Carlo Staudacher

Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial

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

Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes.

OBJECTIVE Autoimmune diseases, including type 1 diabetes, are thought to have a Th17-cell bias and/or a T-regulatory cell (Treg) defect. Understanding whether this is a hallmark of patients with type 1 diabetes is a crucial question that is still unsolved, largely due to the difficulties of accessing tissues targeted by the disease. RESEARCH DESIGN AND METHODS We phenotypically and functionally characterized Th17 cells and Tregs residing in the pancreatic-draining lymph nodes (PLNs) of 19 patients with type 1 diabetes and 63 nondiabetic donors and those circulating in the peripheral blood of 14 type 1 diabetic patients and 11 healthy subjects. RESULTS We found upregulation of Th17 immunity and functional defects in CD4+CD25bright Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood. In addition, the proinsulin-specific Treg-mediated control was altered in the PLNs of diabetic patients. The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus. CONCLUSIONS These data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

Laparoscopic approach to acute abdomen from the Consensus Development Conference of the Società Italiana di Chirurgia Endoscopica e nuove tecnologie (SICE), Associazione Chirurghi Ospedalieri Italiani (ACOI), Società Italiana di Chirurgia (SIC), Società Italiana di Chirurgia d’Urgenza e del Trauma (SICUT), Società Italiana di Chirurgia nell’Ospedalità Privata (SICOP), and the European Association for Endoscopic Surgery (EAES)

BackgroundIn January 2010, the SICE (Italian Society of Endoscopic Surgery), under the auspices of the EAES, decided to revisit the clinical recommendations for the role of laparoscopy in abdominal emergencies in adults, with the primary intent being to update the 2006 EAES indications and supplement the existing guidelines on specific diseases.MethodsOther Italian surgical societies were invited into the Consensus to form a panel of 12 expert surgeons. In order to get a multidisciplinary panel, other stakeholders involved in abdominal emergencies were invited along with a patient’s association. In November 2010, the panel met in Rome to discuss each chapter according to the Delphi method, producing key statements with a grade of recommendations followed by commentary to explain the rationale and the level of evidence behind the statements. Thereafter, the statements were presented to the Annual Congress of the EAES in June 2011.ResultsA thorough literature review was necessary to assess whether the recommendations issued in 2006 are still current. In many cases new studies allowed us to better clarify some issues (such as for diverticulitis, small bowel obstruction, pancreatitis, hernias, trauma), to confirm the key role of laparoscopy (such as for cholecystitis, gynecological disorders, nonspecific abdominal pain, appendicitis), but occasionally previous strong recommendations have to be challenged after review of recent research (such as for perforated peptic ulcer).ConclusionsEvery surgeon has to develop his or her own approach, taking into account the clinical situation, her/his proficiency (and the experience of the team) with the various techniques, and the specific organizational setting in which she/he is working. This guideline has been developed bearing in mind that every surgeon could use the data reported to support her/his judgment.

Analysis of Prognostic Factors Influencing Long-term Survival After Hepatic Resection for Metastatic Colorectal Cancer

BackgroundThe aim of this study was to analyze the prognostic factors associated with long-term outcome after liver resection for colorectal metastases. The retrospective analysis included 297 liver resections for colorectal metastases.MethodsThe variables considered included disease stage, differentiation grade, site and nodal metastasis of the primary tumor, number and diameter of the lesions, time from primary cancer to metastasis, preoperative carcinoembryonic antigen (CEA) level, adjuvant chemotherapy, type of resection, intraoperative ultrasonography and portal clamping use, blood loss, transfusions, complications, hospitalization, surgical margins status, and a clinical risk score (MSKCC-CRS).ResultsThe univariate analysis revealed a significant difference (p < 0.05) in overall 5-year survival rates depending on the differentiation grade, preoperative CEA >5 and >200 ng/ml, diameter of the lesion >5 cm, time from primary tumor to metastases >12 months, MSKCC-CRS >2. The multivariate analysis showed three independent negative prognostic factors: G3 or G4 grade, CEA >5 ng/ml, and high MSKCC-CRS.ConclusionsNo single prognostic factor proved to be associated with a sufficiently disappointing outcome to exclude patients from liver resection. However, in the presence of some prognostic factors (G3–G4 differentiation, preoperative CEA >5 ng/ml, high MSKCC-CRS), enrollment of patients in trials exploring new adjuvant treatments is suggested to improve the outcome after surgery.

