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Biomedical subjects

E Shiloni

Publications and source records attributed to E Shiloni.

At least 73 records · Page 4Linked to original sources
PubMed1989

Sequential dacarbazine chemotherapy followed by recombinant interleukin-2 in metastatic melanoma. A pilot multicentre phase I-II study.

Between April 1988 and August 1989, 30 melanoma patients were entered in a multicentre Phase II study of dacarbazine (DTIC) 850 mg/m2 i.v. bolus on day 1, and recombinant interleukin-2 (rIL-2) (Cetus) 18 x 10(6) IU/m2/day i.v. continuous infusion on days 4-9. Six treatment cycles were given: the first two at an interval of 13 days, and further cycles at intervals of 20 days. Twenty patients are currently evaluable for toxicity and 18 for response. Two of these patients presented with metastatic intraocular melanoma. Median age was 48 years (range 18-83), and median Karnofsky index was 100 (range 80-100). Four patients had received prior radiotherapy and one had received prior immunotherapy. Seventeen patients received two cycles of treatment and nine patients received three or more cycles. Four patients responded (22%): two complete remissions and two partial remissions. Stable disease was seen in six patients (33%). Responses occurred in the lung, skin, spleen and lymph nodes. Seventy-five percent of the patients received the full dose of rIL-2 during cycle 1, whilst only 2 out of 9 (22%) received the planned dose on the third cycle. Rebound lymphocytosis of 5.3 x 10(3)/L (range 1.2-18.1) occurred 24-48 h after rIL-2, but was not predictive for response. Currently, there is no evidence that pretreatment with DTIC impacts negatively on the rIL-2-stimulated lymphocyte proliferation. The toxicity profile of this treatment regimen did not differ significantly from that already described for similar regimens of rIL-2. However, in this interim analysis, there was a trend for a higher percentage of patients (25%) to experience severe weight gain (greater than 10%). This study shows that this treatment regimen is active in metastatic melanoma, with acceptable toxicity. Further research will focus on using other chemotherapeutic agents and/or other biological response modifiers (e.g. interferons, tumour necrosis factor) in combination with rIL-2.

Adolescent↗
PubMed1988

Modulation of lipoprotein lipase activity in mouse peritoneal macrophages by recombinant human tumor necrosis factor.

Thioglycollate-elicited mouse peritoneal macrophages spontaneously secrete lipoprotein lipase during culture. Exposure of the cultures to 50 ng/ml of recombinant human tumor necrosis factor (rTNF) for 48 h resulted in a 69% reduction in lipoprotein lipase activity in the culture medium with a concomitant decrease in cellular enzyme activity. The decrease in enzyme activity was not the result of rTNF-dependent reduction in the total protein synthesis, since the presence of rTNF did not affect [3H]leucine incorporation into cellular proteins. The effect of rTNF on lipoprotein lipase was reversible; upon TNF withdrawal, enzyme activity returned to basal levels after 60 h. The reduction of lipoprotein lipase in rTNF-treated cultures could be completely prevented by preincubation with a specific antiserum against recombinant human TNF. The late onset of decrease of lipoprotein lipase (LPL) activity suggests that rTNF might induce a mediator, which in turn suppresses LPL production. While rTNF was very effective in reducing lipoprotein lipase activity in mouse peritoneal macrophages, it did not affect lipoprotein lipase activity when added to the murine J774 cell line and to CT2 macrophage-like cells, a variant of the J774 cell line.

Animals↗
PubMed1988

Lipoprotein lipase in heart cell cultures is suppressed by bacterial lipopolysaccharide: an effect mediated by production of tumor necrosis factor.

Exposure of rat heart cell cultures, consisting mainly of nonbeating mesenchymal cells, to 50 ng/ml of bacterial lipopolysaccharide (LPS) for 24 h resulted in a more than 80% reduction in lipoprotein lipase activity. The loss of enzymic activity was accompanied by a concomitant reduction in enzyme protein, as shown by immunoblotting. Addition of LPS to the culture medium resulted also in the production of tumor necrosis factor (TNF), and the fall in lipoprotein lipase in LPS-treated cultures could be prevented by an antibody to TNF. Addition of recombinant human TNF to the heart cell cultures also depressed lipoprotein lipase activity. LPS treatment of preadipocytes in culture resulted in a fall in lipoprotein lipase activity and TNF production. Since TNF is known as a macrophage product, the cultures were tested for phagocytic capacity, and only 0.2-1.3% of the cells were shown to engulf Staphylococcus albus. Immunofluorescent staining with monoclonal antibodies OX-1, which identify leukocyte common antigen, was negative, and only 0.1 +/- 0.07% of the cells were positive after staining with OX-42 antibody to iC3b receptor. Both antibodies stained more than 98% of rat peritoneal macrophages used as controls. Since LPS treatment of macrophages at numbers comparable to or exceeding the number of phagocytic cells present in the heart cell cultures did not induce measurable amounts of TNF, it is suggested that in the heart cell cultures, TNF may be produced by cells other than macrophages.

