Sergio Alfieri

Influence of preservation versus division of ilioinguinal, iliohypogastric, and genital nerves during open mesh herniorrhaphy: Prospective multicentric study of chronic pain

Objective:To evaluate whether the various surgical treatment reserved for ilioinguinal, iliohypogastric, and genital branch of the genitofemoral nerves, during open hernia mesh repair, is effective in reducing chronic postoperative pain. Background:Interest in chronic groin pain following herniorrhaphy has escalated, in recent years, due both to treatment and legal implications. However, much debate still exists concerning which treatment to reserve for the 3 inguinal sensory nerves. Methods:A multicentric prospective study involving 11 Italian institutions led to the recruitment of 973 cases of hernioplasty. All surgeons were asked to report whether or not each nerve had been identified and preserved or divided. The main endpoint of the study was the evaluation of moderate to severe chronic pain at 6 months and 1 year. Results:Overall, the presence of groin pain at the 6-month and 1-year follow-up was 9.7% and 4.1%, respectively. Pain was mild in 7.9% and moderate to severe in 2.1%, at 6 months, and mild in 3.6% and moderate to severe in 0.5%, at 1 year. Univariate and multivariate analysis showed that lack of identification of nerves is significantly correlated with presence of chronic pain, the risk of developing inguinal pain increasing with the number of nerves not detected. Likewise, division of nerves was clearly correlated with presence of chronic pain. Conclusions:The present findings indicate that identification and preservation of nerves during open inguinal hernia repair reduce chronic incapacitating groin pain and that, in the majority of patients with chronic pain at 6 months, the pain at 1 year is resolved only with conservative or medical treatment.

Ki-67 grading of nonfunctioning pancreatic neuroendocrine tumors on histologic samples obtained by EUS-guided fine-needle tissue acquisition: a prospective study

BACKGROUND Preoperative determination of Ki-67 expression, an important prognostic factor for grading nonfunctioning pancreatic endocrine tumors (NF-PETs), remains an important clinical challenge. OBJECTIVE To prospectively evaluate the feasibility, yield, and clinical impact of EUS-guided fine-needle tissue acquisition (EUS-FNTA) with a large-gauge needle to obtain tissue samples for histologic diagnosis and Ki-67 analysis in patients with suspected NF-PETs. DESIGN Prospective cohort study. SETTING Tertiary-care academic medical center. PATIENTS Consecutive patients with a single pancreatic lesion suspicious for NF-PET on imaging. INTERVENTION EUS-FNTA with a 19-gauge needle. MAIN OUTCOME MEASUREMENTS Feasibility and yield of EUS-FNTA for diagnosis and Ki-67 expression determination. RESULTS Thirty patients (mean [± SD] age 55.7 ± 14.9 years), with a mean (± SD) lesion size of 16.9 ± 6.1 mm were enrolled. EUS-FNTA was successfully performed without complications in all patients, with a mean (± SD) of 2.7 ± 0.5 passes per patient. Adequate samples for histologic examination were obtained in 28 of the 30 patients (93.3%). Ki-67 determination could be performed in 26 of these 28 patients (92.9%, 86.6% overall), 12 of whom underwent surgical resection. Preoperative and postoperative Ki-67 proliferation indexes were concordant in 10 patients (83.3%), whereas 2 patients were upstaged from G1 to G2 or downstaged from G2 to G1, respectively. LIMITATIONS Single center study with a single operator. CONCLUSION In patients with suspected nonfunctioning low-grade to intermediate-grade pancreatic neuroendocrine tumors (p-NETs), retrieval of tissue specimens with EUS-FNTA by using a 19-gauge needle is safe, feasible, and highly accurate for both diagnosis and Ki-67 determination. A Ki-67 proliferative index acquired through this technique might be of great help for further therapeutic decisions.

Pancreatoduodenectomy for Tumors of Vater’s Ampulla: Report on 94 Consecutive Patients

Evaluation of prognostic factors of adenocarcinoma of Vater’s ampulla is still a matter of debate. The aim of this study was to evaluate retrospectively factors that influence early and long-term outcomes in a 20-year single-institution experience on ampullary carcinoma. A total of 94 consecutive patients with ampullary carcinoma or adenoma with severe dysplasia were managed from 1981 to 2002. Among them, 64 underwent pancreatoduodenectomy, and the remaining 30 submitted to surgical (n = 5) or endoscopic (n = 25) palliative treatment. Demographic, clinical, and pathologic data were collected, and a comparison was made between patients who did or did not undergo resection. Standard statistical analyses were carried out in an attempt to establish a correlation between clinical variables, intraoperative and pathologic factors, and survival in patients with resection. A total of 85 (90.4%) patients had potentially resectable lesions due to the extent of the tumor, but only 64 (68%) underwent curative resection. The surgical morbidity rate was 34.3%. Postoperative mortality was 9.3%, with no deaths among the 38 more recently treated patients. Median survivals were 9 and 54 months for nonresected and resected patients, respectively. The overall 5-year survival was 64.4% for patients undergoing pancreatoduodenectomy. Survival was found to be significantly affected by resection, tumor size, tumor grade, and tumor infiltration. Patients with negative lymph nodes show a trend toward longer survival. In a multivariate analysis, only the depth of tumor infiltration influenced patient survival.Pancreatoduodenectomy is the treatment of choice for ampullary carcinoma and adenomas with high-grade dysplasia, with a good chance of long-term survival. Surgical resection remains the most important factor influencing outcome.

