Hepatocellular carcinoma treatment over sorafenib: epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel?

INTRODUCTION: Sorafenib is currently the only approved therapy in hepatocellular carcinoma (HCC). Alternative first- and second-line treatments are a significant unmet medical need, and several biologic agents have been tested in recent years, with poor results. Therefore, angiogenic pathways and the cytokine cascade remain possible targets in HCC. Recent studies suggest a role of epigenetic processes, associated with the initiation and development of HCC. In this field, DNA methylation, micro-RNAs (miRNAs) and tumor microenvironment cells became a possible new target for HCC treatment. AREAS COVERED: This review explains the possible role of DNA methylation and histone deacetylase inhibitors as predictive biomarkers and target therapy, the extensive world of the promising miRNA blockade strategy, and the recent strong evidence of correlation between HCC tumors and peritumoral stroma cells. The literature and preclinic/clinic data were obtained through an electronic search. EXPERT OPINION: Future research should aim to understand how best to identify patient groups that would benefit most from the prescribed therapy. To overcome the 'therapeutic stranding' of HCC, a possible way out from the current therapeutic tunnel might be to evaluate the major epigenetic and genetic processes involved in HCC carcinogenesis, not underestimating the tumor microenvironment and its 'actors' (angiogenesis, immune system, platelets). We are only at the start of a long journey towards the elucidation of HCC molecular pathways as therapeutic targets. Yet, currently this path appears to be the only one to cast some light at the end of the tunnel.

A modified technique of pancreaticojejunostomy after pancreatoduodenectomy: a preliminary experience.

Pancreatoduodenectomy currently represents the treatment of choice for resectable pancreatic and periampullary malignant tumours, symptomatic chronic pancreatitis, duodenal cystic dystrophy, large adenomas, diverticula and benign periampullary tumours. Pancreato-jejunostomy failure remains the main complication following pancreatoduodenectomy, even leading to death. To improve the safety of this anastomosis, a modified technique of pancreato-jejunal anastomosis with posterior double-layer suture and Wirsung duct evagination is proposed. We report our experience in eight consecutive patients (4 females, 4 males; average age 66, range 57-74) undergoing Traverso-Longmire pylorus-preserving pancreatoduodenectomy using Wirsung duct evagination and posterior double-layer suture technique. There was no mortality; the post-operative recovery was uneventful with no pancreatic anastomotic leakage. The mean post-operative stay was 15 days (range 12-19). This proposed procedure could be considered an additional opportunity in the performance of a pancreato-enteric anastomosis, yielding good results and preserving from post-operative pancreatic ductal obstruction.

Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells.

Oleuropein (OL) and hydroxytyrosol (HT), the main olive oil polyphenols, possess anti-proliferative effects in vitro. Fatty acid synthase, a key anabolic enzyme of biosynthesis of fatty acids, plays an important role in colon carcinoma development. Our aim was to investigate whether gene expression of FAS, as well as its enzymatic activity, is regulated by HT and OL in two human colon cancer cell lines, as HT-29 and SW620. In addition, we investigated the effects of these polyphenols on growth and apoptosis in these cells. FAS gene expression and activity in treated HT-29 and SW620 cells were evaluated by real-time PCR and radiochemical assay, respectively. Cell growth and apoptosis, after polyphenols treatment, were measured by MTT test and flow cytometry, respectively. The inhibition of proliferation, detected after HT treatment, was mediated by an inhibition of FAS expression and its enzymatic activity in SW620 cells, while the anti-proliferative effect in HT-29 cells seems to be independent from FAS. OL exerted an anti-proliferative effect only on SW620 cells with a mechanism which excluded FAS. Olive oil polyphenols used were able to induce apoptosis in both cell lines studied. The increase of apoptosis in these cells was accompanied by the block of cell cycle in the S phase. This study demonstrates that HT and OL may induce anti-proliferative and pro-apoptotic effects only in certain human colorectal cancer cell types. These effects are FAS mediated only in SW620 cells after treatment with HT.

Mucinous cystic neoplasm of the pancreas: a case report.

