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ABSTRACT: 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.
Journal of Gastrointestinal Surgery 11/2012; · 2.83 Impact Factor
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ABSTRACT: 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.
Updates in surgery. 07/2012; 64(3):179-83.
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ABSTRACT: To analyze the characteristics and outcomes following enucleation and pancreatic resections of insulinomas.
Retrospective cohort study; prospective database.
Academic, tertiary, and referral centers.
Consecutive patients with insulinomas (symptoms of hyperinsulinism and positive fasting glucose test) who underwent surgical treatment between January 1990 and December 2009.
Operative morbidity, tumor recurrence, and survival after treatment.
A total of 198 patients (58.5% women; median age, 48 years) were identified. There were 175 (88%) neuroendocrine tumors grade G1 and 23 (12%) neuroendocrine tumors grade G2. Malignant insulinomas defined by lymph node/liver metastases were found in 7 patients (3.5%). Multiple insulinomas were found in 8% of patients, and 5.5% of patients had multiple endocrine neoplasia type 1. Surgical procedures included 106 enucleations (54%) and 92 pancreatic resections (46%). Mortality was nil. Rate of clinically significant pancreatic fistula was 18%. Enucleations had a higher reoperation rate compared with pancreatic resections (8.5% vs 1%; P = .02). Multiple endocrine neoplasia type 1 was significantly associated with younger age at onset (P < .005) and higher rates of malignancies and multiple lesions. Median follow-up was 65 months. Six patients (3%; 5 patients had neuroendocrine tumors grade G2) developed tumor recurrence. Four patients (2%) died of disease. New exocrine (1.5%) and endocrine (4%) insufficiencies were associated only with pancreatic resections.
Outcomes following surgical resection of insulinomas are satisfactory, with no mortality and good functional results. Recurrence is uncommon (3%), and it is more likely associated with neuroendocrine tumors grade G2. Insulinomas in multiple endocrine neoplasia type 1 are at higher risk for being malignant and multifocal, requiring pancreatic resections.
Archives of surgery (Chicago, Ill.: 1960) 03/2012; 147(3):261-6. · 4.32 Impact Factor
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Michele Reni,
Gianpaolo Balzano,
Giuseppe Aprile,
Stefano Cereda,
Paolo Passoni,
Alessandro Zerbi,
Maria Chiara Tronconi,
Carlo Milandri,
Piercarlo Saletti,
Alessia Rognone,
Clara Fugazza,
Alessandro Magli,
Nadia Di Muzio, Valerio Di Carlo,
Eugenio Villa
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ABSTRACT: 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/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 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/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and β=.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.
Annals of Surgical Oncology 01/2012; 19(7):2256-63. · 4.17 Impact Factor
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ABSTRACT: Despite the close relationship between hospital volume and mortality after pancreaticoduodenectomy (PD), the role of surgeon volume still remains an open issue. Retrospective multi-institutional reviews considered only in-hospital mortality, whereas no data about major complications are available so far. The aim of this study is to assess the independent impact of surgeon volume on outcome after PD in a single high-volume institution.
Demographics and clinical and surgical variables were prospectively collected on 610 patients who underwent PD from August 2001 to August 2009. The cutoff value to categorize high- and low-volume surgeons (HVS and LVS, respectively) was 12 PD/year. The primary endpoint was operative mortality (death within 30-day post-discharge). Secondary endpoints were morbidity, pancreatic fistula (PF), and length of hospital stay (LOS).
In the whole series, mortality was 4.1%, overall morbidity was 61.3%, and PF rate was 27.5%. Two HVS performed 358 PD (58.6%), while six LVS performed 252 PD (41.4%). Mortality was 3.9% for HVS and 4.3% for LVS (p=0.84). The major complication rate was similar for HVS and LVS (14.5% vs. 16.2%). The PF rate was higher for LVS (32.4% vs. 24.1%, p=0.03). The mean LOS was 15.5 days for HVS vs. 16.9 days for LVS (p=0.11). At multivariate analysis, risk factors for PF occurrence were LVS, soft pancreatic stump, small duct diameter, and longer operative time.
