Elena Orsenigo

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.

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.

The mobilization and effect of endogenous bone marrow progenitor cells in diabetic wound healing.

Diabetic patients suffer from impaired wound healing, characterized by only modest angiogenesis and cell proliferation. Stem cells may stimulate healing, but little is known about the kinetics of mobilization and function of bone marrow progenitor cells (BM-PCs) during diabetic wound repair. The objective of this study was to investigate the kinetics of BM-PC mobilization and their role during early diabetic wound repair in diabetic db/db mice. After wounding, circulating hematopoietic stem cells (Lin-c-Kit+Sca-1+) stably increased in the periphery and lymphoid tissue of db/db mice compared to unwounded controls. Peripheral endothelial progenitor cells (CD34+VEGFR+) were 2.5- and 3.5-fold increased on days 6 and 10 after wounding, respectively. Targeting the CXCR4—CXCL12 axis induced an increased release and engraftment of endogenous BM-PCs that was paralleled by an increased expression of CXCL12/SDF-1α in the wounds. Increased levels of peripheral and engrafted BM-PCs corresponded to stimulated angiogenesis and cell proliferation, while the addition of an agonist (GM-CSF) or an antagonist (ACK2) did not further modulate wound healing. Macroscopic histological correlations showed that increased levels of stem cells corresponded to higher levels of wound reepithelialization. After wounding, a natural release of endogenous BM-PCs was shown in diabetic mice, but only low levels of these cells homed in the healing tissue. Higher levels of CXCL12/SDF-1α and circulating stem cells were required to enhance their engraftment and biological effects. Despite controversial data about the functional impairment of diabetic BM-PCs, in this model our data showed a residual capacity of these cells to trigger angiogenesis and cell proliferation.

Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation

Background In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold. Methods and Findings We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant. Conclusions Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.

Sentinel node mapping during laparoscopic distal gastrectomy for gastric cancer

BackgroundThe goal of this study was to evaluate the feasibility and accuracy of sentinel node (SN) mapping with endoscopic submucosal blue dye injection during laparoscopic distal gastrectomy for gastric cancer.MethodsThirty-four patients affected by gastric adenocarcinoma without gross clinical serosal invasion and distant metastasis were prospectively enrolled. At the start of the surgery, 2 ml of 2% patent blue was endoscopically injected into the submucosal layer at four points around the site of the primary tumor. Sentinel nodes were defined as nodes that were stained by the blue dye within 5–10 min after the dye injection. After identification and removal of sentinel lymph nodes, each patient underwent laparoscopic distal gastrectomy with D1 (n = 2) or D2 (n = 32) lymphadenectomy.ResultsOf the 34 patients, 14 had positive nodules (41%). SNs were detectable as blue nodes in 27 (80%) of 34 patients. The mean number of dissected lymph nodes per patient was 31 ± 10 (range = 16–64) and the mean number of blue nodes was 1.5 (range = 1–4). Only five (sensitivity 36%) of 14 N(+) patients had at least one metastatic lymph node among the SNs identified. In these 14 patients the sentinel node was traced in 12 cases. Sentinel node status diagnosed the lymph node status with 74% accuracy. In early gastric cancer (n = 18), three patients had lymph node metastasis. These early gastric cancer patients with nodal metastases had at least one metastatic lymph node among the SNs identified (sensitivity 100%).ConclusionsBlue dye SN mapping during laparoscopic distal gastrectomy seems to be a feasible and accurate diagnostic tool for detecting lymph node metastasis in patients with early-stage gastric cancer in which the accuracy of the method was 100%. However, in more advanced gastric cancer the results are not satisfactory. Validation of this method requires further studies on technical issues, including selection of the tracers.

Laparoscopic assisted duodenopancreatectomy

BackgroundIn the past few years, minimally invasive therapy for pancreatic diseases has made significant strides but the role of laparoscopic pancreaticoduodenectomy is still controversial.MethodsFour patients with a mean age of 44 ± 11 years were chosen for a laparoscopic pancreaticoduodenectomy. Pathological diagnoses were ductal adenocarcinoma in one, neuroendocrine tumor in two, and metastatic malignant melanoma in one.ResultsThe procedure was laparoscopically completed in all with a mean operating time, blood loss, and hospital stay of 416 ± 77 min, 325 ± 50 ml, and 12 ± 2 days, respectively. There were no complications attributable to this surgery and there were no deaths. The average number of dissected lymph nodes was 26 ± 17 (range 16-47). All the patients remained well at a median follow-up of 4.5 months (range 1-10).ConclusionsIt can be inferred from this small but successful experience that laparoscopic pancreaticoduodenectomy can be considered for the treatment of tumors of the pancreas or periampullary region.

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

Cancer-initiating cells (CICs) that are responsible for tumor initiation, propagation, and resistance to standard therapies have been isolated from human solid tumors, including colorectal cancer (CRC). The aim of this study was to obtain an immunological profile of CRC-derived CICs and to identify CIC-associated target molecules for T cell immunotherapy. We have isolated cells with CIC properties along with their putative non-CIC autologous counterparts from human primary CRC tissues. These CICs have been shown to display “tumor-initiating/stemness” properties, including the expression of CIC-associated markers (e.g., CD44, CD24, ALDH-1, EpCAM, Lgr5), multipotency, and tumorigenicity following injection in immunodeficient mice. The immune profile of these cells was assessed by phenotype analysis and by in vitro stimulation of PBMCs with CICs as a source of Ags. CICs, compared with non-CIC counterparts, showed weak immunogenicity. This feature correlated with the expression of high levels of immunomodulatory molecules, such as IL-4, and with CIC-mediated inhibitory activity for anti-tumor T cell responses. CIC-associated IL-4 was found to be responsible for this negative function, which requires cell-to-cell contact with T lymphocytes and which is impaired by blocking IL-4 signaling. In addition, the CRC-associated Ag COA-1 was found to be expressed by CICs and to represent, in an autologous setting, a target molecule for anti-tumor T cells. Our study provides relevant information that may contribute to designing new immunotherapy protocols to target CICs in CRC patients.

Laparoscopic treatment of advanced colonic cancer: a case-matched control with open surgery.

The safety, feasibility and oncological results of laparoscopic resection for advanced colon cancer were evaluated.