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Biomedical subjects

D Aderka

Publications and source records attributed to D Aderka.

At least 19 recordsLinked to original sources

PET/CT in the evaluation of response to treatment of liver metastases from colorectal cancer with bevacizumab and irinotecan.

The present approach at our institution for the treatment of patients with colorectal (CRC) cancer and with liver metastases planned for metastasectomy is the neoadjuvant administration of Bevacizumab with Irinotecan based therapy. Metabolic imaging of tumor viability with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and simultaneous anatomic localization provided by low-dose non-enhanced computed tomography (CT), can be obtained in a combined modality FDG-PET/CT scan. The purpose of this study was to evaluate the possible contribution of FDG-PET/CT as a surrogate marker to evaluate treatment response of liver metastases in vivo. This is a retrospective evaluation of 18F-FDG PET and CT findings in the first seven consecutive patients. FDG-PET/CT scans were performed before the start of the neoadjuvant and after four cycles of therapy, just prior to surgery. Results were compared to concurrent contrast-enhanced CT, when required, and pathology. Response to treatment was determined according to RECIST size criteria obtained from data from thin (3-5mm) slice CT, and changes in uptake of 18F-FDG uptake on PET. A total of 20 liver lesions were evaluated in seven patients. Overall, 6/7 patients had favorable response to treatment, and only one had progression of disease. One patient was found to be inoperable at surgery. Biopsy was obtained in 1/4 lesions in this patient, while pathology was unable for the remaining three lesions. As such, pathologic validation of findings was available for 17/20 lesions. Complete response (CR) was evident on FDG-PET in 10/17 (58%) lesions, whereas only 4/17(23%) were deemed CR by CT. Similarly, only 1/17 (6%) lesion appeared stable by FDG-PET criteria, whereas three (18%) were termed stable disease (SD) according to size on CT. FDG-PET findings correlated better than CT with pathology, and were more indicative of pathology. Overall PET/CT correctly predicted necrosis at pathology in 70% vs. 35% by CT. Our results suggest that 18F-FDG PET may be instrumental for predicting the pathologic response to Bevacizumab based therapy.

Adult↗

PET/CT detects abdominal wall and port site metastases of colorectal carcinoma.

Abdominal wall metastases from colorectal cancer (CRC) may be resected with curative results. Such lesions, often indicators of additional intra-abdominal lesions, may appear in surgical scars, stomas and port site metastases after laparoscope-assisted surgery (LAS). Post-operative changes, primarily surgical scars, alter local physical findings making early detection of small lesions challenging. The purpose of this study was to retrospectively evaluate the contribution of PET/CT to the diagnosis of recurrent colorectal cancer in the post-operative abdominal wall. 120 patients were referred for PET/CT with suspected recurrent CRC based on clinical, radiological or laboratory findings. All underwent whole body PET/CT imaging. 12 of these 120 (10%), were found to have abdominal wall lesions. A total of 16 abdominal wall lesions were detected, located to surgical scars, stomas, drain and laparoscope ports. Additional findings on PET/CT in this group included liver metastases, intra-abdominal lesions and retroperitoneal lymph node involvement. In general, the patients in this small group were young with high grade tumours presenting in advanced stages. In conclusion, PET/CT appears to be a sensitive tool for the diagnosis of abdominal wall recurrence of CRC. The accuracy of localization afforded by the fused functional and anatomic images makes PET/CT a likely tool for diagnosing abdominal wall lesions, including port site metastases of other aetiologies.

Abdominal Wall↗

Primary papillary serous carcinoma of the peritoneum in a man.

BACKGROUND: Primary papillary serous carcinoma of the peritoneum is a well-known entity in women. The tumour is derived from the extraovarian mesothelium and the pelvis and lower abdomen mesothelia. The treatment strategies are similar to ovarian serous papillary carcinoma. PATIENTS AND METHODS: A case of primary serous papillary carcinoma of the peritoneum in a man is presented. The patient, 53 years old, died 2 months after diagnosis. RESULTS: The histologic and immunohistochemical studies of the tumour will be presented. These studies, made during lifetime and at autopsy of the patient, confirm a diagnosis of primary serous papillary carcinoma of the peritoneum. CONCLUSIONS: primary serous papillary carcinoma of the peritoneum can occur in men, and should be considered in the differential diagnosis in cases of abdominal carcinomatosis of unknown origin. Treatment options remain to be determined.

