Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study.

BACKGROUND: The long-term outcome for patients with aggressive non-Hodgkin's lymphoma (NHL) is poor. Consequently, the European Organization for Research and Treatment of Cancer Lymphoma Group designed a prospective randomized trial to investigate whether high-dose chemotherapy plus autologous bone marrow transplantation (ABMT) after standard combination chemotherapy improves long-term survival. METHODS: Patients aged 15-65 years with aggressive NHL received three cycles of CHVmP/BV polychemotherapy (i.e., a combination of cyclophosphamide, doxorubicin, teniposide, and prednisone, with bleomycin and vincristine added at mid-cycle). After these three cycles, patients with a complete or partial remission and at that time no lymphoma involvement in the bone marrow were randomly assigned to the ABMT arm (a further three cycles of CHVmP/BV followed by BEAC [i.e., a combination of carmustine, etoposide, cytarabine, and cyclophosphamide] chemotherapy and ABMT) or to the control arm (five more cycles of CHVmP/BV). All statistical tests are two-sided. RESULTS: From December 1990 through October 1998, 311 patients (median age = 44 years) were registered and received the first three cycles of CHVmP/BV, and 194 patients were randomly assigned to the treatment arms. Approximately 70% (140 patients) of these patients were of low or low-intermediate International Prognostic Index (IPI) risk. After a median follow-up of 53 months, an intention-to-treat analysis showed a time to disease progression and overall survival at 5 years of 61% (95% confidence interval [CI] = 51% to 72%) and 68% (95% CI = 57% to 79%), respectively, for the ABMT arm and 56% (95% CI = 45% to 67%) and 77% (95% CI = 67% to 86%), respectively, for the control arm. Differences between arms were not statistically significant. A subset analysis on IPI risk groups, although too small for reliable statistical analysis, yielded similar results. CONCLUSIONS: Standard combination therapies remain the best choice for most patients with aggressive NHL. We recommend that patients with IPI low or low-intermediate risk not be subjected to high-dose chemotherapy and ABMT as a first-line therapy.

Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: The present study investigates the role of short chemotherapy (five cycles) versus prolonged (12 cycles) chemotherapy in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Six hundred eighty-seven patients with SCLC were registered in a multicenter study to receive five cycles of chemotherapy consisting of cyclophosphamide 1 g/m2 on day 1, doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1, 3 and 5 (CDE), every 3 weeks. Four hundred thirty-four nonprogressing patients after five cycles of chemotherapy were randomized either to receive seven further cycles of the same chemotherapy or to follow-up. RESULTS: The response rate of 585 assessable patients was 79%, with 36% attaining a complete response. Toxicity was mainly hematologic, with 16 toxic deaths (2.4% of all eligible patients), 13 of which were due to sepsis. Median survival time from registration of all patients was 326 days (396 and 267 days for limited and extensive disease, respectively) with 3.2% of patients alive at 5 years. No difference in survival between the two arms was observed, with the same number of 5-year survivors in both arms. The patients randomized to the maintenance arm had a progression-free survival (PFS) duration approximately 2 months longer than the patients randomized to follow-up (median of 177 days v 114 days from randomization; P = .0004). Among patients with a partial response who were randomized to receive maintenance chemotherapy, 12 achieved a complete response after 12 cycles. More patients in the follow-up arm than in the maintenance arm received subsequent treatment on progression and responded more frequently to that treatment. Twelve patients developed second malignancies (seven non-small-cell lung cancers). CONCLUSION: Prolonged chemotherapy does not offer a better chance of cure than short chemotherapy (five cycles) and does not prolong survival in patients with SCLC. Short, combination chemotherapy appears to be a reasonable choice for standard treatment of SCLC and for attempts to improve the cure rate of this disease.

Epirubicin in previously untreated patients with small cell lung cancer: a phase II study by the EORTC Lung Cancer Cooperative Group.

