Prognostic significance of flow cytometric DNA analysis in patients with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) due to environmental exposure to asbestos and erionite is a relatively common cancer in Turkey. In this study, we investigated the value of flow cytometric (FCM) DNA analysis and other prognostic factors such as age and etiologic factor in the patients with MPM, treated with surgery+/-combination chemotherapy+/-radiotherapy. A total of 40 patients with a median age of 50 (range 30-68) were included in the study. Twenty-nine patients had asbestos exposure in etiology, while 11 had fibrous zeolite (erionite). Paraffin-embedded tumor specimens were studied by FCM for DNA analysis. Twelve patients (30%) had aneuploid tumors and 28 (70%) had diploid ones. Mean S-phase fraction (SPF; %) was 9.1+/-1.1 and proliferation index (PI, SPF+G2/M phase; %) was 11.3+/-0.9. While the median overall survival (OS) was 10+/-2 months (6-14; 95% CI), 1-year survival rate was 45.2%. Only PI was found to be statistically significant for OS in univariate analysis (P=0.013). PI was also found to be an independent prognostic factor for all patients (P=0.035). Aneuploidy was significantly higher in erionite group compared with asbestos group. Male predominance and poor survival were also prominent in erionite group, though not statistically significant. In conclusion, PI is an independent prognostic factor for patients with MPM and the biologic features of the disease may show differences with respect to different etiologies.

A randomized trial of four cycles of adjuvant AC (adriamycin + cyclophosphamide) +/- two cycles of EP (etoposide + cisplatin) in node positive patients with breast cancer.

BACKGROUND: Four cycles of AC have been accepted as the standard chemotherapy in breast cancer. In the present randomized study we aimed to assess the efficacy of adjuvant etoposide + cisplatin (EP) combination following four cycles of standard adriamycin + cyclophosphamide (AC) in premenopausal patients with operable breast cancer and axillary lymph node metastasis. PATIENTS AND METHODS: Premenopausal patients with positive axillary lymph nodes following curative modified radical mastectomy were randomized to either four cycles of AC (82 patients) or four cycles of AC + two cycles of EP (83 patients). RESULTS: Median follow-up is 72 months. All randomized and eligible patients are included in the analysis (AC: 80 patients, AC + EP: 78 patients). The five-year disease-free survival (DFS) for the AC + EP group was significantly better when compared to AC group (45.5% vs. 30.4%; P = 0.048). Again, the five-year overall survival (OS) of the whole group was in favor of AC + EP arm, though without statistical significance (68.6% vs. 59.1%; P = 0.247). CONCLUSION: Two cycles of EP following four cycles of AC decreased the relapse rate in operable breast cancer patients.

Value of combined 67Ga and 99Tc(m)-human immunoglobulin G whole-body scanning in malignant lymphoma.

Human immunoglobulin G labelled with 99Tc(m) (99Tc(m)-HIG) is an agent introduced for the localization of inflammatory lesions. There is also a limited number of reports concerning the uptake of this agent by malignant lesions. The aim of this study was to evaluate the uptake of 99Tc(m)-HIG by lymphoma. Twenty-three patients (five female, 18 male) with known Hodgkin's or non-Hodgkin's lymphoma for a period of 2-6 years (mean 4.2 years) and which, by using computed tomography (CT), showed recurrence, were included in the study. The patients were aged between 32 and 68 years (mean 38 +/- 5 years). No evidence of inflammation or infection was seen in any of these patients. CT, 99Tc(m)-HIG and a 67Ga scan were performed in the same week. CT showed abdominal involvement in 17 patients, pelvic involvement in 11, and thorax involvement in 11. 99Tc(m)-HIG showed higher sensitivity (94.1%) in the abdomen, a similar sensitivity (63.6%) in thorax, but lower (18.1%) in pelvic area than for 67Ga. 99Tc(m)-HIG was found to be more useful for the evaluation of abdominal involvement compared to 67Ga due to gastrointestinal excretion of the latter. The resolution of 67Ga was better than 99Tc(m)-HIG in thorax and pelvis. Using 99Tc(m)-HIG and 67Ga together in lymphoma may increase sensitivity.

Diurnal variations of serum GM-CSF levels.

