Modulation of osteoclast-activating factor activity of multiple myeloma bone marrow cells by different interleukin-1 inhibitors.

We have studied the effects of several interleukin-1 (IL-1) inhibitors--IL-1 receptor antagonist (IL-1ra), soluble IL-1 receptor (sIL-1R) types I and II, and neutralizing monoclonal antibody (mAb) specific for IL-1 receptor type I--on the osteoclast-activating factor (OAF) activity of recombinant IL-1beta and of culture supernatants of unfractionated bone marrow mononuclear cells from multiple myeloma (MM) patients. The latter activity sharply correlated with the IL-1 content of culture supernatants (r = 0.949; p < 0.001). IL-1ra and sIL-1R types I and II had a clear-cut modulating effect on the OAF activity of IL-1beta at saturating doses (2-10 ng/mL); their effect was evident at 2 ng/mL and was dose-dependent over a large range of concentrations. Similarly, the three reagents neutralized the OAF activities of all MM cell supernatants in a dose-dependent fashion and completely abolished them when tested at the fixed concentration of 5 nM. The bone-resorbing activity of tumor necrosis factor-alpha (TNF-alpha) or lymphotoxin (LT), tested alone or added to MM cell supernatants, was affected not at all by IL-1ra and only minimally by sIL-1R types I and II, suggesting that little or no endogenous IL-1 was produced by the rat cells in the assay under TNF-alpha or LT stimulation. Consistent with these findings, PGE2 production elicited by IL-1beta or IL-1-rich supernatants in the rat long-bone assay was abolished by each reagent. Also, mAbs to the IL-1R p80 (type I) chains could modulate the effects of IL-1--recombinant or plasma cell-derived--in the OAF assay, but their activity was markedly less pronounced when compared with the IL-1 inhibitors, since they could never completely abolish bone resorption. Taken together, these findings demonstrate that inhibition of IL-1 interaction with cognate surface receptors on bone cells effectively counteracts its biologic activity. The findings also strongly indicate that OAF activity in conditioned medium of unfractionated myeloma bone marrow cells is predominantly, if not solely, related to IL-1beta.

HCV and tumors correlated with immune system: a case-control study in an area of hyperendemicity.

Hepatitis C virus (HCV) is a RNA virus that cannot be integrated with the host genome; it can, however, exert its oncogenetic potential indirectly by contributing to the modulator effects of the host immune system, probably through a capacity to elude the immune system. We have carried out a case controlled study on tumors correlated with the immune system (multiple myeloma, non-Hodgkin lymphoma and Hodgkin disease) and HCV, in a high prevalence area. The relationship between each cancer and HCV infection was assessed by means of odds ratios (ORs) and corresponding 95% confidence intervals. Risks were greater for B-cell non-Hodgkin lymphoma (OR=3.7, 95%CI, 1.9-7.4, P=0.0001) and multiple myeloma (OR=4.5, 95%CI, 1.9-10.7, P=0.0004). Our study is particularly important for public health, since it shows that during the coming years in the South of Italy, because of the high prevalence of HCV, there are good reasons to expect not only an increase of liver cancer, but also an increased incidence of great number of tumors correlated with the immune system.

Acute Myeloid Leukemia Expressing T-Cell Antigens: Clinico-Hematological Report on Six Cases.

In a series of 107 patients suffering from acute myeloid leukemia (AML), blast cells from six patients were found to simultaneously express CD2 and CD7 antigens along with CD13, CD33, and CDw 65 in various combinations. The frequency of the expression of both lymphoid markers recurred with a higher incidence than that anticipated by multiplying single antigens frequency. The clinical and hematologic features from CD2+/CD7 + AML patients were studied as well as compared with those of CD2-/CD7- AML patients observed in the same period. Morphologically, bone marrow smears from the AML hybrid subset showed a preponderant population of agranular blasts along with a minority of typical myeloid cells, characterized by larger amount of cytoplasm and, in three cases, by rare but distinct Auer Rods. In all cases more than 3% of blast cells were positive for myeloperoxidases and all samples were classified as M1 according to FAB classification. Clinically, CD2 + /CD7 + patients presented with a higher incidence of adenopathy and meningeal leukemia than did patients with CD2 + /CD7 - AML and were characterized by poor response to therapy in terms of both achievement and duration of remission. We conclude that simultaneous expression of CD2 and CD7 in AML is a non random event, recurring in more than 5% of cases and is associated with distinct clinical and hematologic features.