Epirubicin 110 mg/m2 was administered intravenously every 3 weeks to 41 elderly and/or unfit, previously untreated patients with small cell lung cancer (SCLC). There were three complete responses, 16 partial responses and 14 treatment failures, with a response rate of 57% in 33 evaluable patients. The main toxicity was haematological, characterised by leukopenia and, less frequently, thrombocytopenia and anaemia. There were three toxic deaths due to infection occurring during leukopenia. Non-haematological side effects were alopecia, nausea, stomatitis and diarrhoea. WHO grade 2 cardiac toxicity was seen in 3 patients after a cumulative dose of more than 740 mg/m2. In conclusion epirubicin is an active agent in untreated SCLC.

Etoposide in malignant pleural mesothelioma: two phase II trials of the EORTC Lung Cancer Cooperative Group.

Intravenous and oral etoposide (VP 16-213) were tested in two sequential phase II trials in chemotherapy-naive patients with malignant pleural mesothelioma. In the first trial, etoposide was given intravenously (i.v.) at a dose of 150 mg/m2 on days 1, 3 and 5 every 3 weeks. The second trial investigated a daily oral dose of 100 mg for 21 days followed by a 2-week treatment-free period, and then recycling. In both trials, the treatment was given until disease progression, intolerable toxicity or patient refusal. In the i.v. trial, 49 patients were included, 2 patients were ineligible. The oral trial recruited 45 patients, 4 patients were not eligible. In both trials, the main side-effects were moderate leucopenia, alopecia, nausea and vomiting. Two partial responses (4%) and three partial responses (7%) were reported in the i.v. and oral trials, respectively. The median survival was 29 weeks and 38 weeks in the i.v. and oral trials, respectively. In conclusion, further investigation of etoposide in malignant mesothelioma is not recommended.

The influence of oral contraceptives on the time-integral of thrombin generation (thrombin potential).

The thrombin potential (TP) has been defined as the time integral of (i.e. the area under) the thrombin generation curve. It has been shown that this parameter decreases with all types of anticoagulant treatment and increases with ATIII deficiency. We evaluated the use of this parameter for detection of the hypercoagulative state known to accompany oral contraception. In fresh frozen control plasma the TP could be determined with high reproducibility (n = 82, c.v. 2.9%). The TP was linearly diminished by mixing fresh frozen plasma with prothrombin deficient plasma while a high coefficient of correlation was observed (r = 0.997). Women using oral contraceptives showed a significantly (p < 0.0001) higher TP (TP = 569 nM.min, SD = 55, n = 17), compared to men or, to women not using oral contraceptives (TP = 484 nM.min, SD = 52, n = 41). This suggests that the thrombin potential indicates the prethrombotic state known to exist in women using oral contraceptives.

PIP: The thrombin potential (TP) has been defined as the time integral of the thrombin generation curve. It has been shown that the TP decreases as a result of heparin treatment, with oral anticoagulation, and by a variety of other anticoagulants. The TP could therefore serve as a general indicator of hypocoagulability. The authors explored whether the TP would be a practical test in a hospital laboratory and whether it could detect the somewhat subtle hypercoagulative state which accompanies the use of oral contraceptives. The Thrombin Generation Test was evaluated using fresh frozen human plasma for reproducibility and linearity with respect to prothrombin concentration. The distribution of TP values was established for female oral contraceptive users and nonusers as well as for men. 17 female oral contraceptive users, 18 female nonusers, and 23 men participated in the study. In fresh frozen control plasma, the TP could be determined with high reproducibility. The TP was linearly diminished by mixing fresh frozen plasma with prothrombin deficient plasma while a high coefficient of correlation was observed. Women using oral contraceptives showed a significantly higher TP compared to men and women not using oral contraceptives. The authors have therefore found TP to indicate the prethrombic state known to exist in women using oral contraceptives.

Aprotinin protects platelets against the initial effect of cardiopulmonary bypass.