We aimed to investigate the daily variations of serum granulocyte-macrophage colony-stimulating factor (GM-CSF) levels and to correlate them with peripheral blood cells counts. Venous blood samples from eleven healthy volunteers were taken four times a day, being at 08:00, 14:00, 20:00 and 02:00h and serum GM-CSF levels measured by ELISA. We could not find a significant overall difference among GM-CSF levels at four different times of the day using the Friedman test. On the other hand, serum GM-CSF levels at night (20:00h) were found to be significantly increased when compared to the morning levels (08:00h) using the Wilcoxon test (P=0. 022). The levels of lymphocytes and white blood cells (WBCs) at 20:00h were also higher than the morning levels (08:00h) as expected. While there was a strong relationship between the morning levels of GM-CSF (08:00h) and all measurements of peripheral blood cells during the day, the levels of GM-CSF measured at 02:00, 14:00 and 20:00h were found to be significantly correlated with only the WBC levels. It was concluded that there may be a significant difference between morning and night levels of GM-CSF and morning levels of GM-CSF may be more important in the regulation of WBC counts during the day. These variations warrant further studies about diurnal rhythms of haematopoiesis chronotherapy with CSFs.

Prevalence of hepatitis-G virus and hepatitis-C virus infection in patients with non-Hodgkin's lymphoma.

Several studies have reported that hepatitis-C virus may have a role in the development of non- Hodgkin's lymphoma. Hepatitis-G virus has hepatitis-C virus like characteristics. The possible association between hepatitis-G virus infection and non-Hodgkin's lymphoma is not clear. The aim of this study was to determine the prevalence of hepatitis-G virus and hepatitis-C virus infection in patients with non-Hodgkin's lymphoma without blood transfusion. Forty-four patients with non-Hodgkin's lymphoma were enrolled in the study. Serum samples derived from the patients were tested for antibodies against hepatitis-C virus by ELISA. Hepatitis-G virus and hepatitis-C virus RNA were detected by reverse transcription-polymerase chain reaction. Only two of 44 patients (5%) with non-Hodgkin's lymphoma were positive for Anti- HCV and hepatitis C virus RNA. One patient had low grade non-Hodgkin's lymphoma with follicular mixed histopathology while the other had intermediate grade with diffuse large cell histopathology. Hepatitis-G virus infection was detected in none of the patients. We concluded that hepatitis-G virus does not seem to be in association with non-Hodgkin's lymphoma.

Prospective randomized comparison of morning versus night daily single subcutaneous administration of granulocyte-macrophage-colony stimulating factor in patients with soft tissue or bone sarcoma.

BACKGROUND: Hematopoietic growth factors (HGFs) have been used to reduce the neutropenic complications of cytotoxic chemotherapy so that higher doses may be given. The authors have previously shown that endogenous serum granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) levels at night (p.m.) were significantly higher than those in the morning (a.m.). METHODS: Twenty-four patients with soft tissue or bone sarcoma who were treated with high dose ifosfamide-based chemotherapy were enrolled in this study. Patients were randomized to either a.m. or p.m. treatment. GM-CSF was administered at a dose of 5 microg/kg/day at 10 a.m. or 10 p.m., beginning 36-48 hours after the last chemotherapy dose. GM-CSF therapy was continued until the neutrophil count exceeded 1,000/mm3 for 2 consecutive days. Leukocyte, neutrophil, monocyte, and platelet counts were measured immediately before GM-CSF administration and exactly 12 hours after the first dose of GM-CSF, and every 24 hours until 3 days after the cessation of GM-CSF. RESULTS: The mean duration of Grade 3-4 neutropenia was 5.3 +/- 0.4 days for the a.m. treatment arm and 6.5 +/- 0.3 days for the p.m. treatment arm (P = 0.017). Although the duration of neutropenia in the a.m. arm was significantly shorter than in the p.m. arm, there were no differences related to the number of febrile neutropenic episodes or the duration of antibiotic administration. Also, there were no differences in the side effects observed in the a.m. and p.m. arms. CONCLUSIONS: The finding of 1.2 days' difference in the duration of Grade 3-4 neutropenia warrants further study of chronotherapy with HGFs.

Clinicopathologic features and prognostic factors of primary extranodal non-Hodgkin's lymphomas in Turkey.

