Detection of t(14;18) in turkish follicular lymphomas using the polymerase chain reaction.

A t(14;18) translocation is closely associated with the follicular lymphoma but is also seen in diffuse B cell lymphomas with a previous history of a follicular lymphoma as well as de novo diffuse lymphomas. Estimation of the frequency of t(14;18) in follicular lymphoma vary widely from 33 to 89%. Furthermore, no extensive data have been published on the frequency of t(14;18) in Turkish cases of follicular lymphoma. Representative tissue blocks from 67 patients with follicular lymphoma, 12 cases of diffuse large B cell lymphomas and 11 cases of reactive hyperplasias were examined for the presence of this translocation using PCR. DNA probes capable of detecting rearrangement at both the major and minor break point regions were employed. We could detect t(14;18) in 46 out of 67 cases (68.7%) of follicular and 25% of diffuse large B cell lymphomas. In follicular lymphomas 64.2% of these break points were at mbr and 4.5% were at the mcr region. Review of the literature showed that comparable results have been obtained previously using molecular techniques. Our data showed that despite the relative infrequency of follicular lymphomas in the Turkish population these lymphomas share a common molecular pathogenesis with involvement of bcl-2 gene and background incidence of such rearrangement is similar in all populations, regardless the incidence of folicular lymphoma.

Preventive effect of hesperidin against inflammation in CD-1 mouse skin caused by tumor promoter.

Our earlier studies have shown that the flavonoid hesperidin inhibits tumor promotion in a two stage skin tumorigenesis protocol in CD-1 mice. In this study hesperidin's significant protection (p < 0.0001) against 12-0-tetradecanoylphorbol-13-acetate (TPA) induced edema in CD-1 mouse ear will be presented. Hesperidin also afforded significant protection against TPA induced hyperplasia in the dorsal skin through multiple application prior to TPA. Protection by hesperidin was 93% of the epidermal thickness and 100% of the vertical cell layers. The data also indicate the protective effect of hesperidin against TPA caused infiltration of neutrophils by 73%. These results suggest that hesperidin may possess potential as chemopreventive agent against tumor promoter induced inflammation and hyperplasia.

Immunomodulating therapy with rIL-2 and interferon alpha-induces in vivo expression of Bcl-2, Fas (APO-1/CD95), and Fas ligand on peripheral lymphocytes (a pilot study).

The first Phase I Trial with a combination of IL-2 and IFN-alpha was published in 1989. There are still some questions though, concerning the in vivo effects of this combination on lymphocytes. We designed a prospective pilot study to evaluate in vivo effects of low dose IL-2 and IFN-alpha combination on expression of Bcl-2, FAS (Apo-1/CD 95), Fas Ligand, IL-2 receptor (CD25), and HLA-DR on peripheral lymphocytes in patients with advanced renal cell carcinoma. After initiation of the immunomodulating therapy, Bcl-2 expressing lymphocytes increased significantly on day 3 (p < 0.025), Fas (Apo-1/CD95) expressing lymphocyte increased significantly on day 5 (p < 0.003), Fas ligand expressing lymphocytes increased significantly on day 3 (p < 0.004), HLA-DR expressing lymphocytes increased significantly on day 5 (p < 0.003), and IL-2 receptor (CD25) expressing cells increased significantly on day 5 (p < 0.01). We conclude that immunomodulating therapy induces in vivo expression of Bcl-2, Fas (Apo-1) and Fas Ligand in lymphocytes significantly.

Magnetic resonance imaging of bone marrow versus bone marrow biopsy in malignant lymphoma.

Bone marrow involvement is a frequent finding in malignant lymphoma. Bone marrow biopsy of the posterior iliac crest is routinely performed for staging. Abnormal magnetic resonance imaging (MRI) signals of bone marrow was also reported to be indicative of bone marrow involvement. This study included 60 patients with malignant lymphoma. Unilateral bone marrow biopsy of the posterior iliac crest was performed. MRI of lumbar spine was studied within 24 hours of bone marrow biopsy. 22 healthy controls were used for the detection of MRI objectivity during visual evaluation. In 83% of patients (50/60), biopsy and MRI results agreed completely. In two patients, histologic sections failed to show any evidence of bone marrow involvement despite abnormal MRI signals suggestive of involvement. In three patients, MRI was completely normal despite biopsy proven bone marrow infiltration. False negativity (3/60) and false positivity (2/60) rates were very low. Negative biopsy findings with positive or equivocal MRI results should not exclude bone marrow involvement and needs further evaluation with bilateral or guided biopsy. Thus, we conclude that MRI of bone marrow is a fairly sensitive, noninvasive modality and might be of potential value in detecting bone marrow infiltration in malignant lymphoid neoplasms which can be utilized as a useful adjunct to standard staging procedures.