Remarkable improvement in hemostasis after cardiopulmonary bypass has been achieved by treatment with the proteinase inhibitor aprotinin, but the mechanism is still unclear. The present study is designed to elucidate the importance of platelet adhesive (glycoprotein Ib) or aggregatory (glycoprotein IIbIIIa) receptors on this hemostatic function in cardiopulmonary bypass and its improvement by aprotinin treatment. To determine whether the first pass of blood through the circuit or a continuous proteolytic attack is the main cause of platelet damage, we gave two different dose regimens of aprotinin treatment to patients undergoing coronary artery bypass grafting. Part I of the study consisted of a double-blind trial on 60 patients. Patients received placebo or aprotinin infusion (total 6.10(6) KIU) before and during bypass. A consecutive group of 22 matching patients received one single bolus of aprotinin in the pump prime (2.10(6) KIU). Blood samples were collected before and during operation to assess the effect of bypass and aprotinin on platelets and the activation of the various proteases in relation to hemostasis expressed in blood loss and blood requirements. The adhesive platelet membrane Ib glycoproteins were decreased by 50% in the untreated patients within 5 minutes of cardiopulmonary bypass and remained low during bypass, whereas glycoprotein Ib did not decrease in either group of aprotinin-treated patients. The platelet membrane IIbIIIa glycoproteins did not significantly change during bypass in either group, but fibrinogen binding to these receptors improved significantly in the 6.10(6) KIU aprotinin-treated group at the end of bypass as compared with initial values. The high continuous dose of 6.10(6) KIU aprotinin inhibited the clotting and kallikrein/kinin system throughout the operation; the pump prime dose of 2.10(6) KIU inhibited these systems only initially. Although the fibrinolytic activity was effectively inhibited in both aprotinin groups, fibrinolytic activity became apparent only at the end phase of bypass in the placebo group. However, improved hemostasis was observed intraoperatively from the start of bypass and resulted in a 40% lower blood loss intraoperatively and postoperatively and consequently a 40% lower total blood requirement in the aprotinin-treated patients than in the untreated patients. Our results therefore demonstrate that the improved hemostasis during and after bypass in patients treated with aprotinin has specifically to be attributed to a preserved adhesive capacity of platelets that was affected in the first pass of blood through the cardiopulmonary bypass circuit.

Increased anticoagulation during cardiopulmonary bypass by aprotinin.

In this prospective study, the effect of the antiproteinase aprotinin on anticoagulation during cardiopulmonary bypass was compared with placebo treatment in a randomized double-blind fashion. The kallikrein-inhibiting capacity was significantly increased in aprotinin-treated patients and decreased in the control patients. The intrinsic clotting system was also inhibited by aprotinin. We demonstrated during cardiopulmonary bypass and in vitro a significantly prolonged activated clotting time and a remarkable prolongation of the activated partial thromboplastin time by aprotinin at low heparin concentrations, whereas the antithrombin III consumption was significantly reduced. Aprotinin synergistically enhanced the anticoagulation by heparin, which allowed reduced heparinization. This is of clinical importance for use in both heparin-resistant and heparin-sensitive patients undergoing cardiopulmonary bypass and may also have advantages for routine use during bypass to reduce the adverse effects of heparin-protamine complexes.

Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass.

A placebo-controlled double-blind study of patients undergoing cardiopulmonary bypass was conducted, comparing the effects of dexamethasone and a placebo on the activation of the plasmatic systems and blood cells and on the postoperative course after cardiopulmonary bypass. In the placebo group two patterns of blood activation could be distinguished. From the start of bypass, blood-material interaction caused an increase in complement C3a and elastase concentration. After release of the aortic cross-clamp, a statistically significant increase was observed in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity (p less than 0.01, p less than 0.05, p less than 0.05, respectively). Dexamethasone treatment was not able to inhibit complement activation and elastase release during cardiopulmonary bypass. However, dexamethasone treatment effectively inhibited the increase in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity after release of the crossclamp (p less than 0.01 compared with the placebo group). In the postoperative period the patients in the placebo group had hyperthermia and hypotension and required considerable intravenous fluid administration and cardiotonic treatment. The dexamethasone-treated patients, however, showed normothermia (p less than 0.01), had significantly higher blood pressures (p less than 0.01) without supportive treatment, and consequently were in the intensive care unit for a shorter period of time. We conclude that dexamethasone prevents the hemodynamic instability after cardiopulmonary bypass and thus improves the postoperative course by inhibition of the leukocyte and tissue plasminogen activator activity generated after release of the aortic crossclamp.

Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass.