Animals↗
PubMed1988

Combined effects of chemotherapy and interleukin 2 in the therapy of mice with advanced pulmonary tumors.

We have evaluated the effects of chemotherapeutic agents on the toxicity and antitumor benefit of therapy of established murine tumors by high-dose interleukin 2 (IL-2). Cyclophosphamide (Cy), doxorubicin, and bischloroethylnitrosourea were given to normal mice prior to IL-2 administration to test the effects of these agents on IL-2-induced toxicity. Cy at doses of 100 mg/kg and 150 mg/kg completely protected mice from a 100% lethal dose of IL-2, and doses of 50 mg/kg and 150 mg/kg allowed the administration of a median of 4.5 and 10.0 more doses of IL-2, respectively, before death from IL-2 toxicity occurred. Doxorubicin at 8 mg/kg and bischloroethylnitrosourea at 20 mg/kg did not impact on toxicity in IL-2-treated mice. In mice bearing pulmonary metastases of the weakly immunogenic MCA-105 sarcoma, IL-2 increased median survival time from 33 (no IL-2) to greater than 60 days for all doses of IL-2 tested when combined with a single injection of Cy at 75 mg/kg (P less than 0.002). Increasing doses of either Cy or IL-2 produced increasing benefits on survival which were always greater than either treatment alone. These effects of Cy and IL-2 were also seen in mice bearing the nonimmunogenic MCA-101 sarcoma and a murine adenocarcinoma (MCA-38). Doxorubicin and bischloroethylnitrosourea did not consistently enhance the effects of IL-2 treatment. Cy appears to reduce the yield of in vivo generated lymphokine-activated killer cells, but these lymphokine-activated killer cells are still lytic for fresh tumor targets in vitro. Thus, the mechanism of this synergy does not appear to involve stimulation of lymphokine-activated killer cell activity, but may in part involve reduction of tumor burden by the chemotherapeutic agent, an increase in susceptibility of tumor to cellular immune lysis, and/or a decrease in suppressor cell activity mediated by the chemotherapy.

Animals↗
PubMed1988

Antitumor effect of recombinant tumor necrosis factor-alpha against murine sarcomas at visceral sites: tumor size influences the response to therapy.

We examined the antitumor efficacy of rTNF-alpha administration on established tumor at two visceral sites, lungs and liver. Treatment of B6 mice harboring multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) 10-day pulmonary macrometastases from the MCA-106 sarcoma, with dosages of rTNF-alpha (5-10 micrograms, single dose i.v.) that caused hemorrhagic necrosis and regression of a 6 mm MCA-106 s.c. tumor, had no impact on the number (or size) of lung nodules. Similarly, rTNF-alpha failed to show an antitumor effect in B6 mice with advanced day 8 or 10 multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) hepatic metastases at single i.v. doses up to 20 micrograms, as measured by either enumeration of residual liver nodules or survival. B6 mice injected s.c. with MCA-106 sarcoma and treated with rTNF-alpha as a single i.v. dose on day 0, 3, 5, or 7 experienced marked tumor regression only after the day 7 rTNF-alpha injection, when the tumor had achieved a size of 5-6 mm in diameter. Since tumor size appeared important for rTNF-alpha susceptibility in vivo, we next induced a single hepatic tumor of the MCA-106 sarcoma by the direct injection of cells into the left lobe of the liver and treated these mice at day 10 when the nodule had achieved a size of 5-6 mm in diameter. Increasing doses of rTNF-alpha (up to 8 micrograms) given as a single i.v. injection resulted in increasingly greater reductions in hepatic tumor as well as significant survival benefit of the treated mice. Sites of regressing hepatic tumor exhibited central necrosis accompanied by polymorphonuclear leukocytes and lymphocytes. Collectively, these results show that rTNF-alpha administration can mediate a significant antitumor effect on visceral tumor and suggest that tumor size is an important factor in rTNF-alpha susceptibility not only for tumors growing at s.c. sites but also for those established at visceral sites.

