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1.  Autologous Pancreatic Islet Transplantation in Human Bone Marrow 
Diabetes  2013;62(10):3523-3531.
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.
PMCID: PMC3781459  PMID: 23733196
2.  Combined laparoscopic spleen-preserving distal pancreatectomy and islet autotransplantation for benign pancreatic neoplasm 
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.
PMCID: PMC3983459  PMID: 24744593
Pancreas; Benign neoplasm; Laparoscopy; Minimally invasive treatment; Spleen preservation; Pancreatogenic diabetes; Autologous islet transplantation
3.  Short and long-term outcomes of laparoscopic colectomy in obese patients 
AIM: To investigate the impact of laparoscopic colectomy on short and long-term outcomes in obese patients with colorectal diseases.
METHODS: A total of 98 obese (body mass index > 30 kg/m2) patients who underwent laparoscopic (LPS) right or left colectomy over a 10 year period were identified from a prospective institutionally approved database and manually matched to obese patients who underwent open colectomy. Controls were selected to match for body mass index, site of primary disease, American Society of Anesthesiologists score, and year of surgery (± 3 year). The parameters analyzed included age, gender, comorbid conditions, American Society of Anaesthesiologists class, diagnosis, procedure, and duration of operation, operative blood loss, and amount of homologous blood transfused. Conversion rate, intra and postoperative complications as were as reoperation rate, 30 d and long-term morbidity rate were also analyzed. For continuous variables, the Student’s t test was used for normally distributed data the Mann-Whitney U test for non-normally distributed data. The Pearson’s χ2 tests, or the Fisher exact test as appropriate, were used for proportions.
RESULTS: Conversion to open surgery was necessary in 13 of 98 patients (13.3%). In the LPS group, operative time was 29 min longer and blood loss was 78 mL lower when compared to open colectomy (P = 0.03, P = 0.0001, respectively). Overall morbidity, anastomotic leak and readmission rate did not significantly differ between the two groups. A trend toward a reduction of wound complications was observed in the LPS when compared to open group (P = 0.09). In the LPS group, an earlier recovery of bowel function (P = 0.001) and a shorter length of stay (P = 0.03) were observed. After a median follow-up of 62 (range 12-132) mo 23 patients in the LPS group and 38 in the open group experienced long-term complications (LPS vs open, P = 0.03). Incisional hernia resulted to be the most frequent long-term complication with a significantly higher occurrence in the open group when compared to the laparoscopic one (P = 0.03).
CONCLUSION: Laparoscopic colectomy in obese patients is safe, does not jeopardize postoperative complications and resulted in lower incidence of long-term complications when compared with open cases.
PMCID: PMC3831222  PMID: 24259971
Obesity; Colon cancer; Laparoscopy; Right colectomy; Left colectomy; Colorectal disease
4.  Inotuzumab Ozogamicin Murine Analog–Mediated B-Cell Depletion Reduces Anti-islet Allo- and Autoimmune Responses 
Diabetes  2011;61(1):155-165.
B cells participate in the priming of the allo- and autoimmune responses, and their depletion can thus be advantageous for islet transplantation. Herein, we provide an extensive study of the effect of B-cell depletion in murine models of islet transplantation. Islet transplantation was performed in hyperglycemic B-cell–deficient(μMT) mice, in a purely alloimmune setting (BALB/c into hyperglycemic C57BL/6), in a purely autoimmune setting (NOD.SCID into hyperglycemic NOD), and in a mixed allo-/autoimmune setting (BALB/c into hyperglycemic NOD). Inotuzumab ozogamicin murine analog (anti-CD22 monoclonal antibody conjugated with calicheamicin [anti-CD22/cal]) efficiently depleted B cells in all three models of islet transplantation examined. Islet graft survival was significantly prolonged in B-cell–depleted mice compared with control groups in transplants of islets from BALB/c into C57BL/6 (mean survival time [MST]: 16.5 vs. 12.0 days; P = 0.004), from NOD.SCID into NOD (MST: 23.5 vs. 14.0 days; P = 0.03), and from BALB/c into NOD (MST: 12.0 vs. 5.5 days; P = 0.003). In the BALB/c into B-cell–deficient mice model, islet survival was prolonged as well (MST: μMT = 32.5 vs. WT = 14 days; P = 0.002). Pathology revealed reduced CD3+ cell islet infiltration and confirmed the absence of B cells in treated mice. Mechanistically, effector T cells were reduced in number, concomitant with a peripheral Th2 profile skewing and ex vivo recipient hyporesponsiveness toward donor-derived antigen as well as islet autoantigens. Finally, an anti-CD22/cal and CTLA4-Ig–based combination therapy displayed remarkable prolongation of graft survival in the stringent model of islet transplantation (BALB/c into NOD). Anti-CD22/cal–mediated B-cell depletion promotes the reduction of the anti-islet immune response in various models of islet transplantation.
PMCID: PMC3237644  PMID: 22076927
5.  New approach to anal cancer: Individualized therapy based on sentinel lymph node biopsy 
Oncological treatment is currently directed toward a tailored therapy concept. Squamous cell carcinoma of the anal canal could be considered a suitable platform to test new therapeutic strategies to minimize treatment morbidity. Standard of care for patients with anal canal cancer consists of a combination of radiotherapy and chemotherapy. This treatment has led to a high rate of local control and a 60% cure rate with preservation of the anal sphincter, thus replacing surgical abdominoperineal resection. Lymph node metastases represent a critical independent prognostic factor for local recurrence and survival. Mesorectal and iliac lymph nodes are usually included in the radiation field, whereas the inclusion of inguinal regions still remains controversial because of the subsequent adverse side effects. Sentinel lymph node biopsies could clearly identify inguinal node-positive patients eligible for therapeutic groin irradiation. A sentinel lymph node navigation procedure is reported here to be a feasible and effective method for establishing the true inguinal node status in patients suffering from anal canal cancer. Based on the results of sentinel node biopsies, a selective approach could be proposed where node-positive patients could be selected for inguinal node irradiation while node-negative patients could take advantage of inguinal sparing irradiation, thus avoiding toxic side effects.