Low-volume surgeons had a higher PF rate. However, this did not increase mortality and major morbidity rates probably because of the protective effect of high-volume hospital in improving patient rescue from life-threatening complications.
Journal of Gastrointestinal Surgery 11/2011; 16(3):518-23. · 2.83 Impact Factor
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ABSTRACT: To develop and validate a simple prognostic score to predict major postoperative complications after pancreaticoduodenectomy (PD).
PD still carries a high rate of severe postoperative complications. No specific score is currently available to stratify the patient's risk of major morbidity.
Between 2002 and 2010, preoperative, intraoperative, and outcome data from 700 consecutive patients undergoing PD in our institution were prospectively collected in an electronic database. Major complications were defined as levels III to V of Clavien-Dindo classification. On the basis of a multivariate regression model, the score was developed using a random two-thirds of the population (n = 469) and was validated on the remaining 231 patients.
Major complication rate was 16.7% (117/700). Significant predictors included in the scoring system were: pancreas texture, pancreatic duct diameter, operative blood loss, and ASA score. The mean risk of developing major postoperative complications was 7% in patients with score 0 to 3, 13% in patients with score 4 to 7, 23% in patients with score 8 to 11, and 36% in patients with score 12 to 15. In the validation population, the predicted risk of major complications was 15.2% versus a 16.9% observed risk (C-statistic index = 0.743).
This new score may accurately predict a patient's postoperative outcome. Early identification of high-risk patients could help the surgeon to adopt intraoperative and postoperative strategies tailored on individual basis.
Annals of surgery 11/2011; 254(5):702-7; discussion 707-8. · 7.90 Impact Factor
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ABSTRACT: Oxidative stress due to ischemia/reperfusion injury increases systemic inflammation and impairs immune defenses. Much interest has developed for the administration of antioxidant substrates in surgical patients. The purpose of this study was to perform a pilot evaluation of the impact of a carbohydrate- containing preconditioning oral nutritional supplement (pONS) enriched with glutamine, antioxidants, and green tea extract on postoperative oxidative stress.
We performed a double-blind placebo-controlled randomized clinical trial, involving 36 cancer patients undergoing pancreaticoduodenectomy. Patients were randomized to receive either pONS or placebo twice the day before surgery and once 3 hours before surgery. Total endogenous antioxidant capacity (TEAC), plasma levels of vitamin C, vitamin E, selenium, zinc, F2-isoprostanes, and C-reactive protein were measured at baseline and on postoperative day (POD) 1, 3, and 7.
At surgery, the mean gastric residual volume (mL) was 54.2 in the pONS group versus 51.3 in the placebo group (P = NS). On POD 1 plasma levels of vitamin C (P = 0.001), selenium (P = 0.07), and zinc (P = 0.06) were higher in the pONS group compared to placebo. TEAC was improved on POD 1, 3, and 7 in the pONS group compared to placebo (P = 0.01). No difference was found in plasma C-reactive protein levels after surgery in both groups.
Perioperative pONS administration positively affected plasma vitamin C levels and improved TEAC shortly after surgery, but did not reduce oxidative stress and systemic inflammation markers.
Nutrition 09/2011; 28(2):160-4. · 3.03 Impact Factor
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ABSTRACT: To evaluate long-term outcomes in a large series of patients who randomly received laparoscopic or open colorectal resection.
From February 2000 to December 2004, six hundred sixty-two patients with colorectal disease were randomly assigned to laparoscopic (LPS, n = 330) or open (n = 332) colorectal resection. All patients were analyzed on an intention-to-treat basis. Long-term follow-up was carried out every 6 mo by office visits. In 526 cancer patients five-year overall and disease-free survival were evaluated. Median oncologic follow-up was 96 mo.
Eight (4.2%) LPS group patients needed conversion to open surgery. Overall long-term morbidity rate was 7.6% (25/330) in the LPS vs 11.1% (37/332) in the open group (P = 0.17). In cancer patients, five-year overall survival was 68.6% in the LPS group and 64.0% in the Open group (P = 0.27). Excluding stage IV patients, five-year local and distant recurrence rates were 32.5% in the LPS group and 36.8% in the Open group (P = 0.36). Further, no difference in recurrence rate was found when patients were stratified according to cancer stage.
