Long-term outcomes after pancreatoduodenectomy for ampullary cancer: The influence of the histological subtypes and comparison with the other periampullary neoplasms.

BACKGROUND: Ampullary carcinoma (AC) is histologically classified as intestinal (In-AC), pancreaticobiliary (Pb-AC) or mixed-AC. The prognostic role of AC subtypes has been debated and remains unclear. The aims of this study were to evaluate outcomes after pancreatoduodenectomy (PD) for each subtype of AC and to compare these with pancreatic ductal adenocarcinoma [PDAC] and distal cholangiocarcinoma [DCC]. METHODS: PDs performed for AC between 2010 and 2018 were retrospectively evaluated. Histological subtype was obtained for all patients. One-year, 3-year and 5-year disease-free-survival (DFS) and overall survival (OS) rates were calculated. Kaplan-Meier survival analysis was performed to compare Pb-AC, In-AC and mixed-AC. Comparison with PDs performed for PDAC and DCC during the same period was also performed. RESULTS: A total of 97 patients undergoing PD for AC were evaluated: 34 (35.1%) In-AC, 54 (55.7%) Pb-AC and 9 mixed-AC (9.3%). DFS and OS rates for Pb-AC were significantly lower compared to In-AC (p < 0.05 and p < 0.01), but similar to mixed-AC (p = 0.3 and p = 0.4). Adjuvant therapy was not associated with increased survival, regardless of the histological subtype (p > 0.05). During the same period, 337 and 53 PDs for PDAC and DCC, respectively, were performed. In-AC was associated with significantly better outcomes compared to PDAC and DCC (p < 0.001); DFS and OS rates for Pb-AC and mixed AC were significantly higher compared to PDAC (p < 0.001), but similar to DCC (p > 0.05). CONCLUSIONS: Pb-AC has significantly worse survival compared to In-AC. Moreover, mixed-AC should be considered as Pb-AC. Pb-AC and mixed-AC seem to have better prognosis compared to PDAC, but similar to DCC.

Immune infiltrating cells in duodenal cancers.

BACKGROUND: Duodenal adenocarcinoma (DA) is a rare yet aggressive malignancy, with increasing incidence in the last decades. Its low frequency has hampered a thorough understanding of the pathogenesis of the disease and of its biology, limiting the identification of tailored therapeutic options. A large body of evidence has clearly shown the clinical relevance of immune cells in solid tumors, correlating immune features with post-surgical prognosis. The aim of this study was to analyze the immune contexture in a cohort of duodenal adenocarcinomas surgically resected at our Institution and define its correlation with clinical variables. METHODS: Tissue slides from paraffin-embedded tumor specimens of 15 consecutive DA and 3 adenomas that underwent a pancreaticoduodenectomy in our center between 2010 to 2018 were immunohistochemically stained. The density (percentage of immune reactive area, IRA%) of immune markers CD45RO, CD8, CD20, IL-17, PD-1, CD68 was quantified by computer-assisted image analysis. Demographic, clinical, histopathological data were collected. RESULTS: In our population, median IRA % (IQR) of immune subsets was respectively CD45RO-TILs 2.19 (2.14), CD8-TIL 0.42 (0.81), CD20-TILs 0.22 (0.51), CD20-TLT 2.84 (4.64), CD68-TAM 2.19 (1.56), IL17+ cells 0.39 (0.39), PD1-TILs 0.19 (0.41). The median follow-up was 47.5 (22.4-63.3) months. At statistical analysis, the density of CD8-TILs inversely correlated with lymph node ratio (p = 0.013), number of metastatic lymph nodes (p = 0.019), and was lower in N+ adenocarcinomas compared to N0 (1.07 vs 0.29; p = 0.093), albeit not significantly. Stratifying patients for the N status, the density of CD8-TILs decreased with the increasing of the N stage (p = 0.065) and was lower in patients who experienced recurrence and died for the disease (0.276 vs 0.641; p = 0.044). Notably, also CD68-TAM distribution was different in patients who had recurrence versus patients who did not (1.028 vs 2.276; p = 0.036). CONCLUSIONS: Immune cells showed variable expression in correlation with common prognostic factors, suggesting T cell infiltration may play a protective role towards lymphatic spread of disease and nodal metastatization. Furthermore, T cell density and macrophage infiltration were associated to a lower risk of recurrence and disease related death. A multicentric approach may be indicated to allow analysis of larger cohorts of patients, potentially increasing the power of our observations.

