Biomedical subjects
Publications and source records attributed to L T Vlasveld.
Epstein-Barr virus-specific polymerase chain reaction was used to diagnose EBV-meningo-encephalitis in a bone marrow transplant recipient. The patient made complete recovery with ganciclovir treatment. Pitfalls in diagnosis with EBV-PCR and the potential therapeutic efficacy of ganciclovir in EBV infections are discussed.
A 40-year-old man developed cortical blindness during cyclosporin treatment shortly after an allogeneic bone marrow transplantation for chronic myeloid leukaemia. At that time the patient had a therapeutic cyclosporin blood level (226 ng/ml), but a low serum magnesium level and a marginally decreased serum cholesterol level. In addition the patient had hypertension, headache and paraesthesia in the oral, palmar and plantar areas. Vision was fully recovered after discontinuation of the cyclosporin treatment and correction of the hypomagnesaemia. Eighteen cases of cortical blindness during cyclosporin treatment are now known in the literature. Hypomagnesaemia appears to be implicated in the pathogenesis.
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BACKGROUND: Previously we described the immunological and clinical effects of prolonged continuous infusion of low dose rIL-2. In this phase II study we explored the therapeutic efficacy of intermittent continuous infusion of low dose rIL-2. PATIENTS AND METHODS: We selected 15 patients with advanced melanoma and 8 patients with renal cell cancer in good clinical condition, with low tumour burden and no previous systemic treatment. A treatment cycle consisted of infusion of 1.8 x 10(6) IU/m2/24 hrs rIL-2 for 3 weeks on an out-patient basis followed by a 3-week rest. A maximum of four cycles were given. RESULTS: A total of 35 cycles were given. Treatment was well tolerated. Transient hyperthyroidism occurred in 8 patients. No objective responses were noted. We noted a high incidence of central nervous system involvement occurring shortly after treatment. CONCLUSIONS: Intermittent continuous infusion of low dose rIL-2 in advanced melanoma and renal cell cancer is well tolerated but the initial therapeutic results are not promising.
We report a patient who developed acute myeloid leukaemia (M2) shortly after successful treatment of a mediastinal germ cell tumour. The leukaemia was preceded by a documented myelodysplastic phase. Complex cytogenetic abnormalities were found in bone marrow and peripheral blood cells including +i(12p), typical of germ cell malignancy. Fluorescence in situ hybridization revealed the presence of +i(12p) in myeloblasts, erythroblasts and neutrophils but not in lymphocytes. This case provides further evidence for a common clonal origin of haematological malignancies and mediastinal germ cell tumours.
In this study we evaluated the catheter-related complications in 52 patients with advanced melanoma, renal cell cancer or non-Hodgkin's lymphoma treated with continuous infusion of low-dose recombinant interleukin-2 by central venous access (CVA) of the port-a-cath type. We noted a high incidence (55.5%) of catheter infection, defined as positive blood cultures drawn from the CVA in symptomatic or asymptomatic patients. Six infections were noted before rIL-2 treatment was started. Twelve of the 30 documented infections were symptomatic (fever and/or chills), with only four documented bacteraemias. The most frequently cultured microorganism was Staphylococcus epidermidis (73%). Treatment initially consisted of systemic antibiotics via the CVA, but as experience increased, the mostly asymptomatic CVA infections were not treated. In 30% of the documented CVA infections a thrombus at the tip of the catheter was found by radiological contrast examination. Local thrombosis can be effectively treated with constant infusion of low dose streptokinase via the CVA.
Peripheral blood stem cells can reconstitute bone marrow function after high-dose chemo-/radiotherapy. We describe 17 patients treated with a three-day course of chemotherapy consisting of cyclophosphamide or ifosfamide and etoposide (malignant lymphoma and germ cell tumor) or a one-day course of 5-fluorouracil, epidoxorubicin and cyclophosphamide (breast cancer), followed by the administration of recombinant human granulocyte colony-stimulating factor (G-CSF). Maximum numbers of peripheral blood stem cells were recruited on day 9-10 of the G-CSF administration with 0.1 x 10(9)/l CD34+ cells (median; range 0-0.36). The total number of peripheral stem cells harvested with two-three leukaphereses was 40 x 10(4)/kg CFU-GM (4-257) or 8 x 10(6)/kg CD34+ cells (1-39). Ten patients with malignant lymphoma or solid tumours received high-dose chemotherapy followed by bone marrow and peripheral stem cell infusion (n = 7) or peripheral stem cell infusion alone (n = 3). The recovery of granulocytes, platelets and reticulocytes after peripheral stem cell infusion, in addition to or instead of bone marrow, was markedly accelerated compared with the infusion of BM alone. The accelerated haemopoietic recovery was associated with a reduction in platelet and red blood cell transfusion, reduction in fever periods and earlier discharge from hospital. Peripheral stem cell transplantation may become an important alternative to autologous bone marrow transplantation. This transplantation technique may also allow application of multiple-cycle intensive chemotherapy.