Cystic neoplasms of the pancreas account for only a small percentage of pancreatic tumours. They include mucinous cystic tumours, which have a higher incidence in females in their forties or fifties. Cystic neoplasms of the pancreas can present in a benign, borderline or malignant form. These tumours have a natural evolution from a benign (mucinous cystadenoma) to a malignant form (cystadenocarcinoma). It is not always easy to diagnose cystic tumours, including mucinous cystic tumours of the pancreas, and the final diagnosis is often reached only after the surgical procedure, which is the gold standard treatment of this disease. We present the case of a 56-year-old woman affected by a mucinous cystic tumour of the body-tail of the pancreas, who underwent distal splenopancreasectomy. She was discharged on postoperative day 12. After an 18-month followup, she is in good general condition and disease-free.

Endoscopic management of large colorectal polyps.

OBJECTIVES: The optimal treatment for large colorectal polyps (LCPs) is still a controversial issue. The aim of this study was to evaluate the safety and effectiveness of endoscopic polypectomy (EP) of colorectal polyps >or=2 cm in size. PATIENTS AND METHODS: One hundred fifty-one EP LCPs were performed over a period of 7 years. Diathermal snare was used for pedunculated and pseudopedunculated polyps and endoscopic mucosal resection (EMR) or biopsy forceps polypectomy for sessile and flat polyps. The resected polyps were recovered and collected for histology. At scheduled follow-up visits 1, 3, 6, and 12 months after polypectomy, complications and recurrences were recorded in all patients. RESULTS: Fifteen polyps were located in the rectum, 84 in the sigmoid colon, 11 in the descending colon, four in the splenic flexure, 11 in the transverse colon, 11 in the hepatic flexure, seven in the ascending colon and eight in the cecum. Fifty-six polyps were sessile, 54 pedunculated, 25 pseudopedunculated, and 16 flat. At histology, most of polyps (131) were adenomas (nine with adenocarcinoma in situ). Five were invasive polypoid carcinomas and required colonic resection. Immediate bleeding occurred in ten patients (7.6%) and it was stopped by endoscopic hemoclips (7), epinephrine injection (1), or surgery (2). There were three perforations (2.3%; all polypoid carcinomas), managed endoscopically (1) or surgically (2). Delayed bleeding occurred in two patients (1.5%) and was treated by endoscopic diathermy and hemoclips (1) or surgery (1). During follow-up, six (4.6%) incompletely excised polyps and three (2.3%) relapses in the site of previous EP were detected and endoscopically removed. CONCLUSION: EP is relatively safe and effective for benign-appearing LCPs.

Basiliximab versus steroids in double therapy immunosuppression in liver transplantation: a prospective randomized clinical trial.

BACKGROUND: : Basiliximab (B), an anti-CD25 monoclonal antibody, may represent an alternative to steroids (S) in immunosuppression after liver transplantation (LTx). The aim of this prospective randomized clinical trial was to compare B with S in a cyclosporin A (CsA)-based immunosuppression regimen in primary LTx. METHODS: : Forty-seven adult recipients of LTx were randomly assigned to receive B or S. CsA was administered at the initial dose of 10 mg/kg/day and adjusted to the target C2 level of 800 to 1000 ng/mL by day 7. Clinically suspected acute cellular rejection (ACR) was histologically confirmed. Endpoints include ACR, survival, and disease-free survival. RESULTS: : In group B (26 patients), there were seven biopsy-confirmed ACR with an ACR rate of 15.4%; in group S (21 patients), 8 ACR with an ACR rate of 28.6% (P=n.s.). Cumulative survival at 36 months after transplantation was 84.3% for group B and 61.0% for group S. In hepatitis C virus patients (n=20: 12 in group B, 8 in group S), the ACR rate was 25% in group B and 50% in group S. The incidence of infection and other adverse events was similar in the two treatment groups. CONCLUSIONS: : B may represent a valid alternative to S in the induction of immunosuppression in LTx. Further studies of basiliximab in a large cohort are needed.

Intragastric balloon and binge eating.