The Number of Metastatic Lymph Nodes is a Useful Predictive Factor for Recurrence after Surgery for Nonmetastatic Nonfunctional Neuroendocrine Neoplasm of the Pancreas.

Nodal involvement (actually categorized as positive or negative) is an important prognostic factor after surgery for pancreatic neuroendocrine neoplasms (pNENs). We aim to evaluate the predictive role of the number of nodal metastases after pancreatic resection for pNENs. We analyzed from a prospectively maintained database all pancreatic resections for nonmetastatic nonfunctioning pNENs performed in our institution from 2011 to 2016. According to the number of nodal metastases, enhancing the actual categorization, we distinguished the following: N0, no nodal metastases; N1, 1-3 metastatic lymph nodes; and N2, metastases in 4 or more regional lymph nodes. Recurrence and disease-free survival (DFS) were evaluated. The predictive value in terms of recurrence for each clinicopathological data, including the number of metastatic lymph nodes, was calculated. Univariate and multivariate analyses were conducted. 77 patients underwent pancreatic surgery for pNENs. N0, N1, and N2 resections were found in 52 (67.5%), 16 (20.8%), and 9 (11.7%) cases, respectively. Mean follow-up of the entire cohort was 48 (±25) months. The recurrence rate was 11.8%, and the mean time of recurrence was 12 (±14) months. DFS was 83.7 months (76.0 - 91.5). At a univariate analysis, factors associated with recurrence were mitotic count (OR 1.19, p = 0.001), Ki67 value (OR 1.06, p = 0.001), the presence of nodal metastases (OR 11.54, p = 0.002), and metastases in 4 or more regional lymph nodes (N2) (OR 30.19, p = 0.002). At a multivariate analysis, only mitotic count (OR 1.51, p = 0.005) and N2 resection (OR 134.74, p = 0.002) were found to be predictive factors of recurrence. The number of metastatic lymph nodes and mitotic count is the most significant predictive factors of recurrence after pancreatic surgery for nonmetastatic nonfunctioning pNENs.

Evaluation of the MDACC clinical classification system for pancreatic cancer patients in an European multicenter cohort.

BACKGROUND: The MDACC group recommends to extend the current borderline classification for pancreatic cancer into three groups: type A patients with resectable/borderline tumor anatomy, type B with resectable/borderline resectable tumor anatomy and clinical findings suspicious for extrapancreatic disease and type C with borderline resectable and marginal performance status/severe pre-existing comorbidity profile or age>80. This study intents to evaluate the proposed borderline classification system in a multicenter patient cohort without neoadjuvant treatment. METHODS: Evaluation was based on a multicenter database of pancreatic cancer patients undergoing surgery from 2005 to 2016 (n = 1020). Complications were classified based on the Clavien-Dindo classification. χ2-test, Kaplan-Meier estimator and Cox regression hazard model were used for statistical analysis. RESULTS: Most patients (55.1%) were assigned as type A patients, followed by type C (35.8%) and type B patients (9.1%). Neither the complication rate, nor the mortality rate revealed a correlation to any subgroup. Type B patients had a significant worse progression free (p < 0.001) and overall survival (p = 0.005). Type B classification was identified as an independent prognostic marker for progression free survival (p = 0.005, HR 1.47). CONCLUSION: The evaluation of the proposed classification in a cohort without neoadjuvant treatment did not justify an additional medical borderline subgroup. A new subgroup based on prognostic borderline patients might be the main target group for neoadjuvant protocols in future.

Parenchyma-sparing surgery for pancreatic endocrine tumors.

