Long-term survival of uveal melanoma patients after surgery for liver metastases.

AIMS: To evaluate the posthepatectomy survival of uveal melanoma patients with liver metastases. METHODS: Data were collected from the files in the Departments of Ophthalmology, General Surgery and Oncology, for uveal melanoma patients who were seen in the Ocular Oncology Clinic at the Hadassah Medical Center from 1988 to 2007. The main outcome was posthepatectomy survival. Statistical analysis was performed using JMP statistical software. RESULTS: Of the 558 patients, 74 (13%) developed metastases after a median of 35.0 months from the initial diagnosis. Thirty-five patients underwent hepatectomy. These patients had similar clinical characteristics as those who did not undergo hepatectomy. The median survival time from the detection of metastasis was 3.7-fold higher in the operated patients in comparison with the non-operated patients. Posthepatectomy survival of patients who were found in surgery to have 1-5 metastatic nodules was 3.1 times longer than those with six or more lesions. The hepatectomies of 13 patients resulted in complete resection of the hepatic metastases with clean histological margins (R0). These patients survived 1.9 times longer than those with residual disease (R1/R2). CONCLUSION: It is possible to extend significantly the life expectancy of uveal melanoma patients who develop isolated hepatic metastases by complete resection of the lesions.

Immunomodulation of experimental colitis: the role of NK1.1 liver lymphocytes and surrogate antigens--bystander effect.

The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytokine-producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis-extracted proteins was previously shown to down-regulate the anti-colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver-associated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non-inflammatory colon-extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS-colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non-tolerized-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNgamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNgamma and a decrease in IL10 serum levels, and down-regulation of NK1.1(+) LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1(+) LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance.

Laparoscopic vs open adrenalectomy for benign adrenal neoplasm.

BACKGROUND: The aim of this study was to compare the outcome of laparoscopic adrenalectomy (LA) performed for benign adrenal neoplasm to the open procedure in a similar group of patients. METHODS: All consecutive patients who underwent LA between June 1996 and February 1999 were evaluated. Data analysis included patient's age and gender, indication for surgery, histological diagnosis, size of specimen, comorbid conditions, length of stay and ileus, postoperative narcotic consumption, and time to return to normal activity. The results were compared retrospectively to a well-matched group of patients who underwent an open adrenalectomy (OA). RESULTS: Twenty-eight LA were performed in 24 patients for the following disorders: adrenocortical adenoma, 16 (four Cushing's syndrome, 12 Conn's syndrome); pheochromocytoma, 10; and nonfunctioning tumor, two. These cases were compared with a well-matched group of 28 patients who underwent OA in the same department. There were two conversions to open surgery (7%) in the laparoscopic group and no deaths in either group. Of all the evaluated parameters, the following statistically significant differences between the two groups were noted: The mean operative time was longer in the LA group (188 vs 139 min, p < 0.001.); however, this became insignificant in the last 10 cases of LA, when the mean length of surgery was reduced to 130 min. The overall morbidity was lower in the LA group (16% vs 39%, p = 0.05), as was the mean time to tolerate a regular diet (2 vs 3.9 days), mean meperidine consumption (mg) (109 vs 209), mean length of stay (4 vs 7.5 days), and mean time to return to normal activity (2.2 vs 5.2 weeks), (p < 0.001 for all). CONCLUSION: LA for benign adrenal disorders is a safe procedure that is associated with significantly lower morbidity, shorter ileus and hospitalization, reduced postoperative pain, and a faster return to normal activity than the open procedure.

Combined colon and hepatic resection for synchronous colorectal liver metastases.

BACKGROUND AND OBJECTIVES: The surgical strategy for the treatment of resectable synchronous hepatic metastases of colorectal cancer remains controversial. This study was performed to assess the outcome of combined resection of colorectal cancer and liver metastases. METHODS: The perioperative data, morbidity, and survival of the patients who underwent combined colon and liver resections for synchronous colorectal liver metastases from 1988 to 1999 were compared to the parameters of the patients who underwent colon resection followed by resection of liver metastases in a staged setting. RESULTS: 198 hepatic resections were performed, of which 112 procedures in 103 patients were done for metastatic colorectal carcinoma. Twenty six patients (25%) had combined hepatic and colon resection and were compared to 86 patients with metachronous metastases who underwent colon and hepatic resection in the staging setting. Postoperative morbidity was 27 and 35%, respectively. There was no hospital mortality in the combined group vs. 2.3% in the staged group. Blood loss, intensive care unit (ICU) stay and length of postoperative stay (LOS) were similar in both groups. The 5 years cumulative survival of the group after combined surgery was 28% vs. 27% of the group after isolated hepatic resections (P = 0.21). CONCLUSION: Combined colon and hepatic resection is a safe and efficient procedure for the treatment of synchronous colorectal liver metastases. It can be performed with acceptable morbidity and no perioperative mortality. The survival after combined procedure is comparable to the one achieved after staged procedure of colon resection followed by liver resection.

The protective effect of acadesine on lung ischemia-reperfusion injury.