A patient with renal cell cancer developed acute renal failure due to biopsy-proven acute tubulo-interstitial nephritis (AIN) in the 6th week of continuous infusion of 9 x 10(6) IU m-2 day-1 recombinant interleukin-2 (rIL-2). We investigated whether the AIN was the result of a cellular cytotoxic reaction induced by the rIL-2 treatment. The cytolytic activity of cryopreserved peripheral blood lymphocytes (PBL), isolated before and at the end of the rIL-2 treatment (at the time of AIN), was studied after 5 days of culture with or without rIL-2 or anti-CD28 and immobilized anti-CD3 antibodies. The PBL isolated before and at the end of the rIL-2 treatment showed cytolytic activity towards a number of allogeneic targets. However, only the PBL isolated at the end of the rIL-2 treatment showed, when stimulated with rIL-2 in vitro, significant cytolytic activity against an autologous renal cell line cultured from the AIN biopsy specimen and against an allogeneic renal cell cancer cell line. These PBL displayed no enhanced killing capacity towards autologous PBL and the melanoma cell line M14. These observations suggest that the AIN may be the result of a cytotoxic lymphocyte-mediated reaction induced by the rIL-2 treatment.
In a previous clinical study using a continuous infusion schedule of recombinant interleukin-2 (rIL-2) we noted a nearly complete loss of activity of EuroCetus rIL-2 when dissolved in 10 ml saline and infused at a very low rate through a plastic infusion device. In the present study, we demonstrated that the loss resulted from a concentration-dependent precipitation of rIL-2 in saline and adherence of the protein to the tubing material. These phenomena were not noted for four other rIL-2 muteins tested [Glaxo, Hoffmann-LaRoche, Amgen (2 muteins)]. EuroCetus rIL-2 was found to be completely soluble in water and 5% glucose.
Previously we described the clinical aspects of a phase I study of prolonged continuous infusion of low-dose recombinant interleukin-2 (rIL-2). In the present paper we report several immunological effects in 13 patients with melanoma and renal cell cancer treated on an out-patient basis with rIL-2 for uninterrupted periods ranging from 5 to 18 weeks. Groups of three patients were treated at following dose levels 0.18, 0.6, 1.8 or 6 x 10(6) IU m-2 24 h-1 and one patient was treated with 3 x 10(6) IU m-2 24 h-1. Prolonged rIL-2 treatment resulted in a dose-dependent and sustained increase in the percentage and absolute number of (CD56+, CD8dim) natural killer cells. Within this population a preferential increase in the CD56bright cells with low expression of CD16 was observed. The CD27 antigen was also upregulated in the CD56bright CD16dim population. This increase of NK cells was accompanied by an enhancement of the cytotoxic capacity of the peripheral lymphocytes. No consistent signs of T cell activation or expansion were noted.
OBJECTIVE: Major thromboses can occur in the venous system in association with central venous catheters. This usually necessitates removal of the catheter. METHODS: The effectiveness of low dose recombinant tissue type plasminogen activator (rt-PA) in combination with heparin was assessed in patients with central venous catheter associated thrombosis. RESULTS: In five patients, all suffering from cancer, a 5-7 day continuous infusion resulted in complete lysis of the thrombus without complications in three. In the other two patients moderately severe haemorrhage was observed with only partial lysis, of the thrombus. CONCLUSIONS: The infusion of heparin and rt-PA is potentially effective in thrombosis related to use of central venous catheters, but the risk of haemorrhage is not inconsiderable.
A 44-year-old man who had achieved a complete remission of malignant peritoneal mesothelioma after the intraperitoneal administration of 25 mg/m2 mitoxantrone presented with clinical and radiological signs of intestinal obstruction suggestive of recurrent disease at about 2 years following the initial treatment. However, laparotomy revealed extensive adhesive fibrosis but no sign of malignant mesothelioma. The peritoneal complications of intraperitoneal cytostatic treatment are discussed.
