New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide.

OBJECTIVE: Assessing a diverse biomarker panel (NT-proBNP, TNF-α, galectin-3, IL-6, Troponin I, ST2 and sFlt-1) to detect subclinical cardiotoxicity after treatment with anthracyclines. METHODS: Of 55 breast cancer patients biomarkers were assessed and echocardiography was performed one year after treatment with anthracyclines. RESULTS: 29.1% of patients showed abnormal biomarker levels: NT-proBNP in 18.2%, TNF-α and Galectin-3 in 7.3%. IL-6, troponin I, ST2 and sFlt-1 were normal in all patients. A correlation between left ventricular ejection fraction (LVEF) and NT-proBNP was observed (r = -0.564, p ≤ 0.01). CONCLUSION: The evaluated biomarkers do not contribute to early detection. Future research should focus on NT-proBNP.

Thalidomide and lenalidomide in primary myelofibrosis.

Primary myelofibrosis is a clonal haematopoietic stem cell disease, characterised by marrow stromal fibrosis, extramedullary haematopoiesis, splenomegaly, hepatomegaly and progressive cytopenia. Therapeutic options once cytopenia has developed are limited to supportive care, such as erythrocyte transfusions and growth factors. The aetiology has become more clear, especially since JAK-2 mutations were found, resulting in increased production of cytokines. The immune-modulating drug thalidomide and its derivative lenalidomide have shown to be effective in reducing cytopenia, most probably by inhibiting the cytokine responses. In some patients the bone marrow fibrosis disappears. We describe the experience with these drugs in a cohort of 14 patients for thalidomide and seven for lenalidomide (in six patients lenalidomide was given after thalidomide and one patient received lenalidomide upfront). Thalidomide gave clinical improvement in 6/14 patients, but its use was limited mainly due to toxicity, especially the development of neuropathy. The drug could be given for a median period of 15.5 months in responding patients. Lenalidomide was effective in 4/7 of the patients, in some patients with no response on thalidomide. Due to the more favourable toxicity profile, the median duration of therapy was 19 months, with 3/4 patients on therapy longer than 19 months. These data are discussed in view of the clinical studies published. We conclude that lenalidomide is preferred in myelofibrosis, given a higher response rate and more favourable toxicity profile. If no response the addition of prednisone can be considered. In some patients it can normalise haemoglobin and make them transfusion independent.

[Cardiotoxicity of trastuzumab of significance in the adjuvant treatment of breast cancer]. / Cardiotoxiciteit van trastuzumab van betekenis bij de adjuvante behandeling van borstkanker.

Three women aged 53, 52 and 36 years, respectively, underwent surgery for breast cancer, i.e. right-sided grade II invasive ductal carcinoma, left-sided grade III invasive ductal carcinoma, and left-sided multifocal grade III invasive ductal carcinoma, respectively. All 3 received adjuvant anthracycline-containing chemotherapy followed by trastuzumab. They developed significant cardiac dysfunction, as determined by a decrease in left ventricular ejection fraction (LVEF), which necessitated trastuzumab discontinuation. Trastuzumab therapy was resumed in the third patient after LVEF recovery but was stopped definitively when the LVEF decreased again. Trastuzumab has been shown to improve both disease-free and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, symptomatic cardiac failure due to cardiomyopathy has been observed in 0.6-4.1% of patients treated with trastuzumab after adjuvant anthracycline-based chemotherapy, whereas in 5-19% of the patients the decline in cardiac function led to permanent discontinuation of trastuzumab therapy. Cardiac function should be monitored regularly during trastuzumab therapy. An LVEF less than 50% or an absolute reduction of more than 10% warrant treatment discontinuation and close follow-up. Cardiac dysfunction is usually reversible; however, the long-term consequences of LVEF reduction following trastuzumab therapy are still unknown and warrant close attention, given the relatively young age and long life expectancy of these patients.

Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation.

Donor lymphocyte infusions (DLI) are used to treat relapsed haematological diseases after allogeneic stem cell transplantation (SCT). We treated seven patients with DLI for indolent non-Hodgkin's lymphoma relapsed after SCT. In available blood and bone marrow samples, lymphoma cells were analysed by real-time quantitative polymerase chain reaction of t(14;18)-positive cells in follicular lymphoma, and by immunophenotyping in small lymphocytic lymphoma. Before DLI, three patients were treated with chemo- and/or radiotherapy, and one with rituximab. Evaluable responses to pre-DLI therapy were stable disease in one and partial remission (PR) in two patients. Six patients responded to DLI (complete remission (CR) in four and PR in two). After DLI, acute graft-versus-host disease (GVHD) occurred in 3/6 patients, classified as grade 2, whereas only limited chronic GVHD was seen (n=5). The four continuous CR are lasting for median 65+ (43-89) months. In the remaining patient, not responding to DLI, progressive disease was seen later on; chemotherapy followed by another DLI resulted in CR. In three cases, clinical responses to DLI could be substantiated by molecular or immunophenotypic analysis of lymphoma cells. We conclude that DLI is effective for treatment of indolent lymphoma relapsing after SCT.