Antigens, Neoplasm↗

Tumour necrosis factor mediates bacterial translocation after haemorrhagic shock and endotoxaemia.

OBJECTIVE: To assess the extent of bacterial translocation after haemorrhagic shock and reperfusion, and the involvement of tumour necrosis factor (TNF) in its mediation. DESIGN: Controlled, randomised prospective experiment. SUBJECTS: 87 rats in 7 groups. INTERVENTIONS: Haemorrhagic shock was induced in rats for 1 hour. Endotoxaemia was induced in a second group by the injection of lipopolysaccharide. A third group was injected with exogenous TNF. Some of the animals were further treated with anti-TNF. MEASUREMENTS: After 24 hours, bacterial translocation in blood and in several remote organs, and serum TNF concentrations were measured. RESULTS: High bacterial counts were found in all remote organs of rats with haemorrhagic shock or endotoxaemia. Their serum TNF concentrations were significantly higher than in the corresponding sham-operated controls. Anti-TNF significantly reduced the extent of bacterial translocation. Rats, the only treatment of which was exogenous TNF, developed substantial bacterial translocation. CONCLUSION: Bacterial translocation is associated with increased serum TNF, and can be minimised by anti-TNF. This, and the triggering of translocation in unprovoked animals by TNF alone, suggest that TNF may be the stimulator, and not the consequence, of bacterial translocation.

Animals↗

Shedding kinetics of soluble tumor necrosis factor (TNF) receptors after systemic TNF leaking during isolated limb perfusion. Relevance to the pathophysiology of septic shock.

We examined the kinetics of shedding of the soluble TNF receptors (TNF-Rs) in response to TNF leakage during isolated limb perfusion procedures and correlated them to the resulting hemodynamic effects. Shedding of the TNF-Rs started 7 min after TNF leakage into the systemic circulation. Three waves of shedding were observed peaking at 1, 8-12, and 48-72 h both in vivo and in cell cultures. The soluble receptors prolonged the half-life of TNF in the systemic circulation to 2.5-6 h. Excess shedding of the p75 compared with p55 TNF-Rs was noted during the first wave. The amount and speed of shedding of the p75 TNF-Rs were proportional to the serum TNF levels (P < 0.001). A maximal shedding capacity was attained only during the first wave of shedding, at TNF concentrations of approximately 1.5 ng/ml. Above this level, the linearity between TNF and its soluble receptors was lost. TNF-induced hypotension coincided with the initial imbalance between the concentrations of TNF and its soluble receptors. Despite the spontaneous correction of this imbalance at 8-12 h, the hemodynamic and biochemical alterations persisted and were further aggravated at 18 h, suggesting that other factors induced earlier by TNF are responsible for the perpetuation of the hemodynamic instability. This study may provide the basis for a more physiological therapeutic approach to TNF neutralization in septic shock patients.

Adult↗

Soluble tumor necrosis factor receptors and interleukin-6 levels in patients with severe preeclampsia.

OBJECTIVE: To investigate whether serum and amniotic fluid (AF) levels of soluble tumor necrosis factor receptors and interleukin-6, markers of immune activation and endothelial dysfunction, are altered in patients with severe preeclampsia. METHODS: Plasma was collected before induction of labor, at delivery, and postpartum from 19 patients with severe preeclampsia. Amniotic fluid was also obtained in early labor from these patients. Similar samples were obtained from an antepartum control group matched for gestational age and a term control group without preeclampsia. All plasma and AF samples were assayed for p55 and p75 soluble tumor necrosis factor receptors and for interleukin-6 by specific enzyme-linked immunoassays. Levels in preeclamptic patients and the control groups were compared. RESULTS: Levels of both receptors were significantly elevated in AF and all maternal plasma samples except those collected 24 hours postpartum for patients with preeclampsia relative to levels in controls. Interleukin-6 was detected more frequently and in higher concentrations in the plasma collected before labor for preeclamptic patients compared with controls, but no difference was noted in interleukin-6 detection rates or plasma concentrations at delivery. Conversely, AF concentrations of interleukin-6 were significantly reduced in patients with preeclampsia. CONCLUSION: The increased levels of soluble tumor necrosis factor receptors found in patients with severe preeclampsia may represent a protective response to increased tumor necrosis factor activity and be a marker for immune activation. Increased interleukin-6 concentrations in maternal plasma before labor suggest the involvement of this cytokine as well in the altered immune response and its contribution to endothelial cell dysfunction.