To determine whether aprotinin can provide a significant improvement of hemostasis in cardiopulmonary bypass using a membrane oxygenator, we tested this drug in a prospective, randomized, double-blind, placebo-controlled clinical trial. The subjects were 80 male patients undergoing cardiopulmonary bypass for coronary artery bypass grafting. Forty patients received aprotinin and 40 patients served as placebo controls. Aprotinin (4 x 10(6) KIU) was given as a continuous infusion, starting before operation and continuing until after cardiopulmonary bypass; additionally, 2 x 10(6) KIU aprotinin was added to the pump prime. Intraoperative and postoperative bleeding, respectively two thirds and one third of the total perioperative blood loss, were both significantly reduced in the aprotinin-treated group (p less than 0.01). The total average perioperative blood loss, corrected to a hemoglobin concentration of 7 mmol/L, was 550 mL in the aprotinin-treated patients versus 900 mL in the control patients. This reduction in blood loss, furthermore, significantly decreased the amount of postoperative blood transfusions (p less than 0.05) and increased the percentage of patients who did not receive postoperative donor blood from 42% to 68%. Aprotinin increased the activated clotting time significantly during cardiopulmonary bypass, which led to a reduction in heparin usage. The improved hemostasis during operation, despite the prolonged activated clotting time, might even abolish the need for heparin conversion with protamine at the end of cardiopulmonary bypass, thus allowing retransfusion through cardiotomy suction to be continued, which saves the blood that is currently lost with vacuum suction.

Cytogenetic toxicity of paraquat and streptonigrin in Fanconi's anemia.

We reported earlier that the frequency of chromosomal aberrations observed in Fanconi's anemia lymphocyte cultures depends on the oxygen tension during growth of the cultures, suggesting that "activated oxygen species" (superoxide, O2-; hydrogen peroxide, H2O2; hydoxyl radical, OH; and singlet oxygen, 1O2) or other reactive products generated during oxygen metabolism may be involved in the production of chromosomal damage in this syndrome. Paraquat and streptonigrin, agents that have been proposed as model compounds exerting cellular toxicity through overproduction of superoxide, were tested for their clastogenic potency in lymphocyte cultures from healthy controls and patients with Fanconi's anemia. Paraquat, at concentrations that severely affected mitotic activity (100-200 micrograms/ml), appeared to be a weak clastogen in human lymphocytes, whereas a clastogenic effect of streptonigrin was demonstrable already at a concentration as low as 0.005 microgram/ml. The results indicate that Fanconi's anemia lymphocytes fail to exhibit an increased sensitivity to the antimitotic and clastogenic effects of paraquat and streptonigrin. This suggests that intracellular superoxide is not critically involved in the generation of spontaneous chromosomal aberrations in Fanconi's anemia. We infer from these and previous data that singlet oxygen (1O2) may be a critical contributor to the chromosomal breakage in this disorder.

t(5;12)(q31;p12). A clinical entity with features of both myeloid leukemia and chronic myelomonocytic leukemia.

We report two patients with a myeloproliferative disorder (Philadelphia chromosome-negative chronic myeloid leukemia) and t(5;12)(q31;p12). Until now, only three cases of a translocation (5;12)(q31;p12) have been reported. All investigators had problems classifying their patient's disease into one of the well-defined entities of either MPD or myelodysplastic disorders. We postulate that this translocation may represent a subgroup of patients with features of both chronic myeloid leukemia and chronic myelomonocytic leukemia (CMMoL).

Platelet preservation during cardiopulmonary bypass with aprotinin.