BACKGROUND: In recent years, particular attention has been paid to the effect that eating disturbances and especially binge eating can have on the outcome of surgical treatments for obesity. Endoscopic positioning of the Bioenterics intragastric balloon (BIB) is mainly used in the work-up for surgical treatment of morbid obesity. Available data show that the BIB is a valid tool for reducing weight and co-morbidity, even if only a temporary treatment in morbidly obese patients. We evaluated the results of treatment with the BIB with the patient's tendency to indulge in binge eating. METHODS: Between April 2003 and March 2006, 89 patients with morbid obesity (BMI 39-55) were enrolled in the study. Before introducing the BIB and within 3 months after removal, patients underwent a psychiatric evaluation and the following psychodiagnostic tests: SCID (Structured Clinical Interview for DSM IV), ED-SCID (Eating Disorder Module, Structured Clinical Interview) and BSQ (Binge Scale Questionnaire). All those positive for the BED criteria according to the DSM IV, and who had at least one binge eating episode per week, were considered Binge Eaters (BE). RESULTS: Of the 89 patients enrolled, 75 were eligible for evaluations (M:F = 12:63), and 27 were positive for binge eating (BE). There were no significant differences in age and preoperative BMI between the BE group and the 48 patients without BE (NBE group). The complication and failure rates with the BIB treatment were significantly higher in the BE group (P<0.01). After treatment with the BIB, both groups showed a significant reduction in BMI (P<0.01), but the NBE-group showed a significantly higher weight (BMI 5.7 +/- 2.5 kg/m2) than the BE-group (BMI 3.3 +/- 2.2 kg/m2) (P=0.03). CONCLUSION: The results of treatment with the intragastric balloon appear to be affected by binge eating pattern in morbidly obese patients, even if the presence of this behavior does not prevent a successful reduction in the BMI. Binge eating does not seem to be a contraindication for the adjuvant use of the BIB before a bariatric operation. A limitation of our study is the short period of observation, related to the period of the BIB in the gastric lumen (not more than 6 months). Further studies may show whether the association of psychiatric treatment with the BIB in patients affected by binge eating may enhance the results of the treatment.

Comparison of hemodynamic and respiratory effects of propofol and sevoflurane during carbon dioxide pneumoperitoneum in a swine model.

The aim of this study was to compare intraoperative hemodynamic and respiratory parameters using propofol and sevoflurane during laparoscopic surgery in a porcine model. After induction of general anaesthesia in 16 pigs with fentanyl (0.005 mg kg(-1)) followed by propofol (6 mg Kg(-1)), it was maintained with fentanyl (0.01 mg kg(-1)h(-1)) and sevoflurane in O2 in group 1 (G1, n = 8) and fentanyl and propofol (12 mg kg(-1)h(-1)) in group 2 (G2, n = 8). The parameters monitored were heart rate, airway pressure (PAW), arterial and venous blood pressures and arterial blood gas analysis. The carbon dioxide pneumoperitoneum was maintained at 12 mmHg for 2 hours. Data were expressed as mean +/- standard deviation and were analysed using the Wilcoxon test (p < 0.05). G1 showed significantly higher PAW values than G2 at T60, T90 and T120. The heart rate values were significantly higher in G1 at T90 and T120. Middle arterial pressure was significantly lower in G1 than G2 at T30 and T60. The base deficit was significantly greater in G1 at T60, T90, T120 and Tpost. In this study propofol assured better hemodynamic and respiratory conditions than sevoflurane during laparoscopy in a porcine model.

Long-term functional assessment of antegrade colonic enema for combined incontinence and constipation using a modified Marsh and Kiff technique.