Adult↗

The potential biological and clinical significance of the soluble tumor necrosis factor receptors.

The role of TNF receptors (TNF-Rs) is not limited to signal transduction but includes extracellular regulatory functions affecting systemic TNF bioavailability. This review summarizes the regulation of TNF-R shedding and its kinetics, the complex interaction between the soluble receptors and their ligand in vitro and in vivo, and the potential diagnostic, prognostic and therapeutic value of the soluble receptors in malignant, inflammatory, infectious and autoimmune disorders.

Animals↗

High levels of soluble p55-TNF receptors in seminal and prostatic fluids of normal and infertile men.

PURPOSE: To study the role of tumor necrosis factor (TNF) in the male reproductive systems by examining the occurrence, source, and possible functional significance of soluble TNF receptors in seminal fluids of normal and infertile men. MATERIALS AND METHODS: Concentrations of soluble TNF receptors (p55-sTNF-R and p75-sTNF-R) were measured by ELISA in human sera, seminal fluids, prostatic fluid and fluid obtained from an epididymal spermatocele. RESULTS: The level of p55-sTNF-R in seminal fluids of normospermic men was approximately equal to 20-fold higher than in normal serum (13.9 +/- 6.9 ng./ml. versus 0.7 +/- 0.2 ng./ml.). In contrast, p75-sTNF-R, which occurs in serum at amounts higher than p55-sTNF-R, was almost indiscernible in the seminal fluids (<0.18 +/- 0.28 ng./ml. versus 1.9 +/- 0.6 ng./ml. in sera). Concentrations of p55-sTNF-R in seminal fluids of oligoasthenospermic and azoospermic men were similar to those of normospermic men (15.6 +/- 8.5 ng./ml. and 14.9 +/- 6.5 ng./ml., respectively). Higher p55-sTNF-R concentrations were found in prostatic fluids and first split ejaculates (39.8 +/- 1.2 ng./ml. and 32 +/- 1.7 ng./ml., respectively), while second split ejaculates and the fluid from an epididymal spermatocele were found to contain p55-sTNF-R at lower levels (10.8 +/- 1 ng./ml. and 1 ng./ml., respectively). CONCLUSIONS: These findings suggest intense local biosynthesis of p55-sTNF-R in the prostate occurring independently of spermatogenesis. Possible functional implications are: 1) shielding of spermatozoa from the inhibitory effect of TNF in the female reproductive tract; 2) a role for TNF in the normal physiology of the prostate; and 3) blocking TNF-mediated immune response in the prostate, which may have bearings on the development of prostatic hypertrophy or cancer.

Antigens, CD↗

Systemic leakage and side effects of tumor necrosis factor alpha administered via isolated limb perfusion can be manipulated by flow rate adjustment.

BACKGROUND: The tolerated systemic dose of recombinant tumor necrosis factor alpha (rTNF-alpha) is very limited, since its administration leads to a severe septic shock-like condition. Its implementation in isolated limb perfusion (ILP) for metastatic melanoma or advanced soft-tissue sarcoma confined to the limb facilitates doses of rTNF-alpha 10 times higher than the systemic tolerated dose. However, with the traditional high flow rate used in ILP, systemic leakage and side effects are not eliminated. OBJECTIVE: To determine if a lower perfusion flow rate would reduce leakage and consequently toxic effects. METHODS: Isolated limb perfusion was performed for melanoma and soft-tissue sarcoma confined to the limb using a flow rate of 869 +/- 122 mL/min in nine patients (group 1) and a lower rate of 286 +/- 62 mL/min in six patients (group 2). RESULTS: The systemic leakage rate was 12.5% +/- 2.9% in group 1, compared with 2.3% +/- 1.0% in group 2 (P = .003). Peak TNF-alpha levels were 29,000 +/- 2700 pg/mL in group 1, higher than 1580 +/- 1355 pg/mL in group 2 (P = .02). The tachycardia, hypotension, increased cardiac output, decreased systemic vascular resistance, bilirubinemia, elevation of liver enzyme levels, hypocholestrolemia, thrombocytopenia, and prolongation of prothrombin and partial thromboplastin times all observed in group 1 were significantly attenuated or eliminated in group 2. The limb PO2, PCO2, pH, and viability remained similar in both groups. Also, the tumor response rate remained high and was unaffected by the decrease in flow rate. CONCLUSIONS: Decreasing perfusion flow rate during ILP results in diminished leakage of TNF-alpha. Consequently, the systemic hemodynamic, metabolic, and hematologic toxic effects are virtually abolished.