A remarkable reduction of postoperative blood loss after cardiopulmonary bypass (CPB) has been achieved by prophylactic treatment with the proteinase inhibitor aprotinin. To reveal the mode of action of aprotinin, 23 CPB patients were randomised for aprotinin (2 x 10(6) KIU in the pump prime) or placebo treatment during CPB. Blood samples were collected before and during operation. Blood loss and blood requirements were 50% lower in the aprotinin treated patients than in the untreated patients. The adhesive capacity of platelets assessed by the amount of platelet membrane glycoprotein Ib (GP Ib) decreased by 50% in the untreated patients within 5 min of CPB and remained low during CPB, whereas GP Ib did not decrease in the aprotinin treated patients. Fibrinogen degradation products indicating plasmin activity could only be measured after 30 min of CPB in the untreated, but not in the aprotinin treated patients. The kallikrein inhibiting capacity was 34% decreased in the untreated patients within 5 min of CPB, while it increased by 84% and remained high during CPB in the aprotinin treated patients. Our results demonstrate that the improved haemostasis during and after CPB in patients treated with aprotinin can be attributed to the preserved adhesive capacity of platelets. It remains to be found whether aprotinin has a primary effect on platelets or a secondary effect by plasmin or kallikrein inhibition.

HIV-related thrombotic thrombocytopenic purpura: report of 2 cases and a review of the literature.

Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterised by the clinical pentad of microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, renal failure, fluctuating neurologic signs, and fever. The aetiology of TTP is unknown, but associations with various underlying diseases, infections and drugs have been identified. One of these associations is with HIV infection. We describe the clinical picture, the laboratory results and the response to plasma therapy of two cases of HIV-associated TTP. In both patients, a longitudinal semiquantitative assessment of the numbers of schistocytes in blood was made, which correlated well with the more traditional parameters of disease activity. Since 1987, at least 49 patients with HIV-associated TTP have been reported. A case-analysis of the 38 patients who were described in sufficient detail and a review of the literature in the setting of HIV infection is presented. The most important conclusions from these combined data are: (1) TTP usually seems to occur in patients with a CD4+ lymphocyte count < 250 x 10(6).l(-1); (2) more than 50% of the patients present with TTP soon after or during an infectious or malignant disease; (3) plasma exchange is the therapy of choice, still resulting in mortality of 22%; (4) higher initial platelet count and creatinine level are correlated with an adverse outcome.

[Accessory spleens as a cause of recurrent idiopathic thrombopenia]. / Bijmilten als oorzaak van een recidief van idiopathische trombopenie.

A female aged 62 yr developed a recurrence of chronic idiopathic thrombocytopenia 7 years after splenectomy. Two accessory spleens were identified and removed surgically. An increase in platelet count was seen. An analysis of the literature shows that extirpation of accessory spleens was successful in over 60% of the patients (32/52) with recurring idiopathic thrombocytopenia after splenectomy.

[Non-traumatic myositis ossificans circumscripta in the teres major muscle]. / Niet-traumatisch ontstane myositis ossificans circumscripta in de M. teres major.

A 49-year-old male presented with a painful progressive swelling in his right axillar region, without further complaints, which had been present for 2 weeks. On radiological examination a peripheral circumferential zone of mineralisation was seen in the right teres major muscle. An incision biopsy specimen showed a lesion of fibroblastic tissue in which areas of osteoid and fragmented lamellar bone tissue, without signs of malignancy. The diagnosis was myositis ossificans circumscripta. This is a rare benign ossifying lesion in skeletal muscles, mostly caused by a trauma and with an average age of occurrence between 20 and 30 years old. It must be differentiated from extra-skeletal osteosarcoma. The pathogenesis is unknown. Because it is a benign and self-limiting disorder, surgical excision is only necessary in case of mechanical hindrance. The patient's swelling partially regressed and he had no further complaints.

[A gastric signet ring cell carcinoma as the first expression of a breast carcinoma]. / Een zegelringcelcarcinoom van de maag als eerste uiting van een mammacarcinoom.

A 73-year-old woman presented with dull pain in the epigastric region, a rapid feeling of fullness upon eating and a weight loss of 10 kg in 6 months. Further examination showed linitis plastica due to a signet ring cell carcinoma in the stomach, multiple bone metastases, and an occult, small breast tumour. Immunohistochemical comparison of the tumours strongly suggested that all cases involved a metastasised breast carcinoma. At check-up after one year of tamoxifen treatment, the complaints had disappeared and the activity of the tumour marker had dropped. Gastric metastases from breast carcinoma are rare. Nevertheless, this possibility should be kept in mind in women presenting with malignancies of the stomach and mastopathy. Hormonal treatment and chemotherapy may result in reasonable palliation.