9 had not significant influence on survival.CA19.9 response may allow a better selection of patients who will benefit from resection after primary CT for BL or LA pancreatic adenocarcinoma.

Pancreatic cancer patients underwent surgical resection often present distant metastases early after surgery. Detection of circulating tumor cells (CTCs) has been correlated to a worse oncological outcome in patients with advanced pancreatic cancer. The objective of this pilot study is to investigate the possible prognostic role of CTCs in patients undergoing surgery for pancreatic cancer. In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation (SC) and portal vein (PV). Blood sample was analyzed for CTCs with CellSearch® system. All patients underwent an oncologic follow-up for at least 3 years, quarterly. CTCs were detected in nine (45 %) patients: five patients had CTCs in PV only, three patients in both SC and PV, and one patient in SC only. CTC-positive and CTC-negative patients were similar for demographics and cancer stage pattern. No significant differences were found in both overall and disease-free survival between CTC-positive and CTC-negative patients. At 3-year follow-up, portal vein CTC-positive patients presented a higher rate of liver metastases than CTC-negative patients (53 vs. 8 %, p = 0.038). CTCs were found in 45 % of the patients. No correlation between CTCs and survival was found. The presence of CTCs in portal vein has been associated to higher rate of liver metastases after surgery.

Enhanced recovery after surgery (ERAS®) pathways have reduced morbidity and length of hospital stay (LOS) in orthopedics, bariatric, and colorectal surgery. New perioperative care protocols have been tested in patients undergoing pancreaticoduodenectomy (PD), with controversial results on morbidity. Incomplete data about ERAS items compliance have been reported. The aim of this study was to assess compliance with an ERAS protocol and its impact on short-term outcome in patients undergoing PD. A comprehensive ERAS protocol was applied in 115 consecutive patients undergoing PD. Each ERAS patient was matched with one patient who received standard perioperative care. Match criteria were age, gender, malignant/benign disease, and PD-specific prognostic score. No adverse effect related to ERAS items occurred. Compliance with postoperative items ranged between 38 and 66 %. The ERAS group had an earlier recovery of mobilization (p

Introduction A relaparotomy for a pancreatic fistula (PF) after a pancreaticoduodenectomy (PD) is a formidable operation, and the appropriate treatment of anastomotic leakage is under debate. The objective of this study was to compare the outcomes of different strategies in managing the pancreatic remnant during a relaparotomy for PF after a PD. Methods In this retrospective study on prospectively collected data, 669 PD were performed between 2004 and 2011. The study group comprised 31 patients requiring a relaparotomy, because of delayed haemorrhage (n = 19) or sepsis (n = 12). The pancreatic stump was treated either using pancreas-preserving techniques (simple drainage or duct occlusion) or completion of a pancreatectomy (CP). In 2008, autologous islet transplantation (AIT) was introduced for endocrine tissue rescue of CP. Results The mortality rate, blood loss and transfusion requirement were similar for all techniques. Patients undergoing a CP required a further relaparotomy less frequently than patients with pancreas preservation (7% versus 59%, P < 0.01), and the intensive care unit (ICU) stay was reduced after CP (P = 0.058). PF persisted at discharge in 66% of patients after pancreas-preserving techniques. AIT was associated with CP in 7 patients, of whom one died post-operatively. Long-term graft function was maintained in four out of six surviving patients, with one insulin-independent patient at 36 months after transplantation. Conclusions When a PF requires a relaparotomy, CP has become our favoured technique. AIT can reduce the metabolic impact of the procedure. © 2013 International Hepato-Pancreato-Biliary Association.

Background New therapies are needed for pancreatic cancer. Objective To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor growth measured with CT scan and to find the overall survival. Design A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. Setting San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. Patients A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. Intervention Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. Main Outcome Measurements Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. Results The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass (P = .07). Limitations Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. Conclusion EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control.