Dynamics of circulating t(14;18)-positive cells during first-line and subsequent lines of treatment in follicular lymphoma.

In follicular lymphoma the t(14;18) might be useful as a tumor marker in predicting the quality of the response to treatment. We investigated whether analyzing numbers of t(14;18)-positive cells in peripheral blood correlated with remission status in individual patients receiving a variety of treatments. Numbers of circulating t(14;18)-positive cells were determined by real-time polymerase chain reaction (PCR) technique. Disease parameters and response to treatment were related to the pre- and post-treatment numbers of circulating t(14;18)-positive cells for 53 follicular lymphoma patients. In these 53 patients, 70 treatment episodes were investigated. A content of more than 328 t(14;18)-positive cells per 75,000 cells prior to therapy correlated with the more advanced stage IV disease ( P=0.01), bone marrow involvement ( P<0.01), and overt leukemic lymphoma ( P=0.04). Therapy episodes that cleared circulation from t(14;18)-positive cells with more than one log resulted in a significantly longer progression-free survival than treatment episodes with less than one log decline (26 versus 12 months, respectively) ( P<0.01). After first-line treatment episodes, numbers of circulating t(14;18)-positive cells declined in fairly all cases, irrespective of the clinical response. However, for second or later lines of treatment, declining numbers of lymphoma cells correlated with a clinical remission, whereas increasing numbers of lymphoma cells were associated with clinically stable or progressive disease. From this, we conclude that quantitation of circulating t(14;18)-positive cells in peripheral blood is of only limited clinical significance in predicting treatment efficacy for the individual follicular lymphoma patient.

Lack of correlation between numbers of circulating t(14;18)-positive cells and response to first-line treatment in follicular lymphoma.

In follicular lymphoma, the t(14;18) status of the peripheral blood and bone marrow analyzed by polymerase chain reaction (PCR) is assumed to correlate with disease activity in patients with relapsed disease. The clinical significance of quantitating circulating lymphoma cells by real-time PCR is reported in patients on first-line treatment. Thirty-four consecutive patients with previously untreated follicular lymphoma and detectable t(14;18)-positive cells in pretreatment peripheral blood samples were monitored. All patients were treated with standard chemotherapy in combination with interferon alfa-2b. Before and after induction therapy, blood samples were taken for quantitative analysis of t(14;18). At presentation, a median of 262 t(14;18)-positive cells per 75,000 normal cells was found (range, 1-75 000). Patients with lower numbers of circulating tumor cells more frequently had bulky disease (P =.02). Seventy-nine percent of the patients responded clinically to treatment. In 22 of 28 patients, including 4 patients in whom treatment had failed clinically, the number of circulating t(14;18)-positive cells decreased to undetectable or low levels after therapy. In the remaining responding patients, circulating tumor cells persisted after therapy. These quantitative data on circulating t(14;18)-positive cells call into question the usefulness of molecular monitoring of the blood in a group of patients with follicular lymphoma uniformly treated with a noncurative first-line regimen. T(14;18)-positive cells decreased in peripheral blood after treatment, irrespective of the clinical response. Therefore, the significance of so-called molecular remission should be reconsidered in follicular lymphoma. (Blood. 2001;98:940-944)

A novel method to compensate for different amplification efficiencies between patient DNA samples in quantitative real-time PCR.