Clinical, histopathologic, and prognostic features of 114 patients with primary extranodal non-Hodgkin's lymphoma were evaluated. Median age of the patients was 48 (range, 15-76) and the ratio of male/female was 55/59. Thirty-seven patients had stage 1, 55 patients stage II, 6 patients stage III, and 16 patients stage IV. The most common sites of primary extranodal non-Hodgkin's lymphoma were the gastrointestinal (GI) tract and head-neck region. Stomach (66%) and tonsils (33%) were the most frequently involved organ in GI tract and head-neck region, respectively. Eighty percent of patients had intermediate or high-grade lymphomas, 20% had low-grade subtypes. Complete remission was achieved in 83% of all patients with chemotherapy +/- radiotherapy +/- surgery. Overall and disease-free survival at 5 years were 63% and 59%, respectively. In conclusion, clinical and histopathologic characteristics and prognosis of our cases with primary extranodal non-Hodgkin's lymphoma were usually similar to those of the cases in Western countries with some differences in the incidence of some specific primary extranodal non-Hodgkin's lymphomas and in the histopathologic subtypes.

Concurrent occurrence of three neoplasms including non-Hodgkin's lymphoma, renal cell carcinoma and leiomyoma in the same kidney.

A 53-year-old man with triple renal neoplasms in his left kidney presented. He was initially diagnosed intermediate grade non-Hodgkin's lymphoma (NHL) which involved gastrointestinal tract, left kidney, liver and pancreas. He underwent left nefrectomy because of a persistent renal mass after the completion of chemotherapy. The large renal mass revealed a renal cell carcinoma (RCC). Additionally, multiple small nodules of non-Hodgkin's lymphoma and a solitary leiomyoma were observed.

Phase II study of cisplatin and dacarbazine for metastatic colorectal carcinoma resistant to 5-fluorouracil.

Twenty-six patients with metastatic colorectal cancer were given cisplatin (CDDP) and dacarbazine (DTIC). Patients who relapsed while receiving adjuvant 5-fluorouracil (FU) or had 5-FU-resistant metastatic disease were included. Median age was 52 years and the male-to-female ratio was 1. Performance status (ECOG) was 3 in 5 patients and 0-2 in the remainder. CDDP (20 mg/m2/day i.v.) and DTIC were given (250 mg/m2/day i.v.) on days 1-5. The treatment was repeated every 3 weeks until disease progression. Total response rate was 19.2% (95% confidence interval: 4.5-34.3%) with one clinical complete response (3.8%) and 4 partial responses (15.4%). Median response duration was 5 months. Median survival for the whole group and for responders was 6 and 8 months, respectively. In conclusion, CDDP + DTIC combination has modest activity in patients with colorectal cancer resistant to 5-FU treatment.

The clinical value of flow cytometric DNA content analysis in patients with soft tissue sarcomas.

Purpose. The purpose of this study was to evaluate: (1) the correlation between grade and ploidy or S-phase fraction (SPF), (2) the prognostic value of DNA flow cytometric study in soft tissue sarcomas.Patients /Methods. In all, 47 tissue samples from soft tissue sarcoma patients, surgically treated in the same center, were included. Flow cytometric analyses were performed according to a modified version of the original method of Hedley et al.Results. DNA ploidy status could be determined in 44 samples out of 47 (success rate 94%). Of these 44, S-phase fraction could be calculated in 34 samples (77%). In the study group as a whole, aneuploidy was significantly correlated with high grade. Survival analyses were carried out in 21 patients with soft tissue sarcoma, all surgically treated in the same center, without chemotherapy or radiotherapy. In univariate analyses, DNA ploidy was found to be a significant factor for overall survival (OAS) and metastasis-free survival MFS. Mean OAS for aneuploid tumors and diploid tumors were 35 and 65 months (p=0.034), and mean MFS 23 and 61 months, respectively (p=0.005) .Discussion.There is a relation between histological grade and ploidy in soft tissue sarcomas. It appears that low-grade tumors are generally diploid, whereas high-grade tumors tend to be aneuploid. In a subgroup of patients treated only with surgery, DNA ploidy was found to be an important factor for predicting OAS and MFS.

Diagnostic value of ferritin in the differential diagnosis of malignant effusions.