LPS colorectal resection was associated with a slightly lower incidence of long-term complications than open surgery. No difference between groups was found in overall and disease-free survival rates.
World journal of gastrointestinal oncology. 03/2011; 3(3):43-8.
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ABSTRACT: Pancreatic cancer is a very aggressive disease characterized by a marked desmoplasia with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We found that the ratio of GATA-3+/T-bet+ tumor-infiltrating lymphoid cells is an independent predictive marker of patient survival. Patients surgically treated for stage IB/III disease with a ratio inferior to the median value had a statistically significant prolonged overall survival, implying an active role for Th2 responses in disease progression. Thymic stromal lymphopoietin (TSLP), which favors Th2 cell polarization through myeloid dendritic cell (DC) conditioning, was secreted by cancer-associated fibroblasts (CAFs) after activation with tumor-derived tumor necrosis factor α and interleukin 1β. TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were expressed in the tumor and in the stroma, and TSLPR-expressing DCs were present in the tumor stroma and in tumor-draining but not in nondraining lymph nodes. Collectively, this study identifies in pancreatic cancer a cross talk between tumor cells and CAFs, resulting in a TSLP-dependent induction of Th2-type inflammation which associates with reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis in pancreatic cancer.
Journal of Experimental Medicine 02/2011; 208(3):469-78. · 13.85 Impact Factor
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ABSTRACT: This study aimed to evaluate the surgical treatment of acute pancreatitis in Italy and to assess compliance with international guidelines.
A series of 1173 patients in 56 hospitals were prospectively enrolled and their data analysed.
Twenty-nine patients with severe pancreatitis underwent surgical intervention. Necrosectomy was performed in 26 patients, associated with postoperative lavage in 70% of cases. A feeding jejunostomy was added in 37% of cases. Mortality was 21%. Of the patients with mild pancreatitis, 714 patients with a biliary aetiology were evaluated. Prophylactic treatment of relapses was carried out in 212 patients (36%) by cholecystectomy and in 161 using a laparoscopic approach. Preoperative endoscopic retrograde cholangiopancreatography was associated with cholecystectomy in 83 patients (39%). Forty-seven patients (22%) were treated at a second admission, with a median delay of 31 days from the onset of pancreatitis. Eighteen patients with severe pancreatitis underwent cholecystectomy 37.9 days after the first admission. There were no deaths.
The results indicate poor compliance with published guidelines. In severe pancreatitis, early surgical intervention is frequently performed and enteral feeding is seldom used. Only a small number of patients with mild biliary pancreatitis undergo definitive treatment (i.e. cholecystectomy) within 4 weeks of the onset of pancreatitis.
HPB 11/2010; 12(9):597-604. · 1.60 Impact Factor
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ABSTRACT: To evaluate the data from a survey carried out in Italy regarding the endoscopic approach to acute pancreatitis in order to obtain a picture of what takes place after the release of an educational project on acute pancreatitis sponsored by the Italian Association for the Study of the Pancreas.
Of the 1 173 patients enrolled in our survey, the most frequent etiological category was biliary forms (69.3%) and most patients had mild pancreatitis (85.8%).
344/1 173 (29.3%) underwent endoscopic retrograde cholangiopancreatography (ERCP). The mean interval between the onset of symptoms and ERCP was 6.7 ± 5.0 d; only 89 examinations (25.9%) were performed within 72 h from the onset of symptoms. The main indications for ERCP were suspicion of common bile duct stones (90.3%), jaundice (44.5%), clinical worsening of acute pancreatitis (14.2%) and cholangitis (6.1%). Biliary and pancreatic ducts were visualized in 305 patients (88.7%) and in 93 patients (27.0%) respectively. The success rate in obtaining a cholangiogram was statistically higher (P = 0.003) in patients with mild acute pancreatitis (90.6%) than in patients with severe disease (72.2%). Biliary endoscopic sphincterotomy was performed in 295 of the 305 patients (96.7%) with no difference between mild and severe disease (P = 0.985). ERCP morbidity was 6.1% and mortality was 1.7%; the mortality was due to the complications of acute pancreatitis and not the endoscopic procedure.
