Interferon-alpha as maintenance therapy in patients with multiple myeloma.

BACKGROUND: The effect of interferon-alpha 2b (IFN-alpha-2b) on progression-free and overall survival as well as quality of life (QoL) was studied in mainly elderly patients with multiple myeloma (MM), who reached a plateau phase after melphalan/prednisone induction. PATIENTS AND METHODS: In an open phase III trial, 262 patients, median age 69 years (range 34-91), received at least 10 monthly courses of melphalan/prednisone followed by response evaluation. Plateau phase was reached by 128 patients. Next, 90 patients were randomized between IFN-alpha-2b and no maintenance therapy. Reasons for non-randomization were: refusal (18), concomitant disease (nine), protocol violation (six), WHO performance status >2 (four) and allogeneic transplantation (one) RESULTS: At a median follow-up from diagnosis of 97 months (0-140) for those patients alive, IFN-alpha-2b therapy was associated with improved progression-free survival (median 13.5 versus 8.4 months from randomization), although this did not translate in a better overall survival (41 versus 38.4 months). One-third of patients discontinued IFN-alpha due to toxicity. No differences were observed between patient groups in QoL. CONCLUSIONS: IFN maintenance therapy in MM prolongs progression-free survival and, provided that the burden of toxicity is not too high, does not adversely affect QoL.

Alveolar soft-part sarcoma responding to interferon alpha-2b.

A 23-year-old woman with an alveolar soft-part sarcoma of her calf with pulmonary metastases unresponsive to chemotherapy is described. Interferon (IFN) alpha-2b induced an impressive tumour response still ongoing after IFN treatment had to be stopped because of a psychosis. An explanation of this effect is still speculative.

[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.

[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.

D-TRP-6-LHRH (Triptorelin) is not effective in ovarian carcinoma: an EORTC Gynaecological Cancer Co-operative Group Study.

Between March and September 1988, 74 patients with progressive ovarian cancer after prior platinum-based therapy were treated with the luteinizing hormone-releasing hormone (LHRH) agonist Triptorelin (Decapeptyl degrees). Treatment consisted of i.m. injection of 3.75 mg of microencapsulated Triptorelin on days 1, 8 and 28 followed by 4-weekly injections until tumor progression. No objective responses were observed. Eleven out of 68 evaluable patients (16%) had stable disease. The median progression-free survival was 5 months in patients with disease stabilization and 2 months for all evaluable patients. The median survival for patients with disease stabilization was 17 months, whereas for all patients it was 4 months. The treatment was well tolerated; the only reported adverse events were incidental hot flushes. This study showed that the LHRH agonist Triptorelin has only modest efficacy in patients pretreated with platinum-containing chemotherapy.

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.

Nadroparin versus dalteparin anticoagulation in high-volume, continuous venovenous hemofiltration: a double-blind, randomized, crossover study.

OBJECTIVES: To compare filter survival times during high-volume, continuous venovenous hemofiltration in patients with normal coagulation variables, using anti-factor Xa bioequivalent doses of nadroparin and dalteparin. To evaluate which other factors influence filter survival time. DESIGN: Randomized, prospective, double-blind, crossover study. SETTING: An 18-bed intensive care unit in a 530-bed teaching hospital. PATIENTS: Thirty-two critically ill patients with renal failure, treated with high-volume, continuous venovenous hemofiltration. INTERVENTIONS: High-volume, postdilutional continuous venovenous hemofiltration, with a standard blood flow rate of 200 mL/min and an ultrafiltrate volume of 100 L in 24 hrs, was performed with a highly permeable, large-surface cellulose triacetate membrane. Anticoagulation with anti-Xa bioequivalent doses of nadroparin and dalteparin was administered in the extracorporeal line before the filter. Blood was sampled for determination of coagulation variables before hemofiltration, 0.5, 2, 4, 6, and 12 hrs after starting the treatment, and at the end of the hemofiltration run. MEASUREMENTS AND MAIN RESULTS: Anti-Xa peak activity, time of anti-Xa peak activity, area under the curve for 0-3 hrs and filter survival time were not significantly different using nadroparin or dalteparin. When analyzing the patients according to the length of filter survival time, no relationship among anti-Xa peak activity, area under the curve for 0-3 hrs, and filter survival time was found. However, there was a strong trend toward a negative correlation between baseline platelet count and filter survival time (r2 = .11; p = .07). Mean blood urea nitrogen decreased from 81.0+/-31.9 to 41.1+/-21.2 mg/dL (p<.01) and mean creatinine decreased from 3.4+/-1.8 to 1.9+/-1.2 mg/dL (p<.01). There were no clinically important bleeding complications. CONCLUSIONS: Nadroparin and dalteparin are bioequivalent with respect to their anti-Xa activities. Using either drug, we did not find a difference in filter survival time during high-volume, continuous venovenous hemofiltration. No relationship between anti-Xa activity and filter survival time could be found. However, there is a strong trend toward a negative correlation between baseline platelet count and filter survival time. This suggests that during high-volume, continuous venovenous hemofiltration, patients with a higher baseline platelet count might need a different anticoagulation regimen to obtain longer filter survival times.

Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant.

BACKGROUND: Microparticles from platelets and other cells have been extensively studied and characterized in vitro. Although the level of platelet-derived microparticles is elevated in a variety of diseases, including cardiac surgery, virtually nothing is known about their functions in vivo. The aim of the present study was to investigate the procoagulant properties of microparticles generated in vivo. METHODS AND RESULTS: In 6 patients at the end of cardiopulmonary bypass, 14.8 x 10(9)/L (median; range, 9.7 to 27.4 x 10(9)/L) platelet-derived microparticles were present in pericardial blood, whereas blood obtained from the systemic circulation contained 1.6 x 10(9)/L (median; range, 0.4 to 8.9 x 10(9)/L) of such microparticles, as determined by flow cytometry. Microparticles stained positively for phosphatidylserine as determined with labeled annexin V. In contrast to systemic blood, pericardial blood contained not only microparticles of platelet origin but also microparticles that originated from erythrocytes, monocytes, or granulocytes, and other hitherto unknown cellular sources. Plasma prepared from pericardial blood and to a lesser extent plasma from systemic blood obtained at the same time, stimulated formation of thrombin in vitro. This activity of pericardial plasma was lost after removal of its microparticles by high-speed centrifugation, whereas the corresponding microparticle pellet was strongly procoagulant. The generation of thrombin in vitro involved a tissue factor/factor VII-dependent and factor XII-independent pathway. CONCLUSIONS: This study is the first to demonstrate that microparticles generated in vivo can stimulate coagulation.

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.

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.

Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial.

We performed an open, nonrandomized, multicenter phase-II trial to evaluate the efficacy and toxicity of 1 year of treatment with the oral iron chelator deferiprone in 38 mainly nonthalassemic patients with transfusional iron overload. Initial serum ferritin varied between 996 and 11.644 micrograms/l. Patients were treated with 3-6 g of deferiprone daily. Mean urinary iron excretion (UIE) in 36 evaluable patients was 21.0 mg/24 h and was significantly higher in the patients with thalassemia than in those with myelodysplasia. Negative iron balance was achieved in 20 patients (56%). The median duration of treatment was 10 months; due to side effects and other causes only 20 patients completed 1 year of treatment. Mean serum ferritin levels decreased from 3563 micrograms/l at the start of the trial to 2767 micrograms/l at 6 months (26 patients, p < 0.004) and to 2186 micrograms/l at 12 months (20 patients, p < 0.005). Serum ferritin levels normalized in two patients who were no longer transfusion dependent. Deferiprone was clearly not effective in three patients (two with myelofibrosis, one with myelodysplasia). One patient with myelodysplasia developed agranulocytosis after 12 months of treatment; this was rapidly reversible after stopping deferiprone. Three patients had a mild and transient decrease in white blood cell count. Other side effects leading to withdrawal from the trial consisted mainly of nausea (3 patients), arthralgia (2), and skin rash (1). No clinical signs of zinc deficiency were seen, although zinc excretion was increased in three patients. No changes were seen in liver enzymes, creatinine, antinuclear factor, T-cell subsets, cardiac function, visual acuity, and audiogram. Although our results confirm deferiprone as an effective iron chelator in patients with thalassemia and in some patients with other forms of iron overload, there is still some concern about the safety of this drug, which therefore, at this time, should be used exclusively in well-controlled clinical trials.

Influence of heparin, protamine and polybrene on the time integral of thrombin generation (endogenous thrombin potential).

We investigated the anticoagulating and heparin-neutralizing properties of protamine and polybrene (hexadimethrine bromide), using the endogenous thrombin potential (ETP) as the parameter to access plasma coagulability. The hypocoagulability induced by high doses of heparin (3 IU/ml) could be reversed by addition of protamine to a very limited extent only. Polybrene on the other hand did neutralize heparin at the equivalent concentration and a two-fold excess did not influence the ETP parameters. In vivo neutralization of high-dose heparin with protamine should therefore be reconsidered. Our experiments suggest polybrene to be superior over protamine with respect to neutralization of high doses of heparin.

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.

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.

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).

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.

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.

[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.