PMCID: PMC3508629  PMID: 23197880
Anal carcinomal; Lymphnode metastasis; Sentinel lymphnode; Tumor staging
6.  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 
Diabetes  2011;60(11):2903-2913.
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.
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.
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.
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.
PMCID: PMC3198077  PMID: 21896932
7.  A Novel Clinically Relevant Strategy to Abrogate Autoimmunity and Regulate Alloimmunity in NOD Mice 
Diabetes  2010;59(9):2253-2264.
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.
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.
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).
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.
PMCID: PMC2927948  PMID: 20805386
8.  Laparoscopic surgery for rectal cancer: The state of the art 
At present time, there is evidence from randomized controlled studies of the success of laparoscopic resection for the treatment of colon cancer with reported smaller incisions, lower morbidity rate and earlier recovery compared to open surgery. Technical limitations and a steep learning curve have limited the wide application of mini-invasive surgery for rectal cancer. The present article discusses the current status of laparoscopic resection for rectal cancer. A review of the more recent retrospective, prospective and randomized controlled trial (RCT) data on laparoscopic resection of rectal cancer including the role of trans-anal endoscopic microsurgery and robotics was performed. A particular emphasis was dedicated to mid and low rectal cancers. Few prospective and RCT trials specifically addressing laparoscopic rectal cancer resection are currently available in the literature. Improved short-term outcomes in term of lesser intraoperative blood loss, reduced analgesic requirements and a shorter hospital stay have been demonstrated. Concerns have recently been raised in the largest RCT trial of the oncological adequacy of laparoscopy in terms of increased rate of circumferential margin. This data however was not confirmed by other prospective comparative studies. Moreover, a similar local recurrence rate has been reported in RCT and comparative series. Similar findings of overall and disease free survival have been reported but the follow-up time period is too short in all these studies and the few RCT trials currently available do not draw any definitive conclusions. On the basis of available data in the literature, the mini-invasive approach to rectal cancer surgery has some short-term advantages and does not seem to confer any disadvantage in term of local recurrence. With respect to long-term survival, a definitive answer cannot be given at present time as the results of RCT trials focused on long-term survival currently ongoing are still to fully clarify this issue.
PMCID: PMC2999691  PMID: 21160896
Postoperative complications; Recurrence rate; Transanal endoscopic microsurgery; Robotics; Long-term outcome; Prognosis; Rectal cancer; Laparoscopy
9.  Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation 
PLoS ONE  2010;5(3):e9923.
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.
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.
PMCID: PMC2848014  PMID: 20360867
10.  Endoscopic ultrasound and magnetic resonance imaging for re-staging rectal cancer after radiotherapy 
AIM: To compare the sensitivity and specificity of two imaging techniques, endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI), in patients with rectal cancer after neoadjuvant chemoradiation therapy. And we compared EUS and MRI data with histological findings from surgical specimens.
METHODS: Thirty-nine consecutive patients (51.3% Male; mean age: 68.2 ± 8.9 years) with histologically confirmed distal rectal cancer were examined for staging. All patients underwent EUS and MRI imaging before and after neoadjuvant chemoradiation therapy.
RESULTS: After neoadjuvant chemoradiation, EUS and MRI correctly classified 46% (18/39) and 44% (17/39) of patients, respectively, in line with their histological T stage (P > 0.05). These proportions were higher for both techniques when nodal involvement was considered: 69% (27/39) and 62% (24/39). When patients were sorted into T and N subgroups, the diagnostic accuracy of EUS was better than MRI for patients with T0-T2 (44% vs 33%, P > 0.05) and N0 disease (87% vs 52%, P = 0.013). However, MRI was more accurate than EUS in T and N staging for patients with more advanced disease after radiotherapy, though these differences did not reach statistical significance.
CONCLUSION: EUS and MRI are accurate imaging techniques for staging rectal cancer. However, after neoadjuvant RT-CT, the role of both methods in the assessment of residual rectal tumors remains uncertain.
PMCID: PMC2785059  PMID: 19938195
Endoscopic ultrasound; Magnetic resonance imaging; Rectal cancer; Neoadjuvant chemoradiation therapy; Diagnostic accuracy
11.  Ct-Guided Pancreatic Percutaneous Fine-needle Biopsy in Differential Diagnosis Between Pancreatic Cancer and Chronic Pancreatitis 
HPB Surgery  1989;1(4):309-317.
Differential diagnosis between pancreatic cancer and chronic pancreatitis is still difficult to establish. In 63 patients with suspected pancreatic neoplasm we performed: serum CA 19-9 assessment, abdominal ultrasound, CT scan and CT-guided pancreatic percutaneous fine-needle biopsy. The conclusive diagnosis was pancreatic cancer in 40 patients and chronic pancreatitis in 23 patients. With regard to the differential diagnosis, sensitivity and specificity were respectively 80% and 78% for serum CA 19-9, 75% and 65% for abdominal US, 85% and 70% for CT scan, 00% and 87% for percutaneous fine-needle biopsy. We conclude that CT-guided percutaneous fine-needle biopsy is the most reliable method for differential diagnosis between pancreatic cancer and chronic pancreatitis.
PMCID: PMC2423540  PMID: 2487070

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