Background: High hospital volume improves outcomes after pancreatic resection. The aim of this study was to assess if practice and outcomes differed between high- and low-volume centers across which chief surgeons shared a similar training and mentoring. Methods: Data on patients undergoing standard pancreatic resections (2010-2013) at 7 Italian hospitals were collected. Chiefs of pancreatic surgery at each hospital had received the same training, with the same mentor. Two centers were high-volume referral hospitals for pancreatic disease, while 5 were low-volume hospitals. Results: A total of 856 patients were included, with median annual volume of resections 82 at high-volume referral hospitals and 11 at low-volume hospitals. Patients at low-volume hospitals were older, had more comorbidities, and were more often referred from the emergency room. Intraoperative techniques and reconstruction methods were similar. Comparable rates of major postoperative complications (18 vs. 22%; p = 0.236) and pancreatic fistula (29 vs. 32%; p = 0.287) were achieved in both groups, with no significant increases in failure to rescue from grade B-C fistula (6.2 vs. 15.0%; p = 0.108) and mortality (2.4 vs. 4.1%; p = 0.233) in low-volume hospitals. Postoperative length of stay was shorter in high-volume referral hospitals (10 vs. 15 days; p < 0.001). Conclusion: Similar postoperative outcomes can be achieved across high- and low-volume centers where chief surgeons shared a similar training and mentoring. However, multidisciplinary postoperative provision more often associated with high-volume centers may also affect outcomes.

Aim To investigate the effect of diabetes mellitus (DM) on disease-free and overall post-resection survival of patients with pancreatic ductal adenocarcinoma (PDAC) Methods Prospective observational study on patients admitted for pancreatic disease from January 2008 to October 2012. DM was classified as recent-onset (

Background Identification of a specific diabetes signature associated to pancreatic ductal carcinoma (PDAC) could be a key to detect asymptomatic, early stage tumors. We aim to characterize the clinical signature and the pathogenetic factors of the different types of diabetes associated with PDAC, based on the time between diabetes and cancer diagnosis. Methods Prospective observational study on 364 PDAC patients admitted to a referral center for pancreatic disease. Hospital and/or outpatient medical records were reviewed. Blood biochemical values including fasting blood glucose, insulin and/or C-peptide, glycosylated hemoglobin and anti-islet antibodies were determined. Diabetes onset was assessed after surgery and during follow-up. Results The prevalence of diabetes in patients was 67%. Considering 174 patients (47.8%) already having diabetes when diagnosed with PDAC (long duration, short duration, concomitant), the clinical and biochemical profile was similar to that of patients with type 2 diabetes (T2D). Diabetes was associated with known risk factors (i.e., age, sex, family history for diabetes and increased BMI) and both beta-cell dysfunction and insulin resistance were present. Considering 70 patients (19.2%) with onset of diabetes after PDAC diagnosis (early and late onset), the strongest predictor was the loss of beta-cell mass following pancreatectomy in patients with risk factors for T2D. Conclusion Different types of diabetes according to the time between diabetes and PDAC diagnosis are clinical entities widely overlapping with T2D. Therefore, the success of a strategy considering diabetes onset as a marker of asymptomatic PDAC will largely depend on our ability to identify new diabetes-unrelated biomarkers of PDAC.

Background: Nab-paclitaxel-gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m(-2) every 2 weeks, respectively; PAXG regimen). Methods: Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m(-2) (level three) every 2 weeks in cohorts of 3-6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma. Results: Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31%; fatigue 19%; anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by >= 49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%. Conclusions: The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m(-2) every 2 weeks. The preliminary results are promising and warrant further exploration. ZB 0 Z8 0 ZR 0 ZS 0

New chemotherapeutic regimens have improved survival for stage IV pancreatic ductal adenocarcinoma and occasionally major response of liver metastases can be observed. Aim of this work is to analyze the outcomes of patients undergoing primary chemotherapy for liver metastases from pancreatic cancer and to evaluate the results of surgical resection.Retrospective analysis.patients with extra-hepatic metastases, patients with Eastern Cooperative Oncology Group performance status ≥3, patients undergoing supportive care alone.127 patients were identified. Liver metastases were unilobar in 28.5% of patients. Chemotherapy regimens included gemcitabine alone or in association with other agents (44%), oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX 8%), and cisplatin, gemcitabine plus capecitabine and epirubicin (PEXG) or capecitabine and docetaxel (PDXG) or epirubicin and fluorouracil (PEFG) (48%). 56 patients (44%) had a complete (7%) or partial response (37%). surgical resection was carried out in 11 patients (8.5%). Median overall survival was 11 months for the entire cohort and 15 months for those with partial/complete response. In this sub-group median survival was significantly longer (46 versus 11 months) for patients undergoing resection (P 0.0001). Independent predictors of overall survival were chemotherapy with multiple agents (HR: 0.512), surgical resection (HR: 0.360),5 liver metastases at diagnosis (HR: 3.515), and CA 19.9 reduction 50% of baseline value (HR: 2.708).Surgical resection of primary pancreatic tumor with or without residual liver disease can be considered in selected cases after primary chemotherapy and it is associated with improved survival.