The results of this survey, as with those carried out in other countries, indicate a lack of compliance with the guidelines for the indications for interventional endoscopy.
World journal of gastrointestinal endoscopy. 09/2010; 2(9):308-13.
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ABSTRACT: Information on pancreatic endocrine tumors (PETs) comes mostly from small, retrospective, uncontrolled studies conducted on highly selected patients. The aim of the study was to describe the clinical and pathological features of PETs in a prospective, multicenter study.
Newly diagnosed, histologically proven, sporadic PETs observed from June 2004 to March 2007 in 24 Italian centers were included in a specific data set.
Two hundred ninety-seven patients (mean age 58.6+/-14.7 years, females 51.2%, males 48.8%) were analyzed. In 73 cases (24.6%), the tumor was functioning (F) (53 insulinomas, 15 gastrinomas, 5 other syndromes) and in 232 (75.4%) it was non-functioning (NF); in 115 cases (38.7%), the diagnosis was incidental. The median tumor size was 20 mm (range 2-150). NF-PETs were significantly more represented among carcinomas (P<0.001). Nodal and liver metastases were detected in 84 (28.3%) and 85 (28.6%) cases, respectively. The presence of liver metastases was significantly higher in the NF-PETs than in the F-PETs (32.1% vs. 17.8%; P<0.05), and in the symptomatic than in the asymptomatic patients (34.6% vs. 19.1%; P<0.005). At the time of recruitment, the majority of patients (251, 84.5%) had undergone surgery, with complete resection in 209 cases (83.3%).
This study points out the high number of new cases of PETs observed in Italy, with a high prevalence of NF and incidentally discovered forms. The size of the tumor was smaller and the rate of metastasis was lower than usually reported, suggesting a trend toward an earlier diagnosis.
The American Journal of Gastroenterology 06/2010; 105(6):1421-9. · 7.28 Impact Factor
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ABSTRACT: The pancreatic stump is the major source of morbidity and mortality of pancreatoduodenectomy (PD). Any surgeon experienced
in pancreatic surgery is often dealing with the dramatic consequences of the failure of the technique he or she adopted; thus
we ask ourselves what technical errors we have committed, or whether it would have been better to perform a different reconstruction,
maybe an anastomosis with the stomach, or an interrupted suture instead of a continuous one, or to use a Roux-en-Y limb, or
to close the stump without anastomosis. In these circumstances the questions are many and legitimate, because pancreatic surgery
requires an extremely accurate technique and we need to choose the proper solution based on the pancreas’ characteristics
and on our own experience. However, it is important, first of all, to realize that the main actor in the dramatic consequences
of pancreatic surgery is the pancreas itself, with the destructive potential of its digestive secretions. There is no evidence
that any given technique is able to solve the problems of the pancreatic remnant, and no comparative study has proved one
specific technique to be clearly better than another. Nevertheless, if our aim is to expose our patient who is a candidate
for a PD to the smallest possible risk of death (for that is what is at issue), there is one vital element that is frequently
ignored.
05/2010: pages 297-304;
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ABSTRACT: 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.
All patients who underwent PPRs for NF-PETs between 1990 and 2005 were included. Patients with multiple endocrine neoplasia type 1 were excluded.
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%.
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.
Annals of Surgical Oncology 02/2010; 17(6):1621-7. · 4.17 Impact Factor
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ABSTRACT: 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.
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.
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.
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 04/2009; 115(12):2630-9. · 4.77 Impact Factor
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ABSTRACT: Pancreatic cancer is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which favors rapid tumor progression. We previously reported that pancreatic cancer patients have a selective Th2 skew in the anti-carcinoembryonic antigen (CEA) CD4(+) T cell immunity, which correlates with the presence of a predominant GATA-3(+) tumor lymphoid infiltrate. This has negative effects in both effective anti-tumor immunity and further favoring fibrinogenesis. Aim of this study was to evaluate whether the Th2 polarization of CEA-specific CD4(+) T cells from pancreatic cancer patients is stable or can be reverted by immunomodulating cytokines.