Usefulness of the epithelial tumor marker CA-125 in non-Hodgkin's lymphoma.

CA-125, a commonly used tumor marker for epithelial ovarian cancer, is a glycoprotein found in normal tissues derived from coelomic epithelia. Increased serum levels of CA-125 have also been found in nongynecologic tumors and nonmalignant diseases involving the peritoneum. A few recent studies and sporadic case reports have reported increased CA-125 levels in patients with non-Hodgkin's lymphoma (NHL). In our study, we aimed to evaluate the serum levels of CA-125 in patients with NHL and determine its potential role to show disease activity in NHL. Serum levels of CA-125 were measured in 61 patients with NHL and were found to be correlated with clinical stage, site of involvement, and disease activity.

Serum erythropoietin level in anemic cancer patients.

Anemia is a frequent complication of cancer and its treatment. A defect in erythropoietin production has been advocated as being the main cause of anemia in cancer patients. We studied serum erythropoietin levels in 74 patients with solid tumors and in a control group consisting of 20 otherwise healthy individuals without any malignancy, who have only iron deficiency anemia. Serum erythropoietin levels were measured by enzyme immunoassay in cancer patients without anemia (n=34), and in anemic cancer patients (n=40); either receiving chemotherapy (n=21) or not (n=19). Anemic cancer patients were found to have decreased response of erythropoietin for a given hemoglobin level (mean, 40.1+/-34.7 u/ml), compared with the patients having only iron deficiency anemia (mean, 69.7+/-68.6 u/ml) (P<0.05). In patients with iron deficiency anemia having no malignancy, erythropoietin response was remarkably high and inversely correlated with the level of hemoglobin (r=-0.69; P=0. 05). Although there was no correlation between hemoglobin and erythropoietin response in cancer anemia (r=-0.07), serum levels of erythropoietin were found to be higher in anemic cancer patients (mean, 40.1+/-34.7 u/ml), compared with cancer patients with normal hemoglobin values (mean, 19.96+/-18.4 u/ml). There was not any statistically significant difference between erythropoietin levels in anemic cancer patients with or without chemotherapy (mean, 43. 7+/-37.7 u/ml and 41.9+/-30.08 u/ml respectively; P>0.05). No difference in serum erythropoietin levels were noted in patients treated with cisplatin or non-cisplatin containing regimens (mean, 48.36+/-33.12 u/ml and 38.55+/-43.52 u/ml, respectively; P>0.05). In this study, we demonstrated that anemia in cancer patients was caused by blunted erythropoietin response, rather than its quantitative deficiency. Serial measurements, however, should be considered in patients receiving chemotherapy.

Serum cardiolipin antibodies in cancer patients with thromboembolic events.

This study was undertaken to investigate a possible association of anticardiolipin antibodies (ACLAs) in cancer patients with thromboembolic events. Twenty-five patients with solid tumors complicated with acute thrombosis, 36 cancer patients without any thrombotic events, and a group of 20 healthy volunteers without thrombosis or malignancy were included. The mean age of the cancer patients with and without thrombosis and healthy subjects were 50 years (range 20-75), 45 years (range 23-66), and 40 years (range 20-68), respectively. Deep venous thrombosis (n = 16) and thrombosis of the central venous port-catheter systems (n = 9) were confirmed by Doppler sonography in all patients. IgG and IgM isotypes of ACLAs were quantitated by enzyme-linked immunosorbent assay with normal levels of < 23 GPL and < 11 MPL, respectively. Mean values of IgG ACLAs were found similar in cancer patients with acute thrombosis (13.8 +/- 4.9 GPL), without thrombosis (12.8 +/- 5.4 GPL) or in healthy subjects (14.8 +/- 5.5 GPL). Although the mean values of IgM ACLAs were within normal limits in all groups, cancer patients with thrombotic events had higher levels of IgM ACLAs (mean = 10.5 +/- 2.2 MPL) than cancer patients without thrombosis (mean = 4.6 +/- 2.4 MPL) (p = .01). Healthy subjects also had lower levels of IgM ACLAs (mean = 7.1 +/- 3.2 MPL) than cancer patients with thrombosis (p = .16). In addition, a higher percentage of cancer patients with or without thrombosis had IgM and IgG ACLA levels above normal limits compared with healthy controls. In conclusion, our study suggests an association between ACLAs or IgG and particularly IgM isotypes and venous thrombosis in malignancy. Identification of cancer patients who are at higher risk for developing thromboembolic events might lead to a better selection of patients for prophylactic anticoagulant therapy.