Animals↗
PubMed1988

Intra-abdominal extrahepatic disease in patients with colorectal hepatic metastases.

The resection of hepatic metastases in patients with extrahepatic disease is of no proven benefit. Preoperative identification of extrahepatic disease may prevent unnecessary laparotomy. Preoperative evaluation including physical examination, computed tomography of the abdomen, full lung tomography or chest-computed tomography, and radionuclide bone scanning identified extrahepatic metastases, most commonly in the lung, in 25 of 132 patients with purported isolated liver metastases. Of 107 patients with negative staging evaluations, intra-abdominal extrahepatic metastases were found in 26 percent (28 of 107) at laparotomy, most commonly in portal and celiac lymph nodes. The presence of extrahepatic disease correlated with greater than 25 percent hepatic replacement by tumor, presence of symptoms, and Dukes' C primary lesions; however, none was predictive. We were unable to develop a model to preoperatively predict the presence of intra-abdominal extrahepatic disease. The authors recommend a preoperative evaluation including physical examination, and computed tomographic scans of the abdomen and chest. A bone scan is required only in patients with symptoms referable to bone. Despite a negative preoperative evaluation, however, a considerable proportion of patients with colorectal hepatic metastases will have extrahepatic disease at the time of abdominal exploration.

Abdominal Neoplasms↗
PubMed1988

Characterization of IL-2-induced murine cells which exhibit ADCC activity.

The incubation of murine splenocytes in recombinant interleukin 2 (IL-2) gives rise to both lymphokine-activated killer (LAK) cells capable of lysing fresh tumor cells and cells capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in the presence of anti-H2 allosera. A similarity between these two IL-2-induced cell populations was found. The precursors of the cells mediating these activities were shown to be ASGM1 positive, Thy 1 negative, and radiosensitive. Cells taken from the spleen, thymus, and bone marrow were able to mediate ADCC after culture in IL-2. The effector cell was either Thy 1 positive or negative and was less affected by anti-Thy 1 plus C' treatment than cells which mediated LAK activity. In addition ADCC was exhibited in IL-2-cultured splenocytes from various murine strains and correlated with their LAK activity with one exception. While IL-2-cultured C57BL/6 splenocytes exhibited LAK activity similar to that of C3H LAK cells, no ADCC activity could be demonstrated in C57BL/6 cells. Study of the difference in the ability of these two strains to mediate ADCC revealed that IL-2-induced FcR+ cells in C3H thymocytes, but not in C57BL/6 thymocytes. Based on FACS analysis and on the radiosensitivity of the induction of both FcR+ cells and ADCC, it was suggested that IL-2 was expanding a small FcR+ cell population rather than inducing an increase in FcR density on the cell surface. The relationship between the IL-2-induced ADCC mediator and other IL-2-induced cells, as well as ADCC effector cells, and the possible implications of the results for the in vivo therapy of cancer based on ADCC are discussed.

Animals↗
PubMed1987

Antibody-dependent cellular cytotoxicity mediated by murine lymphocytes activated in recombinant interleukin 2.

The incubation of murine splenocytes in recombinant interleukin 2 (RIL 2) gives rise to lymphokine-activated killer (LAK) cells that can lyse fresh, NK-resistant tumor cells but not normal cells in 4-hr 51Cr-release assays. Lysis by this IL 2-activated cell population was enhanced up to 100-fold by prior reaction of target cells with specific antisera reactive with antigens on the target cells. This antibody-dependent cellular cytotoxicity (ADCC) also resulted in lysis of fresh normal target cells, which are not usually susceptible to LAK lysis. The ADCC was evident after 24 hr of incubation of splenocytes in RIL 2, but peak lytic activity was reached after 3 to 4 days of incubation. The concentrations of RIL 2 needed for the in vitro activation of the effectors in order to attain maximal ADCC was between 100 and 3000 U/ml and parallel the IL 2 concentrations required to generate LAK cells. ADCC mediated by IL 2-activated splenocytes was completely blocked by anti-FcR monoclonal antibodies. Although antisera directed against MHC antigens were used in most experiments, anti-B16 monoclonal antibodies have also shown the ability to induce ADCC mediated by RIL 2-activated syngeneic and allogeneic cells. Treatment of the precursor splenocyte populations with anti-asialo GM1 and complement eliminated the direct LAK activity and the antibody-dependent cytotoxicity, suggesting that both direct and indirect tumor cell lysis may be caused by the same effector cell. ADCC mediated by LAK cell populations represents another possible mechanism for the in vivo therapeutic effects of these cells.