Objectives Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. Design Retrospective multinational study including SCN diagnosed between 1990 and 2014. Results 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16–99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2–200)), 9% had resection beyond 1 year of follow-up (3 years (1–20), size at diagnosis: 25 mm (4–140)) and 39% had no surgery (3.6 years (1–23), 25.5 mm (1–200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN9s related mortality was 0.1% (n=1). Conclusions After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. Trial registration number IRB 00006477.

Laparoscopic distal pancreatectomy (LDP) for benign and borderline pancreatic lesions is recently becoming the treatment of choice in experienced centres. No data have been published on learning curve so far. The purpose of this study was to identify the learning curve period for performing LDP. Between March 2009 and August 2010 all patients with lesions of pancreatic body or tail were assessed for eligibility for LDP. Exclusion criteria were: major vessels contact in cancer patients, severe organ dysfunction, BMI > 35, and refusing laparoscopic approach. All laparoscopic procedures were carried out by the same surgical team with large experience in open pancreatic surgery. All patients were treated according to an early recovery after surgery protocol. Primary endpoint was conversion rate. Secondary endpoints were operative time, operative blood loss, postoperative morbidity, and length of stay (LOS). Sixty patients were assessed for eligibility. Thirty (50.0 %) patients met the exclusion criteria, while the other 30 patients underwent LDP. Spleen-preserving procedure was planned in the 17 patients with benign lesion and successfully performed in 15 (82.3 %). Overall conversion rate was 23.3 %, but it dropped significantly after the first ten patients (p = 0.01). Mean operative time progressively declined from 254 min in the first subgroup of ten patients to 206 min in the second (p = 0.09 vs. first), and 183 min in the third subgroup (p = 0.006 vs. first). No significant difference was found for operative blood loss, postoperative morbidity rate, and LOS in the different subgroups. Both conversion rate and operative time dropped after the first ten patients who underwent LDP. Strict selection criteria, high-volume hospital, and experienced team in open pancreatic surgery may have played a role in shortening the learning curve.

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/m(2)) and 5-fluorouracil (200 mg/m(2)/day on Days 1-14) and of escalating doses of cisplatin and gemcitabine. The MTD was cisplatin 30 mg/m(2) and gemcitabine 800 mg/m(2). 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 >= 50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine- containing chemotherapy, and progression- free survival ( PFS) < 12 months received a combination of raltitrexed ( 3 mgm (-2)) and oxaliplatin ( 130 mgm (-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 42 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 46 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.

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.

The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being ideal. We recently have shown in mice that the bone marrow (BM) may be a valid alternative to the liver, and here we report a pilot study to test feasibility and safety of BM as a site for islet transplantation in humans. Four patients who developed diabetes after total pancreatectomy were candidates for the autologous transplantation of pancreatic islet. Because the patients had contraindications for intraportal infusion, islets were infused in the BM. In all recipients, islets engrafted successfully as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples analyzed during follow-up. Thus far, we have recorded no adverse events related to the infusion procedure or the presence of islets in the BM. Islet function was sustained for the maximum follow-up of 944 days. The encouraging results of this pilot study provide new perspectives in identifying alternative sites for islet infusion in patients with type 1 diabetes. Moreover, this is the first unequivocal example of successful engraftment of endocrine tissue in the BM in humans. OI Piemonti, Lorenzo/0000-0002-2172-2198 "The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being ideal. We recently have shown in mice that the bone marrow (BM) may be a valid alternative to the liver, and here we report a pilot study to test feasibility and safety of BM as a site for islet transplantation in humans. Four patients who developed diabetes after total pancreatectomy were candidates for the autologous transplantation of pancreatic islet. Because the patients had contraindications for intraportal infusion, islets were infused in the BM. In all recipients, islets engrafted successfully as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples analyzed during follow-up. Thus far, we have recorded no adverse events related to the infusion procedure or the presence of islets in the BM. Islet function was sustained for the maximum follow-up of 944 days. The encouraging results of this pilot study provide new perspectives in identifying alternative sites for islet infusion in patients with type 1 diabetes. Moreover, this is the first unequivocal example of successful engraftment of endocrine tissue in the BM in humans."