Soluble interleukin-2 receptor: a new marker in pancreatic adenocarcinoma?

An increase in soluble Interleukin-2 receptor has been observed in several lymphoproliferative diseases and in certain solid neoplasms. Little is known, however, of the serum levels of this marker in pancreatic cancer. We studied the behaviour of the soluble Interleukin-2 receptor in 32 patients with pancreatic cancer versus 17 patients with alcoholic chronic pancreatitis and 24 healthy controls. The results obtained showed a significant statistical difference (Student's "t"-test and Mann Whitney U test) between pancreatic cancer on one hand and chronic pancreatitis plus healthy controls on the other (p < 0.0001).

Serum interleukin-6 in acute pancreatitis due to common bile duct stones. A reliable marker of necrosis.

In a prospective clinical study we have assessed the value of serum interleukin-6 in comparison with C-reactive protein in discriminating necrotizing from oedematous acute pancreatitis due to common bile duct stones in the first hours of disease. The study comprised 36 patients with acute biliary pancreatitis; inclusion criteria were admission in hospital within 48 hours from the onset of symptoms, availability of contrast enhanced CT scan within 72 hours from admission and presence of common bile duct stones at early ERCP. A sample of serum was taken at hospitalization and interleukin-6 and C-reactive protein were measured. Interleukin-6 levels were significantly higher in necrotizing pancreatitis, being closely related to the extension of necrosis. C-reactive protein showed low efficacy in detecting necrotizing forms, although its levels were higher than in oedematous. We conclude that serum interleukin-6 is a very reliable marker of necrosis in the first 48 hours of acute biliary pancreatitis.

Neopterin in acute pancreatitis.

BACKGROUND: Activation of the cellular immune system may play a role in the pathogenesis of acute pancreatitis (AP); it has recently been proposed that excessive leukocyte stimulation may lead to the most severe forms of AP. The aim of this study was to investigate serum neopterin, a useful in vivo marker of macrophage activation, in mild and severe AP and its relationship with other markers of leukocyte activation, such as interleukin-6 (IL-6) and tumor necrosis factor (TNF). METHODS: Serum levels of neopterin (mmol/ml), IL-6 (pg/ml), and TNF (pg/ml) were measured on the 1st and 7th day of hospitalization in 17 patients with severe AP and 24 with mild AP. Severe AP was defined in accordance with the Atlanta criteria: all patients have necrosis at contrast-enhanced computerized tomography scan. RESULTS: Day 1: Neopterin and IL-6 levels were significantly higher in severe than in mild AP and normal controls; mild AP values were also significantly higher than in normal controls. The best neopterin cutoff level we obtained (30 mmol/ml) reached a specificity of 76% and a sensitivity of 46% in distinguishing severe from mild AP. Day 7: Neopterin was significantly higher in severe AP than in mild AP and in normal controls; no difference was seen between mild AP values and normal controls; neopterin serum levels were significantly higher on day 7 than on day 1 in severe AP but not in mild AP; in both groups of patients IL-6 was significantly higher on day 1 than on day 7. Using a neopterin cutoff level of 40 mmol/ml, we found specificity and sensitivity value of 92% in differentiating severe from mild AP. With regard to TNF values, no difference was seen on day 1 and 7 in the two groups of patients in comparison with normal controls. Neopterin serum values did not correlate with IL-6 and TNF on either day. CONCLUSIONS: These results confirm the activation of the cellular immune system in AP. Initially enhanced NEOP and IL-6 serum levels reflect the severity of the disease; neopterin may be considered a reliable prognostic indicator also at a distance from AP onset because its levels increase during the 1st week of AP in patients with severe forms only.

Neopterin serum levels in pancreatic adenocarcinoma.