Avoiding early postoperative complications in liver surgery. A multivariate analysis of 254 patients consecutively observed

BACKGROUND The number of hepatic resections for benign and malignant lesions has constantly increased over the past 20 years, as a consequence, surgical experience acquired over the past few years has decreased post-operative morbidity and mortality rates. AIMS Analysing the relation between potential preoperative risk factors and the occurrence of severe post-operative complications, an attempt is made to identify the variables determining surgical risk in elective hepatic surgery both in normal and cirrhotic liver. PATIENTS AND METHODS The hospital records of 254 patients who underwent elective liver surgical procedures for hepatic lesions in our department, between 1984 and 1999, were reviewed. The following variables were entered into univariate and multivariate analysis: age, sex, nature of liver lesion (benign or malignant), presence of cirrhosis or cholestasis, synchronous resection of other organs, disorders of blood coagulation, intraoperative blood requirement, the extent of surgical procedures and Pringles manoeuvre. RESULTS AND CONCLUSIONS The multivariate analysis of the 254 surgical operations on the liver indicates that the most powerful independent predictors favouring a serious adverse effect includes intra-operative blood transfusions, advanced age and cirrhosis. Scrupulous preoperative clinical evaluation and expert surgical skills minimize intra-operative bleeding and proved to be the most significant factors influencing morbidity and mortality rates.

Gene profiling of bone marrow- and adipose tissue-derived stromal cells: a key role of Kruppel-like factor 4 in cell fate regulation

BACKGROUND AIMS Bone marrow- and adipose tissue-derived mesenchymal stromal cells (MSC) represent promising sources for regenerative medicine. However, the precise molecular mechanisms underlying MSC stemness maintenance versus differentiation are not fully understood. The aim of this study was to compare the genome-wide expression profiles of bone marrow-and adipose tissue-derived MSC, in order to identify a common molecular stemness core. METHODS Molecular profiling was carried out using Affymetrix microarray and relevant genes were further validated by Q-PCR. RESULTS We identified an overlapping dataset of 190 transcripts commonly regulated in both cell populations, which included several genes involved in stemness regulation (i.e. self-renewal potential and the ability to generate differentiated cells), various signaling pathways and transcription factors. In particular, we identified a central role of the Kruppel-like factor 4 (KLF4) DNA-binding protein in regulating MSC transcriptional activity. CONCLUSIONS Our results provide new insights toward understanding the molecular basis of MSC stemness maintenance and underline the ability of KLF4 to maintain cells in an undifferentiated state.

The Prognostic Effect of Clinical Staging in Pancreatic Adenocarcinoma

BackgroundThe importance of pancreatic cancer staging is uncertain. The aim of this report was to evaluate the accuracy of combined standard imaging techniques in predicting the pathologic stage and to evaluate the prognostic effect of clinical staging to identify patient groups in which laparoscopy and laparotomy could be beneficial.MethodsFifty-four patients were included in this analysis. The techniques used for clinical staging were endoscopic retrograde cholangiopancreatography, abdominal computed tomographic scan, and ultrasonography. All patients underwent both clinical and surgical/pathologic staging. A comparison was performed between presurgical stage and surgical/pathologic stage. The prognostic effect of different factors on survival was evaluated with both univariate (log-rank) and multivariate (Cox) analysis.ResultsSensitivity and specificity for vascular involvement were 73.9% and 96.3%, respectively. Sensitivity and specificity for nodal involvement were 63.6% and 95.4%, respectively. A total of 33.3% of patients showed a higher than expected pathologic stage, and 3.7% showed a lower than expected pathologic stage, by comparing clinical and pathologic evaluation. A highly significant correlation was observed between clinical T stage (P = .0067) and tumor diameter (P = .0037) and patient survival. Maximal prognostic differentiation was observed by dividing patients into two groups based on imaging results: group A (favorable prognosis) and group B (unfavorable prognosis). The median survival was 25.1 and 8.0 months for group A and B, respectively. Five-year survival was 20.1% and 0%, respectively (multivariate analysis: P = .0007).ConclusionsIntegrated standard imaging studies achieved reasonable diagnostic accuracy in our analysis. A single classification based on clinical stage and tumor diameter evaluated by imaging predicts prognosis in patients with pancreatic carcinoma.