Haematological effects of pulse steroid therapy.

The aim of this study was to determine the haematological effects of 1 g methylprednisolone given intravenously as pulse steroid therapy (PST) to 10 cancer patients who had not received any chemotherapy or immunoactive drugs in the previous 3 weeks. Haematological values as determined with flow cytometry were evaluated before, and 1 and 24 h after, the pulse therapy. Total leucocyte count was found to be decreased at the first hour and significantly increased at the 24th hour, whereas total lymphocyte count decreased at the first hour and remained low at 24 h. CD4 lymphocytes were found decreased at the first hour whereas CD8 lymphocytes were significantly decreased at the 24th hour. The CD4/CD8 lymphocyte ratio and the values of haematocrit and platelets did not change significantly. The decrease in the total leucocyte count after 1 hour of steroid administration was notable, in addition to the results which were in accordance with previously reported data about steroid effects on haematological values.

Salmon calcitonin in the treatment of bone metastases.

The effects of salmon calcitonin administered 100 IU i.m. daily for 30 consecutive days were evaluated in patients with painful bone metastasis secondary to different types of solid cancer. The results were compared with placebo-receiving patients. In the 22 patients treated with calcitonin a significant reduction ( p less than 0.001) was observed in the severity of bone pain. Significant reductions were also encountered in the serum alkaline phosphatase (p less than 0.02) and urinary hydroxyproline excretion values (p less than 0.05) in calcitonin-treated patients, indicating an inhibition of bone destruction. It is concluded that salmon calcitonin has an important place in the treatment of patients with metastatic bone lesions both as a potent analgesic and as an effective inhibitor of bone destruction.

Mitochondria-lytic action of warfarin in lymphocytes.

Warfarin given as a single dose of 20 mg induces lysis of mitochondria in lymphocytes from chronic and acute lymphocytic leukemias studied under the electron microscope. Normal lymphocytes remain unchanged. This cytotoxic actin may be due to superoxide radicals produced in the malignant cells by warfarin, which is a potent electron-transferring substance.

A clinical trial of mitoxantrone (novantrone) versus doxorubicin (adriamycin) in combination chemotherapy for metastatic breast cancer.

Mitoxantrone (Novantrone, N) is a new anthracenedione derivative with structural similarities to doxorubicin (Adriamycin, A). It has shown significant activity during phase I and II clinical trials in the treatment of advanced breast cancer. The present trial compares the CNF regimen to CAF. All patients received cyclophosphamide (500 mg/m2) and 5-fluorouracil (500 mg/m2), with either N (10 mg/m2) or A (50-60 mg), repeated every three weeks. There were 30 patients in the mitoxantrone group and 30 patients in the doxorubicin group. The results presented are based on 60 patients: 70% were postmenopausal; 25% had received adjuvant chemotherapy; 29% had prior hormonal therapy in an adjuvant setting or for relapse. There were no significant differences between the pretreatment characteristics of each group. The response rate (complete + partial) for CNF was 57% and for CAF was 40%. The dose limiting toxicity was granulocytopenia seen after the 3rd cycle in the CNF group. Thrombocytopenia was not seen. There was less nausea and vomiting in the CNF group. No cardiotoxicity was seen in CNF; only 2 patients suffered from congestive heart failure in CAF. These preliminary data indicate that CNF seems to be an effective regimen for patients with advanced breast cancer and has fewer adverse effects than CAF.

The effect of coumarin derivatives on the immunological system of man.

Peripheral blood lymphocyte mitogen responsiveness was studied in 12 normal and 51 cancer patients. One group of patients was treated with warfarin, the second group with coumarin. There was a significant increase in lymphocyte response to phytohaemagglutinin (PHA) following both drugs. This increase indicates that both agents are capable of activating lymphocytes and thus stimulating some immunological functions.