Enucleation (EN) and middle pancreatectomy (MP) have been proposed as a treatment for G1 and G2 pancreatic neuroendocrine tumors (PNET). The aim of this study is to analyze the outcomes of parenchyma-sparing surgery (PSS) for PNET in an Italian high-volume center. All patients with a histological diagnosis of PNET who underwent surgical resection in our center between January 2010 and January 2016 were included in the study. Demographic, perioperative, and discharge data were collected in a prospective database. Follow-up was considered until March 31, 2016. 99 patients were included. PSS was performed in 22 cases (22.2 %), 18 EN (82 %), and 4 MP (18 %). 89.8 % patients were staged with CT scan, 69.6 % with endoscopic ultrasonography, 48.4 % with MRI, and 47.4 % with 68Ga-PET. Pre-operative histological diagnosis was obtained in 68.6 %. Most of PSS tumors were G1 (n = 15; 68 %) and there were no G3. Nodal sampling was performed in every PSS. Only two patients showed nodal metastatic disease. The median post-operative length of stay was 7 days after PSS. Eleven (50 %) of these patients developed a complication; two (18.2 %) were major complications. Pancreatic fistula developed in ten patients (45.5 %); two (20 %) were type B. There were no type C fistula and no re-operations after PSS. Readmission rate was 9 %. All patients submitted to PSS are alive and free of recurrence. PSS is a safe technique for G1 and G2 PNETs, but it has to be conducted in experienced centers and an extensive nodal sampling and a long follow-up are required for the best oncologic outcome.

Autologous Islet Transplantation in Patients Requiring Pancreatectomy: A Broader Spectrum of Indications Beyond Chronic Pancreatitis.

Islet autotransplantation (IAT) is usually performed in patients undergoing pancreatic surgery for chronic pancreatitis. In the present series, IAT was offered also to patients undergoing pancreatic surgery for both nonmalignant and malignant diseases, having either completion pancreatectomy as treatment for severe pancreatic fistulas (n = 21) or extensive distal pancreatectomy for neoplasms of the pancreatic neck (n = 19) or pancreatoduodenectomy because of the high risk of pancreatic fistula (n = 32). Fifty-eight of 72 patients who were eligible to this broader spectrum of indication actually received IAT. There was no evidence of a higher-than-expected rate of major complications for pancreatectomy. Forty-five patients receiving IAT were still alive at the time of the last scheduled follow-up (1375 ± 365 days). Eighteen (95%) of 19 and 11 (28%) of 39 patients reached insulin independence after partial or total pancreatectomy, respectively. The metabolic results were dependent on the transplanted islet mass. Thirty-one of 58 patients had malignant diseases of the pancreas or periampullary region, and only three patients developed ex novo liver metastases after IAT (median follow-up 914 ± 382 days). Our data demonstrate the feasibility, efficacy, and safety of IAT for a broader spectrum of clinical indications beyond chronic pancreatitis.

Multivariate analysis of factors affecting patient and graft survival after renal transplant.

AIM: To evaluate factors affecting patient and kidney survival after renal transplant. PATIENT AND METHODS: Among 361 patients undergoing renal transplant: 52% (n = 189) were simultaneous with pancreas transplant (SPKT group) and 48% (n = 172), a kidney transplant alone (KT group). Out of 361 patients, 75% (n = 270) were diabetics. The patients were 220 (61%) men and 141 (39%) women of mean age 41 +/- 9 years. The mean time of dialysis was 42 +/- 21 months (range 0 to 126), and the mean duration of diabetes 24 +/- 7 years (range 5 to 51). A Cox regression analysis was done. RESULTS: The multivariate analysis revealed that in the final model diabetes and donor age were significant predictors of kidney graft survival; moreover, diabetes and recipient age were predictors of patient survival. Overall patient survival was significantly greater among nondiabetic patients (P = .002) or in diabetic patients who received SPKT, when compared with diabetics in whom only the kidney was transplanted (P = .001). CONCLUSIONS: Diabetes and donor age were independent prognostic factors affecting kidney graft survival after renal transplant, and recipient age and diabetes were prognostic factors affecting patient survival. Combined pancreas and kidney transplantation should be offered to patients with end-stage diabetic nephropathy.

Simultaneous pancreas-kidney transplantation: short- and long-term results.