PURPOSE: Constipation and fecal incontinence can severely affect quality of life for patients, particularly when simultaneously present. Malone antegrade colonic enema enables periodic colonic emptying, thus preventing uncontrolled passage of feces and constipation. METHODS: Eleven patients with fecal incontinence and severe constipation or perineal colostomy after Miles' operation underwent a modified Marsh and Kiff ileostomy for antegrade colonic enema. Before and after surgery, the patients were fully evaluated for gastrointestinal functions, including gallbladder and stomach emptying time, H(2)-breath test, colonic transit time, dynamic defecography, and anorectal manometry. The severity of incontinence and constipation was scored preoperatively and postoperatively by using the American Medical System score and Cleveland Clinic Constipation scale, respectively, whereas the quality of life was measured by the Gastrointestinal Quality of Life Index. The surgical technique involved division of the terminal ileum 10 to 15 cm from the ileocecal valve, anastomosis and intussusception of the ileum with the cecum, narrowing of the ileal conduit with a linear stapler, and a small, introflexed ileostomy with an advanced skin flap. RESULTS: During the postoperative period, the mean American Medical System score decreased significantly from 77 to 11 (P<0.01) and the mean Cleveland Clinic Constipation score from 23 to 8.5 (P<0.01) with a significant improvement of quality of life. Antegrade colonic enema did not affect gallbladder, gastric, or orocecal transit time, which remained comparable with baseline. Colonic scintigraphy showed that antegrade colonic enema was efficient to clean the whole colon and rectum, leaving only 24 (range, 6-40) percent of the initial radioactivity after 30 minutes. Ileal manometry confirmed the presence of a high-pressure zone, preventing accidental reflux. CONCLUSIONS: Modified Marsh and Kiff technique is a safe and effective surgical option to treat patients with combined fecal incontinence and severe constipation and those with perineal colostomy after Miles. It should be recommended as a last option before colostomy.

The Italian Registry of Laparoscopic Surgery of the Spleen (IRLSS) A retrospective review of 379 patients undergoing laparoscopic splenectomy.

In December 2000, the Italian Registry of Laparoscopic Surgery of the Spleen (IRLSS) was formally launched under the auspices of the Italian Society for Endoscopic Surgery and New Technologies (SICE). The aim of this multicentre study was to analyse various aspects of the treatment that are still under discussion, such as the extension of the laparoscopic indications in cases of malignancy, independently of the associated splenomegaly, patient selection and operative techniques. A retrospective review of 379 patients undergoing laparoscopic splenectomy for haematological diseases from February 1, 1993, to September 15, 2005, was conducted. Data were collected from the 18 italian centres participating in the IRLSS. The mean length of surgery was 140 minutes (range: 25-420). Conversion was necessary in 25 cases (6.6%), and at least one accessory spleen was found in 30 patients (8%). The mean spleen weight was 1200 g (range: 85-4500). Perioperative death occurred in two cases (0.5%). There were no complications in 312 patients (82.3%), with a mean hospital stay of 5.5 days (range: 2-30). Morbidity occurred in 67 patients (17.8%), mainly consisting in transient fever (n = 22), pleural effusions (n = 16), and actual or suspected haemorrhage (n = 14), requiring re-intervention in 7 patients. This first study carried out on the IRLSS data shows that laparoscopic splenectomy may constitute the gold standard for haematological diseases with a normal-sized spleen. The low morbidity and mortality rates suggest that laparoscopic splenectomy can be successfully proposed also for splenomegaly in haematological malignancies.

Solid papillary neoplasm of the pancreas: a case report.

Solid pseudopapillary neoplasm of the pancreas, solid and cystic, is a rare disease compared to ductal adenocarcinoma. The tumor most often affects women of African race aged in their twenties or thirties. We report the case of a 48-year-old man affected by solid pseudopapillary neoplasm of the pancreas treated by distal splenopancreasectomy. The patient was discharged on the 10th postoperative day in good general condition, feeling normal and with blood chemistry values within normal limits. The main characteristic differentiating papillary tumors of the pancreas from ductal adenocarcinoma is that in the latter case surgical eradication is a definitive solution and no other treatment is required, as confirmed by our case and those reported in the literature.

Red blood cell (RBC) surface acetylcholinesterase showing a hemorheological pattern during glaucoma treatment.

BACKGROUND: Glaucoma is currently attributed to two different possible pathogenetic mechanisms: mechanical (the ocular damage is induced by physical injury), and vascular (the ocular damage is sustained by ischemia of the optic nerve head). AIM: We considered the possibility that several anti-glaucoma drugs (beta-blockers, carbonic anhydrase inhibitors and prostaglandins) could have an influence on optic nerve head hemorheology and oxygen supply. MATERIALS AND METHOD: We studied 4 groups of 10 subjects each: a control group, and 3 primary open angle glaucoma (POAG) groups, treated with topical beta-blockers, (10 patients), carbonic anhydrase inhibitors (CAI), and prostaglandin analogs (PG), respectively. In these 4 groups we investigated the RBC surface AchE and cytosolic calcium levels in order to assess their possible influence on the hemorheology and microcirculation in optic nerve head blood perfusion. RESULTS: A significant correlation (p < 0.048) was found between the RBC surface acetylcholinesterase and RBC intracytosolic calcium values in patients with POAG treated with beta-blockers. We found no significant correlation (p = n.s.) between the same patterns in the other Groups or in Controls. CONCLUSION: These data indicate that CAI and PG drugs do not interfere with AchE in POAG patients, whereas beta-blockers negatively affect the RBC deformability.