We first evaluated the influence of IL-12 and IL-27, as single agents and in association, on the polarization of CEA-specific Th2 CD4(+) T cell clones from a pancreatic cancer patient. We found that only the combination of IL-12 and IL-27 modified the polarization of Th2 effectors by both reduction of IL-5, GM-CSF and IL-13 and induction of IFN-gamma production, which lasted after cytokine removal. Second, we evaluated the effect of the combined treatment on polyclonal CEA-specific CD4(+) T cells in short-time re-stimulation assays. In agreement with the data obtained with the clones, we found that the combined treatment functionally modulated the Th2 polarization of CEA-specific CD4(+) T cells and enhanced pre-existing Th1 type immunity.
Collectively, our results demonstrate that tumor antigen specific Th2 CD4(+) T cells in pancreatic cancer are endowed with functional plasticity. Hence, loco-regional cytokines delivery or targeted therapy based on antibodies or molecules directed to the tumor stroma might improve anti-tumor immunity and ameliorate fibrosis, without systemic toxicity.
PLoS ONE 01/2009; 4(10):e7234. · 4.09 Impact Factor
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ABSTRACT: Pancreatic carcinoma is a very aggressive disease with dismal prognosis. Although evidences for tumor-specific T cell immunity exist, factors related to tumor microenvironment and the presence of immunosuppressive cytokines in patients' sera have been related to its aggressive behavior. Carcinoembryonic Ag (CEA) is overexpressed in 80-90% of pancreatic carcinomas and contains epitopes recognized by CD4(+) T cells. The aim of this study was to evaluate the extent of cancer-immune surveillance and immune suppression in pancreatic carcinoma patients by comparing the anti-CEA and antiviral CD4(+) T cell immunity. CD4(+) T cells from 23 normal donors and 44 patients undergoing surgical resection were tested for recognition of peptides corresponding to CEA and viral naturally processed promiscuous epitopes by proliferation and cytokine release assays. Anti-CEA CD4(+) T cell immunity was present in a significantly higher number of normal donors than pancreatic cancer patients. Importantly, whereas CD4(+) T cells from normal donors produced mainly GM-CSF and IFN-gamma, CD4(+) T cells from the patients produced mainly IL-5, demonstrating a skew toward a Th2 type. On the contrary, the extent of antiviral CD4(+) T cell immunity was comparable between the two groups and showed a Th1 type. The immunohistochemical analysis of tumor-infiltrating lymphocytes showed a significantly higher number of GATA-3(+) compared with T-bet(+) lymphoid cells, supporting a Th2 skew also at the tumor site. Collectively, these results demonstrate that Th2-immune deviation in pancreatic cancer is not generalized but tumor related and suggests that the skew might be possibly due to factor(s) present at the tumor site.
The Journal of Immunology 12/2008; 181(9):6595-603. · 5.79 Impact Factor
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Federica Marchesi,
Lorenzo Piemonti,
Giuseppe Fedele,
Annarita Destro,
Massimo Roncalli,
Luca Albarello,
Claudio Doglioni,
Achille Anselmo,
Andrea Doni,
Paolo Bianchi,
Luigi Laghi,
Alberto Malesci,
Luigi Cervo,
Marialuisa Malosio,
Michele Reni,
Alessandro Zerbi, Valerio Di Carlo,
Alberto Mantovani,
Paola Allavena
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ABSTRACT: Tumor perineural dissemination is a hallmark of human pancreatic ductal adenocarcinoma (PDAC) and represents a major source of local tumor recurrence after surgery. In this study, we provide in vitro and in vivo evidence that the chemokine receptor CX3CR1 may be involved in the neurotropism of PDAC cells to local peripheral nerves. Neoplastic cells from PDAC cell lines and surgical specimens express the chemokine receptor CX3CR1, absent in normal pancreatic ducts. Its unique ligand, the transmembrane chemokine CX3CL1, is expressed by neurons and nerve fibers. CX3CR1 + PDAC cell lines migrated in response to human recombinant CX3CL1 and specifically adhered to CX3CL1-expressing cells of neural origin via mechanisms involving activation of G proteins, beta1 integrins, and focal adhesion kinase. In vivo experiments with transplanted PDAC showed that only CX3CR1-transfected tumor cells infiltrated the local peripheral nerves. Immunohistochemistry of CX3CR1 in PDAC specimens revealed that 90% of the samples were positive with a heterogeneous pattern of expression. High receptor score was significantly associated with more prominent tumor perineural infiltration evaluated histologically (P = 0.026). Regression analyses (univariate and multivariate) showed that high CX3CR1 expression and perineural invasion were strongly associated with local and earlier tumor recurrence (P = 0.007). Collectively, this study shows that the CX3CR1 receptor may be involved in PDAC tumor neurotropism and is a relevant and independent risk factor to predict an early local tumor relapse in resected patients. Thus, the CX3CR1-CX3CL1 axis could represent a valuable therapeutic target to prevent tumor perineural dissemination in pancreatic cancer.
