Andrea Pietrabissa

Experience with 647 consecutive tumors of the duodenum, ampulla, head of the pancreas, and distal common bile duct.

Between 1946 and 1987, 647 patients with periampullary tumors were diagnosed at the University of Chicago Medical Center. These included 549 tumors located in the head of the pancreas, 40 in the distal common bile duct, 29 in the duodenum, and 29 at the ampulla of Vater. Ninety-eight per cent of all tumors were adenocarcinoma, with 93% of the remaining being duodenal carcinoid or sarcoma. Operability rate ranged from 81% to 97%, according to the tumor location and histologic type. A combination of laparotomy, biopsy, and bypass was performed in 433 patients and only one survived 5 years (0.2%). Resectability rate ranged from 16.5% for pancreatic adenocarcinoma to 89.3% for ampullary tumors. Of the 133 resections, 80 were pancreatoduodenectomies, 29 total pancreatectomies, 7 duodenectomies, 2 gastrectomies, 8 common bile duct resections, and 7 local excisions. Overall 19% of patients who underwent radical resection died in the immediate postoperative period, although mortality has decreased to 5% since 1981. Mortality was 20% after a standard pancreatoduodenectomy and 24.1% after a total pancreatectomy. Five-year actuarial survival rates, including perioperative deaths, were 8.8%, 20%, and 32% for pancreatic, duodenal, and ampullary adenocarcinoma, respectively. One half of patients with sarcoma and two-thirds with carcinoid of the duodenum survived 5 years. No patient with distal common bile duct adenocarcinoma achieved a 5-year survival rate. Multivariate analysis on all patients operated on (n = 566) revealed that the 5-year survival rate was significantly related to intent of operation (palliative 0.2%, curative 12%; p less than 0.001), histologic type (adenocarcinoma 2%, carcinoid and sarcoma 31%; p less than 0.0001), and site (ampullary and duodenal 21%, biliary and pancreatic 0.9%; p less than 0.001). A second multivariate analysis, evaluating only those patients with adenocarcinoma who survived the perioperative period of the radical resection (n = 97) analyzed the influence of tumor size and differentiation, lymphatic, capillary, and perineural microinvasion, lymph node status, and type of procedure (pancreatoduodenectomy vs. total pancreatectomy) on 5-year survival. None of these additional variables was significantly associated with long-term survival rates. In addition we evaluated the presence of local or distant recurrence after resection by analyzing the findings from all autopsies performed on these patients (n = 49): 29.4% of patients died with local recurrence alone, 23.5% with distant recurrence alone, and 47.1% had both local and distant recurrences.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases.

Objective/Background:The GONO-FOLFOXIRI regimen improved the rate of R0 secondary resection of metastases in initially unresectable metastatic colorectal cancer. The objective of this study was to evaluate the long-term outcome of resected patients and the impact of FOLFOXIRI on perioperative morbidities, mortality, and chemotherapy induced hepatotoxicity. Patients and Methods:Overall, 196 patients with initially unresectable metastatic colorectal cancer were treated with FOLFOXIRI in 2 phase II and 1 phase III trial. This regimen was associated with an elevated response rate (70.4%) and 37 patients (19%) could undergo a secondary R0 surgery on metastases. This study was registered with the Australian New Zealand Clinical Trials Registry Database at http://www.anzctr.org.au/Statistics.aspx and has ID number ACTRN12608000615381. Results:Main characteristics of the 37 radically resected patients were: median age 64 years (45–73), Eastern Cooperative Oncology Group Performance Status (ECOG) PS ≥1 in 30%, synchronous metastases in 65%, multiple sites of disease in 22%, and metastases confined to the liver in 68%. Preoperative FOLFOXIRI was administered for a median of 5.5 months. There was no perioperative mortality and all morbidities (27% of patients) resolved without sequelae. After a median follow up of 67 months, 5-year and 8-year survival are 42% and 33% respectively. At 5 years, 29% of patients are free of disease. The analysis of treatment-induced liver injury showed neither G3 vascular toxicity nor G4 steatosis, and steato-hepatitis in only 5% of patients. Conclusions:The GONO-FOLFOXIRI regimen allow an R0 surgery in approximately 1 out of 5 unselected patients with initially unresectable metastatic colorectal cancer, and the long-term survival of resected patients is considerable. Neoadjuvant FOLFOXIRI for 3-6 months is safe and not associated with severe liver injury.