Cholecystectomy in situs viscerum inversus totalis. Does laparoscopy increase the pitalls?

Situs viscerum inversus is a rare condition in which the organs are transposed, totally or partially, to the opposite side of the body. Normally, there are no organ dysfunctions. Clinically, symptoms of cholelithiasis may be clear but confused by the location of the gallbladder on the opposite side. We report the case of a 43-year-old female with occasional colic pain in the epigastrium radiating to the right side and subscapular region, particularly after lunch. The laboratory findings showed normal values and, at physical examination, deep palpation of the abdomen in the epigastric region provoked pain. X-rays, ultrasonography, and CT scan showed the presence of multiple gallstones and the situs viscerum inversus of the abdominal organs. The only pathological finding was cholecystolithiasis. Laparoscopic cholecystectomy was judged advisable. Situs viscerum inversus is not a contraindication for laparoscopic cholecystectomy. This abnormal anatomical condition may create some initial difficulty for the surgeons, because of the inverted position of the organs. The peculiarity of our case is the unlikely site of the abdominal pain, located in the epigastrium and on the right side although the patient had situs viscerum inversus. Laparoscopic cholecystectomy can be performed on the left-sided gallbladder proceeding with the "american technique". In difficult cases, open cholecystectomy can be unavoidable.

Insulin signaling in human visceral and subcutaneous adipose tissue in vivo.

In this study, we evaluated the activation of various insulin signaling molecules in human fat in vivo and compared signaling reactions in visceral and subcutaneous fat depots. Paired abdominal omental and subcutaneous fat biopsies were obtained from nonobese subjects with normal insulin sensitivity under basal conditions and 6 and 30 min following administration of intravenous insulin. Insulin receptor phosphorylation was more intense and rapid and insulin receptor protein content was greater in omental than in subcutaneous adipose tissue (P < 0.05). Insulin-induced phosphorylation of Akt also occurred to a greater extent and earlier in omental than in subcutaneous fat (P < 0.05) in the absence of significant changes in Akt protein content. Accordingly, phosphorylation of the Akt substrate glycogen synthase kinase-3 was more responsive to insulin stimulation in omental fat. Protein content of extracellular signal-regulated kinase (ERK)-1/2 was threefold higher in omental than in subcutaneous fat (P < 0.05), and ERK phosphorylation showed an early 6-min peak in omental fat, in contrast with a more gradual increase observed in subcutaneous fat. In conclusion, the adipocyte insulin signaling system of omental fat shows greater and earlier responses to insulin than that of subcutaneous fat. These findings may contribute to explain the biological diversity of the two fat depots.

Stop Flow in abdominal and pelvic cancer relapses.

To determinate MTD, DLT and safe doses for phase II study, a dose finding study with Mitomycin and Adriamycin Stop-Flow administration was carried out. A phase II study focused on resectability of pelvic colorectal relapses is in progress. From November 1995, 84 pts, 52 male and 32 female (94 treatments), with advanced not resectable abdominal (14 pts) or pelvic (70 pts) relapses, and resistant to previous systemic chemotherapy, were enrolled in the study. 46 pts entered the phase I-early phase II study, while subsequently 38 pts were recruited in ongoing phase II study. Safe dose were: MMC 20 mg/mq and ADM 75 mg/mq. The phase II study focused on colorectal relapses registered very promising responses: 90% pain control, 1 pCR and 26 PR / 63 (OR 43%), 8 NC (13%) 9/27 responder patients (33%) obtained a complete resectability of colorectal relapses. Stop-Flow is a safe and feasible technique very useful as a palliation treatment.