Cancer Research 12/2008; 68(21):9060-9. · 7.86 Impact Factor
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Vincenzo Valentini,
Felipe Calvo,
Michele Reni,
Robert Krempien,
Felix Sedlmayer,
Markus W Buchler, Valerio Di Carlo,
Giovanni B Doglietto,
Gerd Fastner,
José L Garcia-Sabrido,
GianCarlo Mattiucci,
Alessio G Morganti,
Paolo Passoni,
Falk Roeder,
Giuseppe R D'Agostino
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ABSTRACT: A joint analysis of data from five contributing centers within the ISIORT-Europe program was performed to investigate the main contributions of intra-operative radiotherapy (IORT) to the multidisciplinary treatment of pancreatic cancer.
Patients with a histologic diagnosis of carcinoma of the pancreas, with an absence of distant metastases, undergoing surgery with radical intent and IORT were considered eligible for participation in this study.
From 1985 to 2006, a total of 270 patients were enrolled in the study from five European institutions. Surgery was performed in 91.5% of cases and complicated by adverse events in 59 cases. External radiotherapy (ERT) preceded surgery in 23.9% of cases. One-hundred and six patients received further ERT. After surgery + IORT, median follow-up was 96 months (range 3-180). Median local control was 15 months, 5-year local control was 23.3%. Median overall survival was 19 months, while 5-year survival was 17.7%. A significantly greater local control and survival were observed in patients undergoing preoperative radiotherapy (LC: median not reached; OS: median 30 months) compared to patients treated with postoperative ERT alone (LC: median 28 months; OS: median 22 months), and to patients submitted to IORT exclusively (LC: median 8 months; OS: median 13 months) (p < 0.0001).
From this joint analysis emerges the fact that preoperative radiotherapy increases the effects of IORT in terms of local control and overall survival. The 5-year local control of 23.3% confirms the beneficial "sterilizing" effect of IORT on the tumor bed.
Radiotherapy and Oncology 08/2008; 91(1):54-9. · 5.58 Impact Factor
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ABSTRACT: Abstract In order to evaluate the effect of a combined kidney-pancreas (KP) transplantation in insulin-dependent diabetes mellitus (IDDM) patients on the lipid and lipoprotein profile, 15 KP patients were compared with 11 kidney (K)-transplanted IDDM patients, 19 IDDM patients on hemodialysis (HD), and 15 nondiabetic control subjects. Cholesterol, triglycerides, apo AI, and apo B were measured in total plasma and in VLDL, LDL, and HDL of all participants. VLDL-cholesterol, VLDL-triglycerides, and VLDL-apo B were significantly lower in KP patients, but not in K patients, than in HD patients. In addition, patients in the K, but not in the KP, group showed high levels of apo B in LDL and an increased triglyceride/apo B ratio in VLDL, compared with patients in the HD group. The percentage of apo AI associated with HDL was significantly higher in both transplanted groups than in the HD group. However, compared with a nondiabetic control population, an increase in VLDL particles and in triglyceride content in LDL and HDL still persisted following combined KP transplantation. Insulin resistance (probably due to steroid therapy) associated with high peripheral and potentially low hepatic insulin levels (due to the systemic drainage of the transplanted pancreas) could be the main causes of the remaining lipoprotein abnormalities.
Transplant International 06/2008; 8(3):190 - 195. · 2.92 Impact Factor