Animals↗
PubMed1987

Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo.

The anti-tumor activity of recombinant human tumor necrosis factor (rHTNF) was examined against four newly induced murine sarcomas (MCA-101, -102, -105, and -106) and a murine adenocarcinoma (MCA-38) transplanted s.c. into C57BL/6 mice. The serum half-life after a single i.v. injection of rHTNF was determined to be 30 +/- 2 min. Tumor-bearing mice were more susceptible to the toxic side effects of rHTNF than were normal mice. Forty-eight percent (41/86) of tumor bearing animals that received 10 micrograms rHTNF died within 48 hr after treatment compared with no deaths in 28 normal animals receiving this dose. Treatment of mice bearing either the MCA-101, -102, -105, or -106 sarcoma or the MCA-38 adenocarcinoma with rHTNF resulted in a marked necrosis of the central portion of each tumor within 24 hr. Animals bearing the weakly immunogenic tumors MCA-105, -106, and -38 experienced a reduction in average tumor area of 47% +/- 5, 46% +/- 6, and 37% +/- 11, respectively, by 3 to 4 days after treatment with rHTNF compared with pre-treatment values (p less than 0.001); increases of 79% +/- 11, 74% +/- 10, and 41% +/- 6 were seen in excipient-treated control animals over the same period. In contrast, animals bearing the non-immunogenic tumors MCA-101 and -102 experienced little if any decrease in tumor area at the doses of rHTNF used. rHTNF failed to mediate cures in animals bearing MCA-38, -101, or -102. In contrast, 67 and 28% of animals bearing MCA-105 and -106, respectively, which received 6 to 10 micrograms rHTNF were cured. Likewise, animals bearing MCA-105 and -106 sarcomas treated with 6 to 10 micrograms rHTNF had significantly increased survival compared with excipient-treated control animals. In contrast, no significant difference in mean survival was observed between excipient and rHTNF treated animals bearing MCA-38, -101, or -102. Histologically, the necrotic response of immunogenic MCA-106 and non-immunogenic MCA-102 tumors to systemically administered rHTNF was very similar. These two tumors differed morphologically, however, by the greater degree of chronic inflammation that was present at the periphery of the MCA-106 tumor in comparison with the MCA-102. By 72 hr after rHTNF administration, the sites of regressed MCA-106 tumors were replaced by a heterogeneous population of inflammatory cells and tumor cell "ghosts".(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1986

Total colonic necrosis. A catastrophic complication of systemic lupus erythematosus.

Diffuse ischemic colitis leading to colonic necrosis is a rare complication of systemic lupus erythematosus. A 16-year-old girl who developed such a complication and underwent emergency subtotal colectomy is described. The incidence and significance of intestinal symptoms and the difficulties in the differential diagnosis in patients with systemic lupus erythematosus presenting with abdominal manifestations are discussed.

Adolescent↗
PubMed1986

Paracecal hernia: a cause of intestinal obstruction.

During a two-year period, five patients were treated by us for acute intestinal obstruction caused by an incarcerated paracecal hernia. All patients underwent surgery early, so none required bowel resection. The possibility of an internal hernia as a cause of intestinal obstruction and a profound knowledge of the pericecal anatomy, however, are necessary for successful diagnosis and treatment of paracecal hernias.

Adult↗
PubMed1986

Effect of immunotherapy with allogeneic lymphokine-activated killer cells and recombinant interleukin 2 on established pulmonary and hepatic metastases in mice.