Objective Our goal was to determine the value of MRI in the assessment of vascular invasion in the preoperative staging of pancreatic carcinoma. Materials and Methods In 53 consecutive patients with an established diagnosis of pancreatic ductal adenocarcinoma, SE T1-weighted and breath-hold gradient echo images at 0.5 T were obtained before and after bolus injection of Gd-DTPA. Major peripancreatic vessels were evaluated for the presence of (a) no tumor invasion, (b) contiguity with tumor, and (c) tumor encasement. All patients subsequently underwent surgery. Results of unenhanced and contrast-enhanced MRI studies were compared with the histologie findings in the resected specimens in 34 cases and with the surgical findings in 19 nonresected cases. Results In six patients, pathologic examination showed the presence of tumor confined to the pancreas with no vascular invasion. With MRI, five of these cases were correctly evaluated; in the remaining case, tumor-vessel contiguity was erroneously diagnosed. In 21 patients, tumor contiguity with adjacent vessels was found at pathologic examination. At MRI, 16 of these cases were correctly assessed, and 5 were understaged as tumors confined to the pancreas. Of the remaining 26 patients, 7 had vascular encasement by tumor at pathologic examination of the resected specimen; the other 19 patients had unresectable tumors encasing the adjacent vessels at surgical evaluation. MRI detected vascular encasement in 21 of these 26 cases; in the other 5, tumor contiguity was incorrectly diagnosed. The overall accuracy of MRI for determining vascular invasion was 79%. Conclusion MRI is a helpful method for preoperative assessment of vascular involvement due to pancreatic carcinoma.

Between 1989 and 1993, 62 patients underwent Whipple pancreatoduodenectomy and 75 pylorus-preserving pancreatoduodenectomy (PPPD); 35 patients in the first group and 37 in the second had pancreatic adenocarcinoma while 17 and 21 patients respectively had periampullary adenocarcinoma. The aim of this retrospective study was the comparison of operative outcome, nutritional recovery and survival of patients who underwent these two operations. No significant differences were found between the two groups in operative mortality or morbidity, duration of gastric aspiration and time to start of solid meals. Patients who underwent PPPD had a better nutritional recovery: the increase of both body-weight and serum albumin level at 6 months after discharge was significantly higher for those who had preservation of the whole stomach (P < 0.001 and P < 0.05 respectively). No significant difference in survival was found between the two procedures when patients with pancreatic or periampullary adenocarcinoma were analysed separately.

Background: Preoperative chemotherapy (PCHT) has recently been proposed also in patients with resectable pancreatic adenocarcinoma. Few data are currently available on the impact of PCHT on short-term postoperative outcome after pancreatic resection. The objective of this study is to assess the impact of PCHT on pancreatic structure and short-term outcome after surgical resection. Methods: Fifty consecutive patients successfully underwent resection after PCHT. Each patient was matched with two control patients with pancreatic adenocarcinoma selected from our prospective electronic database. Match criteria were age (±3 years), gender, American Society of Anesthesiologist score, type of resection, pancreatic duct diameter (±1 mm), and tumor size (±5 mm). Primary endpoint was morbidity rate. Secondary endpoints were pancreatic parenchymal structure, mortality rate, and length of hospital stay (LOS). Results: Both degree of fibrosis and fatty infiltration of the pancreas were similar in the two groups. Overall morbidity rate was 48. 0 % in the PCHT group vs. 54. 0 % in the control group (p = 0. 37). Pancreatic fistula rate was 18. 0 % in the PCHT group vs. 25. 0 % in the control group (p = 0. 41). Mortality was 4. 0 % in the PCHT group vs. 2. 0 % in the control group (p = 0. 60). Mean LOS (days) was 12. 7 in the PCHT group vs. 12. 4 in the control group (p = 0. 74). There was no difference in resection margin status, while the rate of patients without nodal involvement was higher in the PCHT group (46. 0 vs. 23. 0 %, p = 0. 004). Conclusion: PCHT did not induce significant structural changes in pancreatic parenchyma and did not adversely affect short-term outcome after surgery.

Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS) > 60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m(2) weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m(2), day 1; gemcitabine 600 mg/m(2), days 1, 8; 5-fluorouracil 200 mg/m(2) daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m(2) daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0 = 35% and P1 = 55%, alpha = .05 and beta = .10, the study was to enroll 51 patients per arm. A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS > 80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. The 4-drug regimen deserves further assessment in resectable pancreatic cancer.