Adolescent↗

Soluble tumor necrosis factor receptors in maternal plasma and second-trimester amniotic fluid.

OBJECTIVES: We assessed maternal plasma and second-trimester amniotic fluid for levels of the p55 and p75 soluble tumor necrosis factor receptors. STUDY DESIGN: Blood was drawn from 61 healthy pregnant women (group A) before second-trimester genetic amniocentesis, and an aliquot of amniotic fluid was also obtained for this study. An additional blood sample was obtained from 13 of these patients at 36 to 40 weeks' gestation. Twenty-three healthy, nonpregnant women of reproductive age donated blood as a control group (group B). All plasma and amniotic fluid specimens were collectively assayed for the p55 and p75 soluble tumor necrosis factor receptors by specific enzyme-linked immunoassays. Additionally, tumor necrosis factor-alpha concentrations were measured in second-trimester plasma and amniotic fluid of 22 patients in group A and in all 23 of the nonpregnant women. RESULTS: The p55 and p75 soluble tumor necrosis factor receptors were detectable in all plasma samples from both groups of patients. The concentrations of both soluble receptors were significantly higher in second-trimester plasma compared with nonpregnant measurements (p < 0.01), and the plasma concentrations of both soluble receptors increased significantly from the second to third trimester (p < 0.01). The p55 and p75 soluble tumor necrosis factor receptors were also detectable in all amniotic fluid samples. Tumor necrosis factor-alpha was detected in the plasma of 15 of 22 patients in the second trimester but in none of the amniotic fluid samples and in none of the plasma samples from the nonpregnant cohort. CONCLUSIONS: Both the p55 and p75 soluble tumor necrosis factor receptors are physiologic constituents of second-trimester maternal plasma and amniotic fluid. Concentrations are elevated in pregnancy and further increase from the second to third trimester.

Adult↗

Soluble tumor necrosis factor receptors and soluble interleukin-6 receptor in fetal and maternal sera, coelomic and amniotic fluids in normal and pre-eclamptic pregnancies.

The aim of this study was (a) to measure soluble tumor necrosis factor receptors (sTNF-Rs) and soluble interleukin-6 receptor (sIL-6-R) in coelomic and amniotic fluids, cord and maternal sera in pregnancy and labor, (b) to examine whether the changes in concentrations of biologically active TNF and IL-6 are related to changes in their soluble receptors, and (c) to determine if levels of soluble receptors in pre-eclamptic disorders differ from normal pregnancies at delivery. Materials collected from 206 women during pregnancy and at delivery were analyzed for soluble receptors by enzyme-linked immunosorbent assay (ELISA). All receptors were present in higher concentrations in coelomic than in the corresponding amniotic fluid. Concentrations increased in amniotic fluid from first to second trimester. The level of sIL-6-R then remained unchanged to term, but there was a decrease in the sTNF-Rs which might account for the simultaneous appearance of bioactive TNF. Labor did not affect the concentration of any receptor in amniotic fluid. In maternal serum, sTNF-Rs increased with gestational age and labor in parallel with IL-6. The origin and physiological importance of these soluble receptors are still unknown. In pre-eclamptic disorders p55 sTNF-R was elevated in maternal serum before initiation of labor compared to normal pregnancy.

Adolescent↗

Relation between uroporphyrin excretion, acute attacks of hereditary coproporphyria and successful treatment with haem arginate.