Long-term survival in pancreatic cancer: Pylorus-preserving versus Whipple pancreatoduodenectomy

BACKGROUND This study compared long-term survival in pancreatic or periampullary cancer treated with Whipple pancreatoduodenectomy (PD) and pylorus-preserving pancreatoduodenectomy (PPPD). METHODS Two hundred twenty-one patients with pancreatic head or periampullary cancer were treated. Prognostic variables included age, gender, type and period of operation, and tumor stage. In the ductal adenocarcinomas variables also included tumor and node status, type of lymphadenectomy, pathologic grade, and presence of microscopic residual tumor. The end point was death as a result of neoplastic recurrence. Survival curves were estimated by using the Kaplan-Meier method, and multifactorial analysis was also performed on the data from the ductal adenocarcinoma group. RESULTS The mortality rate was 8.2% in the PD group versus 7.0% in the PPPD group. Morbidity rates were 34.4% for PD and 45.8% for PPPD. Five-year survival was 9.6% in the ductal adenocarcinoma and 63.8% in the periampullary carcinoma groups. Univariate analysis failed to show statistically significant differences in survival curves between the two treatments in either patient group. Correcting for multiple variables in the ductal adenocarcinoma group did not reveal any significant differences in survival rates between the two treatments. CONCLUSIONS PPPD was as successful as classic PD in the treatment of ductal adenocarcinoma and periampullary cancer of the pancreas. Long-term survival was not influenced by the type of resection.

Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids

1. Resveratrol, a polyphenolic compound present in grape and wine, has beneficial effects against cancer and protective effects on the cardiovascular system. Resveratrol is sulphated, and the hepatic and duodenal sulphation might limit the bioavailability of this compound. The aim of this study was to see whether natural flavonoids present in wine, fruits and vegetables inhibit the sulphation of resveratrol in the human liver and duodenum. 2. In the liver, IC50 for the inhibition of resveratrol sulphation was 12 ± 2 pM (quercetin), 1.0 ± 0.04 μM (fisetin), 1.4 ± 0.1 μM (myricetin), 2.2 ± 0.1 μM (kaempferol) and 2.8 ± 0.2 μM (apigenin). Similarly, in the duodenum, IC50 was 15 ± 2 pM (quercetin), 1.3 ± 0.1 μM (apigenin), 1.3 ± 0.5 μM (fisetin), 2.3 ± 0.1 μM (kaempferol) and 2.5 ± 0.3 μM (myricetin). 3. The type of inhibition of quercetin on resveratrol sulphation was studied in three liver samples and was determined to be non-competitive and mixed in nature. Km (mean ± SD; μM) was 0.23 ± 0.07 (control), 0.40 ± 0.08 (5 pM quercetin) and 0.56 ± 0.09 (10 pM quercetin). Vmax (mean ± SD; pmol·min−1·mg−1) was 99 ± 11 (control), 73 ± 15 (5 pM quercetin) and 57 ± 10 (10 pM quercetin). K1 and K1es estimates (mean ± SD) were 3.7 ± 1.8 pM and 12.1 ± 1.7 pM respectively (p = 0.010). 4. Chrysin was a substrate for the sulphotransferase(s) and an assay was developed for measuring the chrysin sulphation rate in human liver. The enzyme followed Michaelis‐Menten kinetics and Km and Vmax (mean ± SD) measured in four livers were 0.29 ± 0.07 μM and 43.1 ± 1.9 pmol·min−1·mg−1 respectively. 5. Catechin was neither an inhibitor of resveratrol sulphation nor a substrate of sulphotransferase. 6. These results are consistent with the view that many, but not all, flavonoids inhibit the hepatic and duodenal sulphation of resveratrol, and such inhibition might improve the bioavailability of this compound.

Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver

1. Resveratrol, a polyphenolic compound present in grape and wine, has beneficial effects against cancer and protective effects on the cardiovascular system. It has been shown that the compound is sulphated in human liver and the aims of the present investigation were to study resveratrol glucuronidation in human liver microsomes and to determine whether flavonoids inhibit resveratrol glucuronidation. 2. A simple and reproducible radiometric assay for resveratrol glucuronidation was developed. The assay employed uridine-5′-diphosphoglucuronic acid-[14C] and unlabelled resveratrol. Resveratrol-glucuronide was isolated by TLC. The intra- and interassays variabilities were 1 and 1.5%, respectively. 3. The rate of resveratrol glucuronidation was measured in 10 liver samples. The mean ± SD and median of resveratrol glucuronidation rate were 0.69 ± 0.34 and 0.80 nmol/min/mg, respectively. Resveratrol glucuronosyl transferase followed Michaelis-Menten kinetics and the Km and Vmax (mean ± SD; n = 5) were 0.15 ± 0.09 mm and 1.3 ± 0.3 nmol/min/mg, respectively. The intrinsic clearance was 11 ± 4 × 10−3 ml/min.mg. 4. The flavonoid quercetin inhibited resveratrol glucuronidation and its IC50 (mean ± SD; n = 3) was 10 ± 1 μM. Myricetin, catechin, kaempferol, fisetin and apigenin (all at 20 μM) inhibited resveratrol glucuronidation and the percent of control ranged between 46% (catechin) to 72% (apigenin). 5. The present results show that resveratrol is glucuronated in the human liver. Glucuronidation may reduce the bioavailability of this compound however, flavonoids inhibit resveratrol glucuronidation and such an inhibition might improve the bioavailability of resveratrol.

Thrombosis in the portal venous system after elective laparoscopic splenectomy

BackgroundThe occurrence of thrombosis in the portal system is an underappreciated complication of splenectomy. Presenting symptoms are usually mild and nonspecific. The short hospital stay associated with the laparoscopic approach could delay the early diagnosis of this condition unless routine imaging controls are planned after discharge.MethodsThe records of 40 patients who underwent laparoscopic splenectomy at our institution were reviewed for clinical signs of thrombosis in the portal system and associated factors. All patients were also enrolled in a color Doppler ultrasound surveillance program.ResultsNine patients (22.5%) developed thrombosis of the splenic vein, progressing to the portal vein in five cases (12.5%). Six patients (15%) were symptomatic. Thrombosis occurred even as late as 4 months after splenectomy. Spleen weight was the only significant factor predictive of postoperative thrombosis. The combination of splenomegaly and an elevated preoperative platelet count was associated with a 75% incidence of this complication.ConclusionThe high risk of thrombosis after the laparoscopic resection of large spleens should prompt strict postoperative imaging surveillance, combined with a more aggressive anticoagulation prophyaxis.

Investigation of interactions between poly-l-lysine-coated boron nitride nanotubes and C2C12 cells: up-take, cytocompatibility, and differentiation

Boron nitride nanotubes (BNNTs) have generated considerable interest within the scientific community by virtue of their unique physical properties, which can be exploited in the biomedical field. In the present in vitro study, we investigated the interactions of poly-l-lysine-coated BNNTs with C2C12 cells, as a model of muscle cells, in terms of cytocompatibility and BNNT internalization. The latter was performed using both confocal and transmission electron microscopy. Finally, we investigated myoblast differentiation in the presence of BNNTs, evaluating the protein synthesis of differentiating cells, myotube formation, and expression of some constitutive myoblastic markers, such as MyoD and Cx43, by reverse transcription – polymerase chain reaction and Western blot analysis. We demonstrated that BNNTs are highly internalized by C2C12 cells, with neither adversely affecting C2C12 myoblast viability nor significantly interfering with myotube formation.