UNLABELLED: The purine precursor acadesine is highly effective in preventing ischemia-reperfusion (I-R) injury of the heart and intestine. The aim of this study was to test the effect of acadesine on I-R--induced lung injury. The lobar artery of the left lower lung lobe in intact-chest, spontaneously breathing cats was occluded for 2 h (Group 1, ischemia) and reperfused for 3 h (Group 2, I-R). Animals were subjected to one of the following three protocols: acadesine administered IV 15 min before ischemia (Group 3), 15 min before reperfusion (Group 4), or 30 min after reperfusion (Group 5). Acadesine was administered at an initial dose of 2.5 mg. kg(-1). min(-1) for 5 min, followed by 0.5 mg. kg(-1). min(-1) until the end of reperfusion. Injury was assessed by histologic examination. The right lower lobe served as control. Compared with the right lower lobe, which showed no abnormal findings in any group (percentage of injured alveoli, 2% +/- 1% to 4% +/- 2%), the left lower lung lobe in the I-R group revealed a disrupted alveolar structure with 63% +/- 9% injured alveoli. Ischemia alone did not produce alterations in alveolar structure. Acadesine significantly reduced the number of injured alveoli when given before ischemia (4% +/- 1%) or reperfusion (6% +/- 2%) but not when administered after reperfusion (62% +/- 8%). In conclusion, acadesine, when administered before ischemia or reperfusion, can blunt I-R-induced lung injury. The mechanism underlying the protection remains to be elucidated. IMPLICATIONS: Acadesine reduces ischemia-reperfusion-induced lung injury in spontaneously breathing cats when administered before ischemia or reperfusion, but not after reperfusion.

Preclinical evaluation of two human anti-hepatitis B virus (HBV) monoclonal antibodies in the HBV-trimera mouse model and in HBV chronic carrier chimpanzees.

Two human monoclonal antibodies (mAbs) against hepatitis B surface antigen (HBsAg) generated in the Trimera mouse system are described. Both mAbs 17.1.41 and 19.79.5 are of the IgG1 isotype and have high affinity constants for HBsAg binding in the range of 10(-10) mol/L. Monoclonal antibody 17.1.41 recognizes a conformational epitope on the a determinant of HBsAg whereas mAb 19.79.5 recognizes a linear one. The 2 mAbs bind to a panel of hepatitis B virus (HBV) subtypes with distinct patterns. The neutralizing activity of these antibodies was tested in 2 different animal model systems. Administration of each mAb to HBV-Trimera mice, a system that provides a mouse model for human hepatitis B infection, reduced the viral load and the percentage of HBV-DNA-positive mice in a dose-dependent manner. These 2 mAbs were more effective than a polyclonal antibody preparation (Hepatect; Biotest Pharma, Dreieich, Germany) in both inhibition of HBV liver infection and reduction of viral load. A single administration of a mixture of these mAbs into HBV chronic carrier chimpanzees resulted in immediate reduction in HBsAg levels followed by recurrence to initial levels within few days. Thus, these mAbs may be potential candidates for preventive therapy or in combination with other antiviral agents against HBV. Further studies in humans are needed to assess these mAbs in various clinical indications.

[Laparoscopic adrenalectomy].

Constant advances and increasing experience in laparoscopic surgery renders it applicable for adrenal surgery. The wide exposure required for open adrenal surgery makes this minimally invasive procedure an attractive and advantageous alternative. Between 1996-1999, we performed 35 laparoscopic adrenalectomies in 30 patients 20-72-years old. Indications included: Conn's syndrome--14, pheochromocytoma--11, Cushing's syndrome--6, nonfunctioning adenoma--3, and metastatic sarcoma--1. 5 underwent bilateral laparoscopic adrenalectomy. In 3 (8.5%) the procedures were converted to open operations. Overall morbidity was 13% and there was no mortality. Mean operative time was 188 minutes, but only 130 in our last 10 cases. Mean hospital stay was 4 days and they returned to normal activity an average of 2 weeks later. According to our study and previous reports, laparoscopic adrenalectomy is feasible and safe and it may soon become the procedure of choice for adrenal tumors.

Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo.

BACKGROUND AND AIM: Research on hepatitis B virus (HBV) infection in vivo has been limited due to the absence of a suitable animal model. We have developed a human-mouse radiation chimera in which normal mice, preconditioned by lethal total body irradiation and radioprotected with SCID mouse bone marrow cells, are permissive for engraftment of human hematopoietic cells and solid tissues. This resulting human-mouse model, which comprises three genetically disparate sources of tissue, is therefore termed Trimera. This study was aimed at assessing the effect of human IL-6 on HBV infection in vivo in Trimera mice. METHODS: Trimera mice were transplanted with human liver tissue fragments or with HepG2-derived cell lines, which had been previously infected ex vivo with HBV in the presence or absence of human interleukin-6 (hIL-6) and in the presence of anti-IL-6-neutralizing antibodies. RESULTS: HBV sequences appeared in the sera of animals in which the liver tissue was incubated with both HBV and hIL-6 prior to transplantation. A similar result was obtained when a human hepatoblastoma cell line (HepG2), expressing the hIL-6 receptor, was infected ex vivo with HBV in the presence of hIL-6 prior to their injection into spleens of Trimera mice. However, when liver fragments were infected ex vivo and simultaneously treated with neutralizing antibodies against hIL-6 or were incubated with HBV prior to transplantation without hIL-6, the rate of mice positive for HBV DNA in their sera was lower. Human mononuclear cells are also permissive for HBV infection in vitro: in the presence of hIL-6 the infection of these cells is enhanced; and this infection is suppressed by the chimeric protein named Hyper-IL-6, generated by the fusion of hIL-6 to the soluble hIL-6 receptor (sIL-6Ralpha, gp80). CONCLUSION: hIL-6 facilitates HBV infection in vitro and in vivo.

Duodenal duplication cyst manifested by duodeno-jejunal intussusception and hyperbilirubinemia.

A rare case of duodenal duplication cyst containing stones in a 17-year-old patient is presented. The cyst, acting as a leading point for duodeno-jejunal intussusception caused proximal small bowel obstruction and hyperbilirubinemia. Preoperative diagnosis was based on abdominal computerized tomography. At operation, the cyst wall was unroofed creating free drainage into the duodenal lumen without damaging the biliary and pancreatic ducts with resolution of symptoms.