1. The increased urinary excretion of porphyrins as well as of their precursors was studied in a patient with hereditary coproporphyria during two acute attacks in which symptoms differed markedly in character and severity. 2. The increase in urinary coproporphyrin was similar in the 'mild' and in the 'severe' attack, indicating a lack of correlation between coproporphyrin level and clinical symptoms. 3. Aminolaevulinic acid, porphobilinogen and uroporphyrin exhibited significantly higher values during the 'severe' attack than during the 'mild' attack. During the severe attack these three compounds were increased 18-, 14- and 46-fold, respectively, compared with increases of 3-, 3- and 8-fold, respectively, during the mild attack. 4. The striking rise in the formation of uroporphyrin was reflected in the plasma porphyrin profile, which revealed predominance of uroporphyrin. In accordance with this finding, an increase in erythrocyte porphobilinogen deaminase of 130% was recorded. 5. The fluorescence emission spectra of saline-diluted plasma (excitation of 405 nm) showed a distinct peak at 618 nm during the 'severe' episode and a small peak during the 'mild' attack, pointing to the possibility of diagnosing an attack simply by following the fluorometric screen of plasma. 6. The 'severe' attack of coproporphyria was treated with daily infusions of haem arginate, 3 mg/kg, every day for 4 days, at the end of which period a dramatic clinical response was observed. The relief of symptoms was found to be clearly related to the moderate decrease in uroporphyrin excretion observed rather than to the steep decline in the precursors.

Acute Disease↗

Soluble TNF receptor production by activated T lymphocytes: differential effects of acute and chronic exposure to TNF.

Soluble tumour necrosis factor receptors (sTNF-R) are up-regulated at sites of chronic inflammation such as rheumatoid synovial joints. The p75 sTNF-R is the more abundant, suggesting an important role for this TNF inhibitor in regulating TNF bioactivity in vivo. As the precise cellular source of these soluble receptors is not known, we investigated the production and regulation of sTNF-R by T lymphocytes, an abundant cell type in inflammatory infiltrates, which upon activation express high levels of p75 surface receptors. Using panels of T-cell lines and clones expressing high levels of p75 TNF-R, we found that p75 sTNF-R production upon stimulation is a feature common to all subsets of T cells, including cells of the CD4-CD8- double negative phenotype expressing either alpha beta or gamma delta T-cell receptors (TCR). In contrast, levels of p55 sTNF-R were only detected when T cells were stimulated at higher densities and by potent mitogens such as phorbol 12-myristate 13-acetate (PMA). Detailed kinetic analyses revealed that the production of p75 sTNF-R was biphasic, the first phase was activation dependent, occurring in the absence of detectable TNF, while the second phase of p75 sTNF-R production was regulated by cytokines such as TNF. Unlike short-term exposure to TNF which enhances sTNF-R production in vitro and in vivo, prolonged exposure of T lymphocytes to TNF suppressed p75 sTNF-R (but not p55 sTNF-R) production in a dose- and time-dependent fashion. These results suggest that in patients with chronic inflammatory disease, which are exposed to augmented levels of bioactive TNF for prolonged periods, the production of p75 sTNF-R may be impaired.

Clone Cells↗

Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions.

Lesions of the common inflammatory skin disease psoriasis are characterized by epidermal hyperproliferation, leucocyte adhesion molecule expression and leucocyte infiltration. The local release of proinflammatory cytokines, such as TNF-alpha, may play an important role in the induction of these events. We have, therefore, analysed aqueous extracts of lesional and uninvolved (clinically normal) stratum corneum for the presence of TNF-alpha immunoreactivity and biological activity. TNF-alpha immunoreactivity and bioactivity were consistently higher in lesional compared with uninvolved samples. By using an anti-TNF-alpha neutralizing antibody it was demonstrated that the biological activity measured was due to the presence of TNF-alpha alone. Concentrations of soluble TNF receptors (p55 and p75) were also higher in lesional stratum corneum extracts, with the p55 form predominating. The plasma of psoriatic patients was also found to contain elevated concentrations of soluble p55 compared with normal controls. These results confirm the presence of immunoreactive TNF-alpha and, for the first time, conclusively demonstrate TNF-alpha biological activity and quantifiable concentrations of soluble TNF receptors (p55 and p75) in lesional psoriatic samples. TNF-alpha recovery from stratum corneum probably reflects synthesis in deeper, viable layers, where it is likely to exert its biological effects. Local and systemic release of soluble TNF receptors, in particular p55, may serve to regulate the effects of TNF-alpha in psoriasis.