Simultaneous kidney and pancreas transplantation (SKPT) is the treatment of choice for a majority of type I diabetic patients with end-stage renal disease. With continual refinements in surgical technique and an evolving immunosuppressive arsenal, graft and patient survival have continually improved. The purpose of this study was to evaluate the short- and long-term results of SKPTs performed in 174 recipients from June 1985 to March 2003 including 37 segmental grafts with duct occlusion, 73 whole pancreas transplants with bladder diversion, and 64 whole pancreas grafts with enteric diversion. The series includes 160 cases with systemic drainage and 14 with portal drainage. In the segmental pancreas group, patient survival was 85%, 76%, and 53% with pancreas survival of 67%, 36%, and 15%, and kidney survival of 82%, 63%, and 15%, respectively, at 1, 5, and 10 years. Among the bladder diversion group, patient survival was 94%, 83%, and 73% pancreas survival 72%, 67%, and 65%, and kidney survival 89%, 78%, and 58%, respectively, 1, 5, and 10 years. Among the enter diversion group patient survival was 90% and 90% at 12 and 108 months, pancreas survival 80% and 65%, and kidney survival 85% and 85%, respectively. There were significant differences between curves of survival distribution according to the surgical technique applied for patients (P =.04), pancreas (P =.007), and kidney (P =.005). Based on the results from our study, the short- and long-term prognosis after SKPT is satisfactory, especially compared to the outcomes of long-term dialysis among patients with end-stage renal disease caused by type I diabetes.

Paradoxical release of insulin by adult pig islets in vitro. Recovery after culture in a defined tissue culture medium.

In this study, in vitro responsiveness to glucose of fresh and cultured islets from adult pigs was tested under both static (incubation) and dynamic (perifusion) conditions. Islets were isolated by an automated method from pancreases of 24-month-old animals and cultured overnight in CMRL 1066 and 10% FCS plus antibiotics; islets, perifused immediately after the overnight culture, showed a paradoxical decrease in insulin release when exposed to an acute glucose stimulus (16.7 mmol/L), and a normal response to acute glucose when isobutylmethylxanthine (IBMX) was added to the perifusing buffer. In addition, an acute reduction of glucose concentration in the perifusate elicited a paradoxical insulin release. At the microscope, islets appeared loose and irregularly shaped after the overnight culture; immunohistochemistry showed loss of peripheral A and other mantle cells. After the overnight culture, islets were divided into 5 groups and were cultured for a further 48 hr in different tissue culture media: CMRL 1066; RPMI 1640 (without glucose); RPMI 1640 (plus 11.1 mmol/L glucose); Ham's F12; and medium 199 (all media were supplemented with 10% FCS and antibiotics). During this period, insulin release was 11.4 +/- 1.1 pg/islet/min in islets cultured in CMRL 1066, 16.2 +/- 2.4 in islets cultured in RPMI 1640 (11.1 mmol/L glucose), 1.8 +/- 0.2 (P < 0.001 vs. all the other groups), and 9.0 +/- 0.6 and 8.4 +/- 0.9 pg/islet/min in islets cultured in RPMI 1640 (without glucose), Ham's F12, and medium 199, respectively. After the 48-hr culture in different media, the islets' responsiveness to an acute glucose stimulus (16.7 mmol/L; static incubation) was evaluated: islets cultured in CMRL 1066 and in RPMI 1640 (with and without glucose) showed no insulin response to the acute glucose stimulus; in contrast, insulin release rose from 0.42 +/- 0.06 to 0.60 +/- 0.12 pg/islet/min (NS) in islets cultured in Ham's F12, and from 0.24 +/- 0.06 to 0.48 +/- 0.06 pg/islet/min (P < 0.001) in islets cultured in medium 199. During perifusions, the paradoxical insulin release in response to an acute fall in glucose concentration disappeared, but a significant increase in response to high (16.7 mmol/L) glucose was observed only in islets previously cultured in medium 199. To assess the possible role of glucagon and of cAMP, additional perifusions were done in islets cultured for 48 hr in CMRL 1066 in the presence of glucagon (10 mumol/L) and IBMX (10 mumol/L); glucagon and IBMX were unable to modify the insulin response to 16.7 mmol/L glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

Fresh human islet transplantation to replace pancreatic endocrine function in type 1 diabetic patients. Report of six cases.

The aim of this study was to evaluate the feasibility of islet allografts in patients with type 1 diabetes mellitus. Six patients received human islets from either one or two donors via the portal vein, after (n = 4) or simultaneously with (n = 2) a kidney graft. The patients with functioning kidney grafts (nos. 1-4) were already on triple immunosuppressive therapy (cyclosporine A, azathioprine, prednisone). Prednisone was increased to 60 mg/day for 15 days after the islet transplant in patient 1. Patients 2-4 and the patients who underwent a simultaneous kidney-islets graft (nos. 5, 6) also received antilymphocyte globulin. Intravenous insulin was given for the first 15 days to maintain blood glucose concentrations within the normal range. Patient 1 rejected the islets within 15 days of islet transplantation. In patient 2, a 25% reduction in insulin requirement was observed and 12 months after transplantation post-prandial serum C-peptide was 1.5 ng/ml. In patient 3, the insulin requirement decreased from 40 to 8 units/day with a post-prandial serum C-peptide of 4.1 ng/ml 12 months after islet transplantation. In patient 4 the post-prandial secretion of C-peptide increased to 6.4 ng/ml. Six months after the islet infusion, insulin therapy was discontinued and HbA1c, 24-h metabolic profile and oral glucose tolerance test remained within the normal range. He had remained off insulin for 5 months until recently, when foot gangrene paralleled a worsening of post-prandial glycaemic control. Twelve months after transplantation he is receiving 8 units insulin/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolation of the elusive pig islet.