Purpose PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). Methods Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, alpha = 0.05 and beta = 0.10; the study was to enroll 52 patients per arm. Results Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS > 70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. Conclusions The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens. PURPOSE: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). METHODS: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and β = 0.10; the study was to enroll 52 patients per arm. RESULTS: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. CONCLUSIONS: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

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 (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 1167 U/mL, and 8 months for 105 patients who had basal values >1167 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. Cancer 2009;115:2630-9. (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.

Background PEFG regimen (cisplatin and epirubicin 40 mg/m(2) day 1, gemcitabine 600 mg/m(2) days 1 and 8, 5-fluorouracil (FU) 200 mg/m(2)/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/m(2) every 14 days) and of gemcitabine (at 800 mg/m(2) 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.

Summary 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/m 2 cisplatin and 40 mg/m 2 epirubicin both given on day 1, 600 mg/m 2 gemcitabine given intravenously over 1 h on days 1 and 8, and 200 mg/m 2 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/m 2 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 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) ≧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% (α 0.05; β 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.

AIM: To evaluate the safety and feasibility of laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with autologous islet transplantation (AIT) for benign tumors of the pancreatic body-neck. METHODS: Three non-diabetic, female patients (age 37, 44 and 35 years, respectively) were declared candidates for surgery, between May and September 2011, because of pancreatic body/neck cystic lesions. The planned operation was an LSPDP associated with AIT from the normal pancreas distal to the neoplasm. Islets isolation was performed on the residual pancreatic parenchyma after frozen section examination of the margin. Purified autologous islets were infused into the portal vein by a percutaneous transhepatic approach the day after surgery. RESULTS: The procedure was performed successfully in all the three cases, and the spleen was preserved along with its vessels. Mean operation time was 283 ± 52 min and average blood loss was 133 ± 57 mL. Residual pancreas weights were 33, 22 and 30 g, and 105.200, 40.390 and 94.790 islet equivalents were isolated, respectively. Surgical complications occurred in one patient (grade A pancreatic fistula). Postoperative stays were 6, 6 and 7 d, respectively. Histopathological evaluation revealed mucinous cystic neoplasm in cases 1 and 3, and serous cystic neoplasm in patient 2. No postoperative insulin administration was required. One patient developed a transient partial portal thrombosis 2 mo after islet infusion. Patients are insulin independent at a mean follow up of 8 ± 2 mo. CONCLUSION: Combination of LSPDP and AIT is feasible and could be effective to minimize the surgical impact for benign neoplasm of pancreatic body-neck. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

A chronic in ammatory state of the airways is considered the hallmark of asthma (1). However, the incidence, severity, and prognosis of asthma can be affected by a number of factors, including the patient's sex and age. The sex of the fetus seems to in uence the development of the respiratory apparatus. In fact, between weeks 28 and 40 of gestation, the lungs are in a more advanced state in females than in males (2), a fact which could explain, at least in part, the higher incidence of respiratory distress in male infants (3). Clinical observations and epidemiologic studies agree that childhood asthma is more frequent in boys than in girls (4). Moreover, in some children, usually boys, asthmatic symptoms that started in infancy disappear around puberty (5), while many girls have the disease only during adolescence (6). Age has been implicated in the severity of asthma. Asthma beginning during adulthood is generally more severe than childhood-onset asthma (7). Asthma that starts around the menopause or in old age is generally quite severe (5). According to two recent epidemiologic investigations, the patient's sex and age affect the hospitalization rate for asthma (8, 9), which is a marker of severity. In the ®rst study (a retrospective study of 33 269 patients), the admission rate of boys in the 0±10-year age group was almost twice that of girls. In the next decade, sex differences in the hospitalization rate were irrelevant, although there was a small, but signi®cant prevalence of females. At all ages above 20 years, hospital admission rates were higher in women than men, with a female/ male ratio ranging from 3:1 in subjects aged 20±50 years to 2.5:1 in those over 50 years of age (8). Similar data were reported by Elliasson (9). Both studies found a relationship between the age and sex of the patient and the severity of the asthma attack as indicated by duration of hospitalization. In fact, the duration of hospitalization increased with age in both sexes; moreover, hospital stays were longer in women over 30 years of age than in men of the same age (8, 9). Abbreviations. FSH: follicle-stimulating hormone; LH: luteinizing hormone; NK cell: natural killer cell; IL-1, -4, -5, -6: interleukin-1, -4, -5, -6; TGF-b: tumor growth factor-beta; PEFR: peak expiratory ow rate. Allergy 2001: 56: 13±20 Printed in UK. All rights reserved Copyright # Munksgaard 2001