Adult↗

Interleukin-6 inhibits the proliferation of B-chronic lymphocytic leukemia cells that is induced by tumor necrosis factor-alpha or -beta.

Tumor necrosis factor (TNF-alpha) acts as a growth stimulatory factor on leukemic B lymphocytes from many patients with chronic lymphocytic leukemia (CLL). Because TNF induces production of interleukin-6 (IL-6), which has been shown to be a growth factor for myeloma and other transformed B cells, we examined the possibility that IL-6 mediates the growth-stimulatory effect of TNF on B-CLL cells. In fact, we found that IL-6 is an inhibitor of B-CLL growth. The addition of recombinant human IL-6 markedly decreased the TNF-induced B-CLL growth, and this decrease was even greater when soluble IL-6 receptor, known to act as IL-6 agonist, was added with recombinant IL-6. Conversely, neutralizing monoclonal antibodies to IL-6 and to the IL-6 receptor potentiated the growth stimulation of TNF on B-CLL cells, in line with the possibility that IL-6 functions as a negative feedback regulator of an autocrine TNF action on these B-leukemic cells. Evidence is presented that production of IL-6 by monocytes and B cells of CLL patients is low, suggesting that administration of IL-6 may be beneficial in CLL to reduce the eventual growth stimulation by TNF and, possibly, also the deficiency in platelets and Ig production in this disease.

Animals↗

Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus.

OBJECTIVE: To determine the value of measurement of serum soluble tumor necrosis factor receptor (sTNFR), compared with established parameters such as anti-double-stranded DNA, in monitoring systemic lupus erythematosus (SLE) disease activity, and to determine whether serum sTNFR are bioactive and can effectively inhibit TNF bioactivity. METHODS: Fifty-three consecutive ambulatory or hospitalized SLE patients and 140 consecutive healthy subjects were enrolled in a prospective cohort study. Serum levels of sTNFR were measured by a unique 2-sided capture enzyme-linked immunosorbent assay using mouse monoclonal antibodies and rabbit antisera against the sTNFR. RESULTS: The mean +/- SD concentrations of both the p55 (type I) and p75 (type II) soluble receptors were significantly higher in a group of 46 SLE patients than in controls: 1.89 +/- 0.89 ng/ml versus 0.77 +/- 0.19 ng/ml and 7.25 +/- 3.89 ng/ml versus 3.02 +/- 0.57 ng/ml, respectively (P < 0.0001 for both). The incidence and the extent of the increase among the healthy subjects and these patients (as well as in 7 additional patients on whom sequential studies were performed) correlated with disease activity more than did the occurrence of serum anti-DNA antibodies (correlation coefficients with disease activity 0.81 and 0.85 for p55 and p75 sTNFR, respectively, and 0.51 for anti-DNA antibodies). The increase in sTNFR levels seems to reflect, largely, enhanced formation, and only to a minor extent, reduced clearance due to impairment of renal function. Sera of the SLE patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF, and this was shown to result entirely from their higher sTNFR receptor concentration. CONCLUSION: An increase in serum levels of sTNFR may become a useful marker for SLE activity since it shows a stronger correlation than do any other laboratory or clinical parameters employed presently in the daily clinical setting. At the concentrations attained in the serum of SLE patients, sTNFR effectively inhibit the bioactivity of TNF and may thus be a significant determinant of the intensity of the manifestations of SLE.

Adult↗

Levels of soluble receptors for tumor necrosis factor type I and type II in paired synovial fluids of arthritis patients.

The objective of this study was to determine whether levels of soluble receptors for tumor necrosis factor type I and type II (sTNF-RI and sTNF-RII) as measured in paired synovial fluids (SF) of arthritis patients are associated with clinical or laboratory parameters of local inflammation. sTNF-RI and -RII were measured by ELISA. We found that sTNF-RI and -RII did not correlate with activity of local inflammation. sTNF-RI levels correlated with sTNF-RII concentrations. We concluded that sTNF-RI and -II did not represent markers for local disease activity in arthritis patients.

Adult↗