Open versus endoscopic adrenalectomy in the treatment of localized (stage I/II) adrenocortical carcinoma: results of a multiinstitutional Italian survey

BACKGROUND We compared the oncologic effectiveness of open adrenalectomy and endoscopic adrenalectomy in the treatment of patients with localized adrenocortical carcinoma. METHODS One hundred fifty-six patients with localized adrenocortical carcinoma (stage I/II) who underwent R0 resection were included in an Italian multiinstitutional surgical survey. They were divided into 2 groups based on the operative approach (either conventional or endoscopic). RESULTS One hundred twenty-six patients underwent open adrenalectomy and 30 patients underwent endoscopic adrenalectomy. The 2 groups were well matched for age, sex, lesion size, and stage (P = NS). The mean follow-up time was similar for the 2 groups (P = NS). The local recurrence rate was 19% for open adrenalectomy and 21% for endoscopic adrenalectomy, whereas distant metastases were recorded in 31% of patients in the conventional adrenalectomy group and 17% in the endoscopic adrenalectomy group (P = NS). The mean time to recurrence was 27 ± 27 months in the conventional open adrenalectomy group and 29 ± 33 months in the endoscopic adrenalectomy group (P = NS). No significant differences were found between the 2 groups in terms of 5-year disease-free survival (38.3% vs 58.2%) and 5-year overall survival rates (48% vs 67%; P = NS). CONCLUSION The operative approach does not affect the oncologic outcome of patients with localized adrenocortical carcinoma, if the principles of surgical oncology are respected.

Development and in Vitro Testing of a Miniature Robotic System for Computer-Assisted Colonoscopy

In this article we present a new concept for computer-assisted colonoscopy based on a miniature robot capable of propelling itself semiautonomously along the colon. The miniature robot is designed to perform the same functions as current colonoscopy systems-i.e., visualization and tissue sampling for biopsy-and exploits an innovative inchworm-like locomotion principle based on adhering to the colon wall by vacuum suction. The miniature robot is connected by a thin and flexible umbilical cable to an external control unit; this unit provides pneumatic actuation signals in the appropriate sequence to the miniature robot, and information on the robots functioning to the endoscopist, who can either teleoperate or directly supervise its operation. A prototype colonoscopy system using this robot has been fabricated and tested in vitro, with promising results. The proposed concept has strong potential for further development, since miniaturization and functional integration of instrumentation and tools, together with computer assistance, not only make colonoscopy more acceptable, but can also open up a wide range of new applications in endoluminal diagnosis, therapy, and surgery.

A 3-D Mixed-Reality System for Stereoscopic Visualization of Medical Dataset

We developed a simple, light, and cheap 3-D visualization device based on mixed reality that can be used by physicians to see preoperative radiological exams in a natural way. The system allows the user to see stereoscopic ldquoaugmented images,rdquo which are created by mixing 3-D virtual models of anatomies obtained by processing preoperative volumetric radiological images (computed tomography or MRI) with real patient live images, grabbed by means of cameras. The interface of the system consists of a head-mounted display equipped with two high-definition cameras. Cameras are mounted in correspondence of the users eyes and allow one to grab live images of the patient with the same point of view of the user. The system does not use any external tracker to detect movements of the user or the patient. The movements of the users head and the alignment of virtual patient with the real one are done using machine vision methods applied on pairs of live images. Experimental results, concerning frame rate and alignment precision between virtual and real patient, demonstrate that machine vision methods used for localization are appropriate for the specific application and that systems based on stereoscopic mixed reality are feasible and can be proficiently adopted in clinical practice.