CONCLUSIONS: Activation of the immune system in pancreatic cancer is demonstrated by increased serum levels of neopterin, soluble Interleukin 2 receptor (sIL-2R), and Interleukin 6 (IL-6). Determination of these parameters does not provide benefit in the diagnosis of pancreatic cancer. BACKGROUND: The aim of the study was to define the diagnostic value of serum neopterin, an in vivo marker of macrophage activity, in pancreatic cancer. METHODS: Thirty-four patients with pancreatic cancer were studied. According to the UICC TNM classification 6 were in stage I, 9 in stage II, 6 in stage III, and 13 in stage IV. Twenty-four patients with chronic pancreatitis, 72 healthy blood donors, and 20 patients with jaundice resulting from gallstones were used as control groups. Neopterin, tumor necrosis factor (TNF), sIL-2R, and IL-6 were measured in serum in the different groups; Ca 19-9 was also measured in cancer and pancreatitis. RESULTS: Serum levels of neopterin, sIL-2R, and IL-6 were higher in cancer than in pancreatitis and healthy donors, and in pancreatitis higher than in donors. Serum TNF was similar in the three groups. Serum levels of neopterin, TNF, sIL-2R, and IL-6 were not related to the tumor stage or to Ca 19-9 levels. A positive correlation was found between sIL-2R and neopterin levels. Neopterin levels in obstructive jaundice were similar to those of pancreatitis. Ca 19-9 at the recommended cutoff of 37 U/mL showed the best sensitivity and specificity (88.2 and 87.5%, respectively). At the selected cutoff neopterin, TNF, sIL-2R, and IL-6 showed low sensitivity and specificity in differentiating cancer from pancreatitis.

5-Aza-2'-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias.

In this study, the effects of 5-aza-2'-deoxycytidine on differentiation of human leukemic cells in primary suspension culture are reported for the first time. Morphological and functional differentiation was induced in cells from two acute monoblastic leukemias and two of three acute myeloid leukemias following repeated exposures to 1 mumol/L 5-aza-2'-deoxycytidine. The observation that nontoxic concentrations of the drug are able to induce the in vitro differentiation of both monoblastic and myeloblastic leukemic cells into mature elements may encourage the exploitation of the differentiating properties of 5-aza-2'-deoxycytidine in chemotherapy protocols for acute non-lymphoblastic leukemias.

Myeloid antigen expression in adult acute lymphoblastic leukemia: clinicohematological correlations and prognostic relevance.

Fifty adult patients with acute lymphoblastic leukemia (ALL) were prospectively studied to determine the clinical and hematological relevance of surface immunophenotypes. Before treatment, blast cells were assayed for reactivity to monoclonal antibodies to B-cell, T-cell, and myeloid (My) antigens. My antigens (CD13, CD33, and VIM2, singly or in combination) were demonstrated in 16 cases (32%) along with lymphoid specificities. Bone marrow and peripheral blood stains were classified according to French-American-British (FAB) Cooperative Group criteria and evaluated for myelodysplastic changes and azurophilic granules. Mean age of My+ patients was significantly higher. Furthermore, a greater number of My+ cases showed azurophilic cytoplasmic granules and acid ANAE positivity. FAB subtypes and myelodysplastic features did not significantly differ in the two groups analyzed, but patients with myelodysplastic abnormalities represented a significantly older age group. Response to treatment was comparable in My+ and My- cases, in terms of either complete remission rate or median survival duration.

HCV and cancer: a case-control study in a high-endemic area.

BACKGROUND/AIMS: HCV is a RNA virus that cannot be integrated with the host genome; it can, however, exert its oncogenic potential indirectly by contributing to the modulatory effects of the host immune system, probably through a capacity to elude the immune system. We have carried out a case-controlled study on the different oncological pathologies which have, to date, been shown to have a relationship with HCV. METHODS: We screened 495 patients with different types of cancer: 114 cases of liver cancer, 41 of multiple myeloma, 111 non-Hodgkin's lymphomas, 130 thyroid cancers, 63 cases of Hodgkin's disease. The controls were 226 patients with no history of cancer. The relationship between each cancer and HCV infection was assessed by means of odds ratios (OR) and corresponding 95% confidence intervals. RESULTS: Risks were greater for liver cancer (OR=32.9 95% CI 16.5-65.4, p<0.0001), multiple myeloma (OR=4.5 95% CI 1.9-10.7, p=0.0004) and B-cell non-Hodgkin's lymphoma (OR=3.7 95% CI 1.9-7.4, p=0.0001). For Hodgkin's disease there was no significant association (p=0.3). An association between HCV and thyroid cancer was noted (OR=2.8 95% CI 1.2-6.3, p=0.01). CONCLUSION: Our study is particularly important for public health since the high prevalence of HCV in the South of Italy gives reason to expect increases in not only liver cancer, but also tumors associated with the immune system and thyroid cancer in years to come.