UNLABELLED: The diagnostic value of ferritin in pleural effusions or ascites was studied in 151 samples from 147 patients (four patients had both kind of effusions). Samples (99 pleural effusions, 52 ascites) were evaluated in 4 groups: benign transudate (27 cases), benign nontuberculous exudate (26 cases), tuberculous exudate (47 cases) and malignant exudate (51 cases). Median ferritin levels in effusions were 67 ng/ml, 805 ng/ml, 889 ng/ml, 998 ng/ml and median effusion/serum (E/S) ratios were 0.7. 2.0, 4.9, 3.2 respectively. There was a significant difference between the concentrations of ferritin in malignant (51 cases) and nonmalignant effusions (100 cases) (p < 0.001), but the specificity and positive predictive value were low (43% and 45% respectively). Ferritin levels in transudate group were significantly lower than those in the others (p < 0.001). However, ferritin concentrations in three exudate groups were similar (p > 0.05). When compared the all inflammatory effusions (malignant, tuberculous, nontuberculous inflammatory exudates) with noninflammatory effusions (transudate and exudate), we determined a significant difference (p < 0.001). CONCLUSIONS: 1) Elevated ferritin concentration in effusions is significant indicators of exudates; 2) It is not good a parameter to discriminate the malignant effusions from the benign ones; 3) They can be useful in the differential diagnosis of the inflammatory exudations from the noninflammatory ones.

Results of the cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) +/- bleomycin treatment and evaluation of prognostic factors in aggressive lymphomas in Turkey.

Prognostic factors and the results of the cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) +/- bleomycin treatment in 93 consecutive evaluable patients with aggressive lymphomas are presented. The overall response rate, excluding 7 patients with primary extranodal lymphoma who were in complete remission after surgery, was 83% with a complete response (CR) rate of 69%. Overall survival (OS) rates of all patients and disease-free survival (DFS) rates of complete responders at 4 years were 52 and 66%, respectively. Almost two thirds of the patients could be given at least 75% of the planned chemotherapy doses. Treatment toxicities were in acceptable limits, only 10% of the patients had grade 3-4 hematological toxicity. Age, performance status (PS), stage, number of extranodal sites (ENS) (< or = 1 vs. > 1), B symptoms, serum LDH levels were evaluated as prognostic factors. Univariate survival analysis yielded stage, ENS and PS as significant prognostic factors for OS (p = 0.0009, p = 0.0028 and p = 0.0155, respectively). Only involvement of more than 1 ENS was strongly associated with low CR (p = 0.0479) and high relapse rates (p = 0.0118), and it was also determined as the only independent prognostic factor for OS in patients younger than 60 (p = 0.0015). A modified age-adjusted prognostic index, including ENS in addition to stage, LDH and PS, was found to be more significant than the original age-adjusted International Prognostic Index (IPI) for both DFS (p = 0.0030) and OS (p < 0.00001). In conclusion, modified age-adjusted index may be a convenient alternative to the original age-adjusted IPI to identify high-risk patients with aggressive lymphomas in Turkey and probably also in other developing countries for experimental intensive regimens.

Phase II study of a modified combination of etoposide, doxorubicin, and cisplatin for patients with advanced gastric cancer.

BACKGROUND: Based on the promising results of EAP (etoposide, doxorubicin, and cisplatin) combination, a phase II study of modified EAP combination was performed in patients with advanced gastric cancer to evaluate the response, toxicity, and survival. METHOD: Fifty-two consecutive patients with measurable or evaluable advanced gastric cancer, who had no prior therapy except surgery, were treated every 28 days with etoposide 120 mg/m2/day, doxorubicin 25 mg/m2/day, and cisplatin 40 mg/m2/day on days 1 and 8, intravenously. Forty-seven patients were evaluable for response and toxicity. RESULTS: Overall response rate was 40.5% (95% CI = 37-54.7%), including 12.8% complete response. Responses were higher in patients with locally advanced disease (57.89%) as compared to those with distant metastases (28.57%) (P = 0.044). The median overall survivals of the entire group and the responders were 7 months and 11 months, respectively. Complete responders had significantly longer response duration and overall survival (31.5 months and 45.5 months, respectively), as compared to partial responders (6 months and 9 months, respectively). Six of the responders (31.6%) were alive at 2 years. Disease extension and pretreatment performance status had significant effects on survival. Grade 3-4 toxicity was observed in 33% of patients. There were no deaths related to toxicity. CONCLUSIONS: EAP as used in this trial is an effective treatment in advanced gastric cancer. The effect is more pronounced in patients with locally advanced disease.

Two dose levels of ifosfamide in malignant mesothelioma.

Thirty-one consecutive patients with histologically proven and symptomatic malignant mesothelioma were treated with two dose levels of ifosfamide. The first group of 15 patients were given 2.3 g/m2/day for 5 days (group A) and the following 16 patients were treated with 1.2 g/m2/day for 5 days of ifosfamide (group B). Treatment cycles were repeated every 3 weeks. While the partial response rate (PR) in group A was 38.5%, it was only 6.25% in group B (P > 0.05). The 95% confidence interval for the difference in PR rates was 3.3-61.2% > The overall survival (OAS) of groups A and B were similar (8 months and 9 months, respectively). Higher Grade 3-4 myelotoxicity was observed in group A when compared to group B (30.8% vs. 18.7%; P > 0.05). In conclusion, a favourable response rate could be achieved in malignant mesothelioma with high dose ifosfamide at the cost of increased toxicity.