Molecular mechanisms underlying human adipose tissue-derived stromal cells differentiation into a hepatocyte-like phenotype

BACKGROUND Adipose tissue-derived stromal cells (ATSCs) hold great promises in regenerative medicine. In the last decade, several studies have reported the plasticity of ATSCs toward a hepatocyte-like phenotype. Nonetheless, the molecular mechanisms underlying the conversion from a mesenchymal to an epithelial phenotype remain poorly understood. AIM In this study, we compared the full genome expression profiles of ATSCs cultured for 4 weeks under pro-hepatogenic conditions to undifferentiated ATSCs, in order to depict the molecular events involved in ATSC hepatic transdifferentiation. METHODS Analysis was performed using the Affymetrix human focus arrays. Sets of differentially expressed genes were functionally categorized in order to understand which pathways drive the hepatic conversion and interesting targets were validated by Q-PCR. RESULTS ATSC-derived hepatocyte-like cells activate several genes associated with specific liver functions, including protein metabolism, innate immune response regulation, and biodegradation of toxic compounds. Furthermore, microarray analysis highlighted downregulation of transcripts associated with the mesenchymal lineage, while epithelial-related genes were overexpressed. CONCLUSION Our data suggest that the in vitro system used in this study drove ATSCs toward a hepatic conversion through a subtle regulation of molecular pathways controlling lineage commitment that promote mesenchymal-epithelial transition.

Multi-institutional pooled analysis on adjuvant chemoradiation in pancreatic cancer

PURPOSE To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma. METHODS AND MATERIALS A multicenter retrospective review of 955 consecutive patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT. RESULTS Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT (P<.001) and 27.8 months after CT alone (P<.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio [HR] = 0.72; confidence interval [CI], 0.60-0.87; P=.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P<.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P<.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P<.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P=.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P=.014) CONCLUSION: This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT.

Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness

Human ferritin heavy chain (HFt) has been demonstrated to possess considerable potential for targeted delivery of drugs and diagnostic agents to cancer cells. Here, we report the development of a novel HFt-based genetic construct (HFt-MP-PAS) containing a short peptide linker (MP) between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). The peptide linker contains a matrix-metalloproteinases (MMPs) cleavage site that permits the protective PAS shield to be removed by tumor-driven proteolytic cleavage within the tumor microenvironment. For the first time HFt-MP-PAS ability to deliver doxorubicin to cancer cells, subcellular localization, and therapeutic efficacy on a xenogeneic mouse model of a highly refractory to conventional chemotherapeutics type of cancer were evaluated. HFt-MP-PAS-DOXO performance was compared with the novel albumin-based drug delivery system INNO-206, currently in phase III clinical trials. The results of this work provide solid evidence indicating that the stimuli-sensitive, long-circulating HFt-MP-PAS nanocarriers described herein have the potential to be exploited in cancer therapy.

External Beam Radiotherapy Plus 24-Hour Continuous Infusion of Gemcitabine in Unresectable Pancreatic Carcinoma: Long-Term Results of a Phase II Study

PURPOSE To evaluate the efficacy of gemcitabine-based chemoradiation (CT-RT) in treating patients (pts) affected by locally advanced pancreatic cancers (LAPC). METHODS AND MATERIALS Weekly gemcitabine (100 mg/m(2)) was given as a 24-hour infusion during the course of three-dimensional radiotherapy (50.4 Gy to the tumor, 39.6 Gy to the nodes). After CT-RT, pts received five cycles of sequential chemotherapy with gemcitabine (1000 mg/m(2); 1, 8, q21). Response rate was assessed according to World Health Organization criteria 6 weeks after the end of CT-RT. Local control (LC), time to progression (TTP), metastases-free survival (MFS), and overall survival (OS) were analyzed by the Kaplan Meier method. RESULTS Forty pts (male/female 22/18; median age 62 years, range, 36-76) were treated from 2000 to 2005. The majority had T4 tumour (n = 34, 85%), six pts (15%) had T3 tumour. Sixteen pts (40%) were node positive at diagnosis. Grade 3-4 acute toxicity was observed in 21 pts (52.5%). Thirty pts (75%) completed the treatment schedule. A clinical response was achieved in 12 pts (30%). With a median follow-up of 76 months (range, 32-98), 2-year LC was 39.6% (median, 12 months), 2-year TTP was 18.4% (median, 10 months), and 2-year MFS was 29.7% (median, 10 months). Two-year OS (25%; median, 15.5 months) compared with our previous study on 5-fluorouracil-based CT-RT (2.8%) was significantly improved (p <0.001). CONCLUSIONS Gemcitabine CT-RT seems correlated with improved outcomes. Healthier patients who are likely to complete the treatment schedule may benefit most from this therapy.