Laparoscopic vs. Open Colectomies in Octogenarians: A Case-Matched Control Study

PURPOSEThe aim of this study was to define any benefits in terms of early outcome for laparoscopic colectomy in patients over 80 years old compared with open colectomy.METHODSSixty-one patients undergoing laparoscopic colectomy for colorectal cancer were matched to 61 open colectomy patients for gender, age, year of surgery, site of cancer, and comorbidity on admission. Independence status on admission and at discharge from the hospital was also evaluated.RESULTSMean (standard deviation) age was 82.3 (3.5) years in the laparoscopy group and 83.1 (3.3) years in the open group. Conversion rate was 6.1 percent. Operative time was 49 minutes longer in the laparoscopy group (P = 0.001 ). The overall mortality rate was 2.4 percent. The morbidity rate was 21.5 percent in the laparoscopy group and 31.1 percent in the open group (P = 0.30). Patients in the laparoscopy group had a faster recovery of bowel function (P = 0.01) and a significant reduction of the mean length of hospital stay (9.8 vs. 12.9 days for the open group, P = 0.001). Laparoscopy allowed a better preservation of postoperative independence status compared with the that of the open group (P = 0.02).CONCLUSIONLaparoscopic colectomy for cancer in octogenarians is safe and beneficial including preservation of postoperative independence and a reduction of length of hospital stay.

Impact of age on postoperative outcomes in 1118 gastric cancer patients undergoing surgical treatment.

BackgroundThe purpose of the study was to evaluate the impact of age on outcomes in gastric cancer surgery.MethodsPatients on the hospital database who underwent gastric resection for gastric cancer during the period 1990–2005 (n = 1118) were divided into two groups: group A, patients 75 years or older (n = 249), and group B, those younger than 75 years (n = 869).ResultsOverall preoperative complications were diagnosed in 92 (37%) patients of group A, compared with 147 (17%) in group B (P = 0.002). Fifty-five percent of patients underwent resection with D2 or more lymph node dissection (37% [n = 93] in group A, and 60% [n = 521] in group B; P = 0.003). Postoperative overall morbidity was higher in the elderly group (29% in group A versus 23% in group B), but the difference between the two groups was not significant (P = NS). Overall postoperative surgical complications were recorded in 201 (18%) patients; 49 (20%) in the elderly cohort, compared with 147 (17%) in the younger group (P = NS). The postoperative mortality rate was 3% (n = 7) in the elderly group, compared with 3% (n = 26) in the younger cohort (P = NS). Multivariate Cox analysis showed that age was not an independent risk factor for postoperative morbidity and mortality. Overall 5-year survival was 47% in group A and 54% in group B (P = NS).ConclusionDue to improved perioperative management, resection of gastric carcinoma is the treatment of choice in elderly patients. Although comorbidities were more frequent among the elderly patients, postoperative morbidity and mortality, even after extensive resections, was low. Survival rates were comparable to those in the younger patients.

Hemorrhage from a Right Hepatic Artery Pseudoaneurysm: Endovascular Treatment with a Coronary Stent-Graft

PURPOSE To report a novel case demonstrating the successful endovascular treatment of a right hepatic artery pseudoaneurysm using a balloon-expandable coronary stent-graft. CASE REPORT A 60-year-old woman underwent surgical treatment for a Klatskin tumor, but her postoperative course was complicated by serious blood loss. An emergent celiac angiogram through a right transfemoral approach demonstrated a small iatrogenic pseudoaneurysm in the proximal right hepatic artery. A 7-F guiding catheter was positioned at the origin of the celiac trunk, and a Jostent coronary stent-graft mounted on a 2.7-F, 4-mm x 30-mm balloon catheter was successfully placed across the aneurysm neck. The final angiogram demonstrated total exclusion of the pseudoaneurysm with preservation of the arterial lumen. The hemodynamic condition of the patient became stable. At 12-month follow-up, duplex scanning confirmed regular right hepatic artery patency and absence of thrombotic tissue or signs of infection around the stent-graft. CONCLUSION For hepatic artery pseudoaneurysms, endovascular repair using small covered stents may be a viable alternative to transcatheter embolization. The use of coronary instruments facilitates treatment of vascular lesions in small caliber visceral vessels.

A Novel Clinically Relevant Strategy to Abrogate Autoimmunity and Regulate Alloimmunity in NOD Mice

OBJECTIVE To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal. RESEARCH DESIGN AND METHODS Using allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig. RESULTS BALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice). CONCLUSIONS The capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes.

EFFECT ON LOCAL CONTROL AND SURVIVAL OF ELECTRON BEAM INTRAOPERATIVE IRRADIATION FOR RESECTABLE PANCREATIC ADENOCARCINOMA

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.

Autologous Pancreatic Islet Transplantation in Human Bone Marrow

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.