Inhibitory effect of Hesperidin on tumour initiation and promotion in mouse skin.

A flavonoid, Hesperidin was evaluated for its ability to inhibit tumour initiation by a polycyclic aromatic hydrocarbon and tumour promotion by a phorbol ester in the skin of CD-1 mice. Subcutaneous application of Hesperidin did not inhibit 7,12-dimethylbenz(a)anthracene-induced tumour initiation but did inhibit 12-O-tetradecanoyl-13-phorbol acetate-induced tumour promotion. Results provide evidence for a potential chemopreventive activity of Hesperidin.

Chemotherapy in colorectal cancer.

198 patients with colorectal carcinoma were given chemotherapy. Adjuvant chemotherapy was applied to 73 patients, postoperatively, with Dukes A, B, C disease. 125 patients were Dukes D. The four different chemotherapy regimens comprised fluorouracil (5-FU) alone, 5-FU plus levamisole, 5-FU plus mitomycin-C and 5-FU plus adriamycin. Median survival was 18 months in the adjuvant group, with 67%, 30% and 19% of patients alive at the end of 1st, 2nd and 3rd years. 5-FU plus adriamycin and 5-FU plus levamisole give better survival rates. Median survival was 7 months in the metastatic group and only 23% are alive at the end of the first year. Favorable results were observed only with 5-FU plus adriamycin. Even though chemotherapy seems to be of limited value in advanced colorectal cancer, survival and life quality improve when it is given on an adjuvant basis.

Effects of warfarin administration on the immune response of mice.

Administration of warfarin to mice is shown to have little effect on the humoral immune response of these animals to sheep red blood cells (a thymus dependent antigen) or the trinitrophenyl hapten coupled to E. coli lipopolysaccharide (a thymus independent antigen). The ability of low doses of sheep red blood cells to prime T-cells in vivo for helper activity in the in vitro antibody-forming response to trinitrophenyl coupled to sheep red blood cells is also apparently unaffected. By contrast, delayed hypersensitivity responses, measured by foot pad swelling, are significantly stimulated by administration of the drug.

Salivary sialic acid and cancer.

In this preliminary study the salivary sialic acid levels in 56 randomly selected cancer patients of different ages were compared with those of 70 healthy controls of similar age distribution. The cancer patients consisted of 25 women and 31 men. Twenty were suffering from lung cancer. Unstimulated whole saliva was collected by expectoration. The mean sialic acid levels were 185 +/- 22.8 mg/dl in the cancer group and 6.2 +/- 3.72 mg/dl in the controls and the difference between them was significant (p < 0.0001). The subjects were also grouped according to age and cancer type. However there were no significant differences in sialic acid levels between these.

Survival analysis of patients with small cell lung cancer.

The effects of different chemotherapy protocols on survival were evaluated in 197 small cell lung cancer patients followed-up between 1974 and 1987 in our unit. Of these, 170 patients had Stage IV disease and 24 had Stage III disease. Thoracic radiotherapy was given to 73 patients of whom 63 had Stage IV disease. Cytotoxic chemotherapy was given in four main protocols consisting of cyclophosphamide (CYC): CYC + vincristine (VCR); CYC + VCR + adriamycin (ADM) and CYC + VCR + ADM + lomustine (CCNU). The latter protocol was associated with the highest survival rates and differed significantly (p less than 0.05) from the others. In patients with extensive disease, both radiotherapy to the primary site and adjuvant immunomodulation in conjunction with the above chemotherapy regimens lacked any beneficial effect on survival.

Overall survival results of non-small cell lung cancer patients: chemotherapy alone versus chemotherapy with combined immunomodulation.

The effect on long-term survival of immunomodulation adjuvant to various cytotoxic chemotherapy regimens in non-small cell lung cancer (NSCLC) was evaluated in 669 patients followed up between 1974 and 1987. Four hundred seventeen patients were treated only by cytotoxic chemotherapy and served as controls. Two hundred fifty-two patients received warfarin (W), levamisole (L) and tranexamic acid (T) for adjuvant immunomodulation. These drugs, especially when given in combination (W + L + T), led to a significant (p less than 0.05) enhancement of survival in patients with advanced NSCLC, independent of the cytotoxic regimen used.