This study describes a procedure for large scale isolation of swine islets. The reported results are from 15 consecutive isolations. The glands were removed from live animals with no warm ischemia, and the pancreata were digested by a modification of the automated method for human islet isolation. It was possible to separate an average of 690,000 +/- 279,429 islets per pancreas corresponding to 10,360 +/- 4034 islets per gram of pancreas with a volume of 714 +/- 480 mm3. After purification the recovery was 255,000 +/- 32,407 islets corresponding to 4,000 +/- 567 islets per gram of pancreas. Purity of the final preparation was 80% to 95% islets. Insulin content resulted in an average of 146.8 +/- 78 U before purification and 71 +/- 53 U after purification. After a 10 mm3 aliquot of the final preparation was transplanted under the renal subcapsular space of seven nude mice with diabetes, normoglycemia occurred in six of the mice. Thirty days after transplantation, nephrectomy of the kidneys bearing the grafts produced a rapid return to the diabetic state in all cases. This method makes it possible to provide large numbers of intact swine islets for preliminary studies of prevention of the rejection of pig islet xenograft by immunoalteration and immunoisolation procedures.

Swine islet isolation and transplantation.

An isolation procedure for large scale isolation of swine islets is described. The results from 15 consecutive isolations are reported. The glands were excised from heart beating animals with no warm ischemia time. The pancreases were digested by a modification of the automated method for human islet isolation. It was possible to separate an average of 690,000 +/- 279,429 islets per pancreas corresponding to 10,360 +/- 4034 islets for gram of pancreas with a volume of 714 +/- 480 mm3. After purification the recovery was 255,000 +/- 32,407 islets corresponding to 4,000 +/- 567 islets per gram of pancreas. Purity of the final preparation was 80-95% islets. Insulin content resulted in an average of 146.8 +/- 78 U before purification and 71 +/- 53 after purification. After transplantation of an aliquot of the final preparation in diabetic nude mice normoglycemia occurred in six mice. 30 days after transplantation nephrectomy of the kidneys bearing the grafts produced a rapid return to the diabetic state in all cases.

Selection of donors significantly improves pig islet isolation yield.

The purpose of the present study was to test the influence of donor age on islet isolation yield in swines. Large White pigs of 10 months (group 1, n = 10) and 2-3 years (group 2, n = 5) were used. A modification of the automated method for human islet isolation was used for pig islet separation. After ductal injection of a collagenase solution (Seromed, type C-1000) the islets were separated through a continuous digestion process. In group 1 it was possible to obtain an average of 636,100 islets (volume = 476.1 mm3, insulin content = 101.4 Units). In group 2 the average total islet number was 799,800 representing a volume of 1190.6 mm3 (Insulin content 210 Units). Total islet number was not significantly different in the two groups, however when islet volume and total insulin content were considered, older animals allowed a significantly higher yield (P less than 0.01 for volume and P less than 0.05 for insulin content). These findings indicate that it is possible to separate large number of pig islets from both young (10 months) and older (2-3 years) animals and that selection of donor pigs will improve islet isolation yield. These results may be of assistance in the definition of requirements for more effective islet isolation in swines.

[Current knowledge on memory in the elderly]. / Attuali conoscenze sulla memoria degli anziani.

In geriatric practice, much thought must be given to initial changes in intelligence and memory due to old age and often suddenly aggravated by dysmetabolic and circulatory disease. Awareness of the memory faculty in the elderly is vital in clinical practice for the purposes of pharmacological and psychological designed to reduce the intellectual decline of the patients. This deficiency in mental personality is an important limitation to rehabilitation which remains the aim of medical attention.