Mesna/ifosfamide, mitoxantrone, etoposide, bleomycin, vincristine, prednisone (MINE-BOP) combination chemotherapy in the treatment of refractory and relapsed non-Hodgkin's lymphoma.

Twenty-one consecutive patients with refractory or relapsed non-Hodgkin's lymphomas were treated with a novel combination chemotherapy (MINE-BOP), comprising myelosuppressive (ifosfamide, mitoxantrone, etoposide) and non-myelosuppressive (bleomycin, vincristine and prednisone) drugs. Median age of the patients was 42 years and all had intermediate or high-grade lymphoma. Fifteen patients had refractory disease. All patients had previously been treated with one or two regimens, containing anthracyclines. In all cases the duration between the last chemotherapy and the MINE-BOP regimen was shorter than 12 months. Response rate was 57% with 33% complete remission (CR). Median disease-free and overall survivals were 7 and 10 months respectively. The serum LDH level was the only significant prognostic factor in this study. The toxicity of this regimen was moderate with 24% of febrile neutropenia and 9% of microscopic hematuria. Toxic death due to febrile neutropenia was observed in one patient who had bone marrow involvement. To conclude, the addition of non-myelosuppressive drugs to the chemotherapy regimen and shortening the interval between the application of cytotoxic drugs as used in the present study did not show any improvement of response and survival in this group of patients.

Severe vascular toxicity associated with cisplatin-based chemotherapy.

A 19-year-old man with a germ cell tumor who experienced hypertension, acute myocardial infarction, and cerebrovascular accident (CVA) associated with hypomagnesemia as late complications of cisplatin-based chemotherapy is presented, and previously reported cases in the literature are reviewed. Different physiopathologic mechanisms are hypothesized for early and late vascular complications of cisplatin.

Primary gastrointestinal lymphomas in Turkey: a retrospective analysis of clinical features and results of treatment.

UNLABELLED: Thirty-three patients with primary gastrointestinal lymphoma (GIL) followed at Ankara University Medical School have been evaluated. The most frequent locations of the disease are the small intestine (48.4%) and the stomach (39.3%). The intermediate and high grade lymphomas constitute 84.8% of the cases. The mean age of the patients with small intestinal lymphoma is 28.7 years and 47.1 years for those with gastric lymphoma. The patients treated with surgery and chemotherapy (S+CT) have a longer survival than those treated with chemotherapy (CT) alone. IN CONCLUSION: 1) Small intestinal lymphoma occurs more frequently than gastric lymphoma in our study. 2) The median age of the Turkish patients with primary GIL is approximately 10 years less than those in the Western countries. 3) The therapeutic results of S+CT are superior to those of CT in the early stages of the disease.

Cisplatin plus VP-16 combination chemotherapy in advanced refractory breast cancer.

Twenty-nine patients with advanced refractory breast cancer were treated with cisplatin 20 mg/m2/d and VP-16 100 mg/d for 5 days every 3-4 weeks. Ten patients received mitomycin C 10 mg/m2 every 6 weeks additionally. Partial response was obtained in 10 of 26 evaluable patients (38%). The response rates for the group treated with and without mitomycin C were 40% and 37.5%, respectively. Median response duration was 5.5 months in partial responders. Median survival was 9.5 months for partial responders and 2 months for the rest of the patients. Cisplatin and VP-16 combination can be considered as a salvage treatment in heavily pretreated patients with advanced breast cancer.

Treatment of metastatic malignant melanoma with 24 hours continuous venous infusion of dacarbazine and cisplatin.

Twenty consecutive patients with metastatic malignant melanoma were treated with a combination of 24 hours continuous infusion of dacarbazine (250 mg/m2) and cisplatin (20 mg/m2) for 5 days every 3 weeks. One patient (5%) achieved a complete response (CR) and 3 patients (15%) obtained a partial response (PR) with an overall response rate of 20%. Minimal response was observed in 5 other patients (25%). Complete response duration was 8 months. Median response duration of partial responders was 7 months. Median survival of all responders (CR+PR) was 8.5 months. Toxicity was mild to moderate.