The adoptive transfer of lymphokine-activated killer (LAK) cells in conjunction with the systemic administration of recombinant interleukin 2 (RIL-2) results in the regression of established pulmonary and hepatic micrometastases from a variety of immunogenic and nonimmunogenic murine tumors in syngeneic C57BL/6 mice. Recent studies have shown that this therapeutic approach can mediate the regression of cancer in humans as well. Because of the practical difficulties in obtaining syngeneic or autologous LAK cells for the therapy of cancer in humans we have now evaluated the antitumor efficacy of allogeneic LAK cells generated from different strains of mice. The in vitro lysis of fresh tumor targets by LAK cells is not a major histocompatibility complex-restricted phenomenon since LAK cells of BALB/c-H-2d, DBA/2-H-2d, and C3H-H-2k origin all exhibited lytic activity when tested against allogeneic MCA-102-H-2b tumor cells in short term 51Cr release assays. In vivo, the i.v. transfer of allogeneic LAK cells combined with i.p. injections of RIL-2 reduced the number of established pulmonary metastases induced by either MCA-105 or MCA-101 tumors which are syngeneic to C57BL/6 hosts. The extent of reduction of these pulmonary metastases by the allogeneic LAK cells was directly dependent upon the dose of RIL-2 given; increasing doses of systemically administered RIL-2 resulted in increasingly greater reduction in the numbers of established 3-day pulmonary sarcoma metastases. In dose titration experiments, adoptive transfer of at least 2 doses of 10(8) allogeneic LAK cells was necessary to achieve significant antitumor effect in vivo. Allogeneic LAK cells were also successful in mediating significant regression of hepatic micrometastases. Again, the i.v. transfer of allogeneic LAK cells had a smaller therapeutic benefit compared to i.v. transfer of syngeneic LAK cells. When allogeneic LAK cells were injected intraportally, however, they were as effective as syngeneic LAK cells. Allogeneic LAK cells had little, if any, therapeutic effect on established pulmonary and hepatic metastases when administered to recipients previously immunized to the histocompatibility antigens on the donor cells. Taken together, our results indicate that allogeneic LAK cells from several strains of mice are effective in lysing fresh MCA-102 tumor in vitro and that when given i.v. in sufficient numbers, in conjunction with RIL-2, they can mediate significant reduction in the number of established pulmonary and hepatic micrometastases in nonalloimmunized C57BL/6 mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.

We describe here the preliminary results of the systemic administration of autologous lymphokine-activated killer (LAK) cells and the recombinant-derived lymphokine interleukin-2 to patients with advanced cancer. This regimen was based on animal models in which the systemic administration of LAK cells plus interleukin-2 mediated the regression of established pulmonary and hepatic metastases from a variety of murine tumors in several strains of mice. We treated 25 patients with metastatic cancer in whom standard therapy had failed. Patients received both 1.8 to 18.4 X 10(10) autologous LAK cells, generated from lymphocytes obtained through multiple leukaphereses, and up to 90 doses of interleukin-2. Objective regression of cancer (more than 50 per cent of volume) was observed in 11 of the 25 patients: complete tumor regression occurred in one patient with metastatic melanoma and has been sustained for up to 10 months after therapy, and partial responses occurred in nine patients with pulmonary or hepatic metastases from melanoma, colon cancer, or renal-cell cancer and in one patient with a primary unresectable lung adenocarcinoma. Severe fluid retention was the major side effect of therapy, although all side effects resolved after interleukin-2 administration was stopped. Further development of this approach and additional patient follow-up are required before conclusions about its therapeutic value can be drawn.

Adult↗
PubMed1984

Oral cholecystosonography: a method for facilitating the diagnosis of cholesterol gallstones.

During the past two years, floating stones within the gallbladder have been demonstrated in five patients, by both oral cholecystography and sonography. We suggest coupling administration of an oral cholecystographic contrast agent with ultrasound examination in cases of equivocal sonographic findings. The combined study--oral cholecystosonography--can facilitate the demonstration of small cholesterol stones by inducing the phenomenon of layering.

Cholecystography↗
PubMed1983

The role of splenectomy in Gaucher's disease.

Thirteen patients underwent splenectomy for Gaucher's disease. All patients were Jewish; 12, of Ashkenazi descent, had the chronic (type 1) form, and one child, of Sephardic (Persian) origin, probably had the intermediate (type 3) form. Hypersplenism was the indication for surgery in 11 patients, mechanical problems in the remaining two. The weight of the resected spleens ranged from 1.06 to 13 kg. Following surgery, hypersplenism (thrombocytopenia in particular) was improved, and the mechanical disturbances were relieved in all patients. There were no deaths and no morbidity related to the operative procedure. Long-term follow-up demonstrated progressive hepatomegaly without evidence of hepatic dysfunction in any of the patients. Bone marrow involvement manifested by osteoarticular complications appeared in five patients. Splenectomy is, we believe, a safe mode of treatment for type 1 Gaucher's disease.

Adolescent↗