The optimal schedule for recombinant interleukin-2 (rIL-2) administration is unclear. Because the clinical and immunological effects of prolonged continuous exposure to rIL-2 are unknown, we have conducted a phase I study to assess the toxicity and feasibility of continuous low dose infusion of rIL-2 (EuroCetus) using central venous access with a portable infusion device on an out-patient basis. Twenty-two patients entered the study, 13 with melanoma and nine with renal cell cancer, age range 26-66 years (median 51), performance status less than or equal to 1. They were treated with one of the following doses per m2 per 24 h: 0.18 x 10(6) IU, 0.6 x 10(6) IU, 1.8 x 10(6) IU, 3 x 10(6) IU, 6 x 10(6) IU and 9 x 10(6) IU. Toxicity was evaluable in 20 patients receiving greater than or equal to 3 weeks treatment duration or in whom treatment was discontinued prematurely because of toxicity. Constitutional symptoms consisting of fatigue, malaise and fever up to 40 degrees C without significant organ dysfunction occurred with doses greater than or equal to 1.8 x 10(6) IU m-2. The maximum tolerated dose was 6 x 10(6) IU m-2 24 h-1. In all patients toxicity reached a peak at 3 weeks and resolved thereafter despite continued rIL-2 treatment. Peripheral blood eosinophilia (up to 66% of white blood cell count) followed the same pattern. An infection of the central venous access occurred in 55% of the patients but this was mostly asymptomatic. Thirteen patients were treated greater than or equal to 6 weeks and were evaluable for tumour response. A partial remission occurred in a patient with melanoma with a dose of 1.8 x 10(6) IU rIL-2 m-2 24 h-1.
Sixteen patients received a high-dose chemotherapy regimen consisting of carboplatin (1600 mg/m2) and cyclophosphamide (6000 mg/m2) as daily two-hour infusions over four days (CC). All but two of them also received thiotepa (480 mg/m2) in eight 30-minute infusions given every 12 hours (CTC). Bone marrow and/or peripheral stem cell (PSC) reinfusions took place 72 hours after the last course of chemotherapy. The major toxicity was bone marrow suppression, the duration of which was markedly reduced in the patients receiving PSC reinfusions. Non-hematological toxicity was relatively mild and consisted of nausea and vomiting, minor mucositis and skin rashes. All but one patient had mild and completely reversible elevations of serum ALAT and/or LDH levels. One patient, who had received full-dose chemotherapy despite a creatinine clearance of 56 ml/min, developed significant toxicity consisting of transient cyclophosphamide-associated pancarditis, reversible neurotoxicity and partially reversible hearing loss and renal function impairment. There were no toxic deaths. In view of the high carboplatin dose, the CTC regimen may be particularly suitable for use in the salvage treatment of germ cell cancer. Since CTC causes no serious organ toxicity, further studies to determine its suitability for double or even triple transplantation programs are warranted.
Eleven patients with testicular cancer, either relapsing after or refractory to cisplatin-based chemotherapy, underwent salvage chemotherapy with high-dose carboplatin (800 mg/m2 on day 1) and high-dose etoposide (500 mg/m2 on days 1, 3 and 5). A total of 21 courses were administered. The major toxicity consisted of profound myelosuppression. There were two toxic deaths, both caused by infection during neutropenia. Bone marrow recovery was usually complete around day 26 (range 19-129). Other toxicities included mild mucositis, nausea and vomiting, and alopecia. No significant neurotoxicity or hearing loss were observed and only one patient had a moderate decrease in renal function. Nine of ten evaluable patients responded, with one complete remission, 6 partial remissions with normalization of tumor markers, and two partial remissions with over one log decrease of tumor markers. The duration of these remissions was not evaluable, since only three evaluable and responding patients did not receive additional therapy after HD-CE. All three relapsed after discontinuing chemotherapy. HD-CE has activity in relapsing or refractory testicular cancer and can be administered without bone marrow support. The regimen may thus be suitable to be used as a remission induction regimen prior to consolidation with intensive chemotherapy and autologous bone marrow transplantation.
A 47 year old woman presented with invasive pulmonary aspergillosis complicated by subclavian artery occlusion and rib fracture due to fungal osteomyelitis. This followed persistent pancytopenia resulting from autologous bone marrow transplantation for metastatic breast cancer.
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OBJECTIVE: A case in which a possible cisplatin interference with lithium pharmacokinetics is evaluated. DATA SYNTHESIS: A 36-year-old woman with disseminated cervical cancer and multiple metastatic lesions in both kidneys was being treated with five courses of bleomycin, vindesine, mitomycin C, and cisplatin. The patient had also been taking lithium carbonate for the management of a manic-depressive disorder. Serum and urinary lithium concentrations were measured daily during the first course of chemotherapy and on a periodic basis during and between the consecutive courses. Lithium concentrations remained within the therapeutic range during the first course and increased later in association with deterioration of the patient's renal function secondary to progressive disease in both kidneys. This required dose adjustments of lithium. CONCLUSIONS: Lithium therapy should be guided by serial serum concentrations in such patients.