Quantification of residual disease by real-time polymerase chain reaction (PCR) will become a pivotal tool in the development of patient-directed therapy. In recent years, various protocols to quantify minimal residual disease in leukemia or lymphoma patients have been developed. These assays assume that PCR efficiencies are equal for all samples. Determining t(14;18) and albumin reaction efficiencies for sixteen follicular lymphoma patient samples revealed higher efficiencies for blood samples than for lymph node samples in general. However, within one sample both reactions had equivalent efficiencies. Differences in amplification efficiencies between patient samples (low efficiencies) and the calibrator in quantitative analyses result in the underestimation of residual disease in patient samples whereby the weakest positive patient samples are at highest error. Based on these findings for patient samples, the efficiency compensation control was developed. This control includes two reference reactions in a multiplex setting, specific for the beta-actin and albumin housekeeping genes that are present in a constant ratio within DNA templates. The difference in threshold cycle values for both reference reactions, ie, the Ct(2) value, is dependent on the amplification efficiency, and is used to compensate for efficiency differences between patient samples and the calibrator. The beta-actin reference reaction is also used to normalize for DNA input. Furthermore, the efficiency compensation control facilitates identification of patient samples that are so contaminated with PCR inhibitory compounds that different amplification reactions are affected to a different extent. Accurate quantitation of residual disease in these samples is therefore impossible with the current quantitative real-time PCR protocols. Identification and exclusion of these inadequate samples will be of utmost importance in quantitative retrospective studies, but even more so, in future molecular diagnostic analyses.

[Stem cell transplantation in patients with low-grade non-Hodgkin lymphoma]. / Stamceltransplantatie bij patiënten met een non-Hodgkin-lymfoom van lage maligniteitsgraad.

Patients with a non-Hodgkin lymphoma of low-grade malignancy have been considered incurable for decades. Several conventional therapies have resulted in an improved disease-free survival but not in a prolonged overall survival. Intensified treatment of relapsed patients with myeloablative conditioning followed by autologous or allogeneic stem cell transplantation (SCT) is being applied more and more. In both forms of SCT the anti-tumour effect of the high-dose chemo- (and radio-) therapy is used; allogeneic SCT has an additional so-called graft-versus-lymphoma effect. Thus allogeneic SCT appears to be a promising and potentially curative treatment for this patient group, despite complications like graft-versus-host disease and higher treatment-related mortality. Early in the course of a low-grade NHL, especially at first relapse, an allogeneic SCT should at least be considered for a patient having an HLA-compatible stem cell donor.

Allogeneic bone marrow transplantation with T-cell-depleted marrow grafts for patients with poor-risk relapsed low-grade non-Hodgkin's lymphoma.

We present the clinical results of allogeneic bone marrow transplantation (BMT) with T-cell-depleted grafts from HLA-matched sibling donors in patients with poor-risk relapsed low-grade non-Hodgkin's lymphoma (NHL). Poor risk was defined as relapse within 12 months after or progression during prior treatment. The conditioning regimen consisted of cyclophosphamide and total-body irradiation with or without additional idarubicin. Donor marrow was depleted of T lymphocytes using counterflow centrifugation. Post-BMT prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine A. 15 patients with a median age of 47 years (range 30-57) were transplanted. All patients engrafted. After a median follow-up of 36 months (range 9-78), 10 patients were alive and in complete remission (CR). Two of them had relapsed after BMT but re-entered CR following infusions of leucocytes from the original bone marrow donor. Five patients died; causes of death were cardiomyopathy (n = 1), chronic GvHD (n = 1) and infection during chronic GvHD (n = 3). We conclude that allogeneic T-cell-depleted bone marrow transplantation is an efficacious treatment for patients with poor-risk relapsed low-grade NHL. Infusions of donor leucocytes reinduced CR in the two patients with relapse after BMT.

A patient with fatal cold haemagglutinins.

We describe a patient with an acute fatal autoimmune haemolytic anaemia (AIHA) due to idiopathic cold haemagglutinins. According to the literature the dramatic course of this cold haemagglutinin disease is uncommon.

Renal replacement therapy in the elderly.

BACKGROUND AND METHODS: In a retrospective study the medical records of 122 patients aged over 65 years at the start of renal replacement therapy (RRT) in our dialysis centre were analysed. RESULTS: The mean age at the start of RRT was 72.7 +/- 5.7 years (range 65.0-90.3). Seventy-six percent were treated with haemodialysis, 21% with haemofiltration and 3% with continuous ambulatory peritoneal dialysis. There was no significant difference in survival between the different modes of treatment. The median survival was 23.8 months, the actuarial survival rates at 2, 5 and 7 years were 50, 27 and 18%, respectively. Patients aged between 65 and 75 years had a median survival of 36.4 months, patients above 75 years of 12.5 months (P = 0.009). Patients with tubulo-interstitial nephritis had a significantly longer survival than patients with other renal diseases. When chronic obstructive pulmonary disease or peripheral vascular disease was present, there was a significantly shorter survival. There was no difference in survival between patients with malignancy, cardiac diseases, diabetes mellitus or cerebrovascular diseases before the start of RRT and others. After the start of RRT there was a significant increase of infectious and psychiatric disease. During the study period 70% died, most frequently from cardiovascular causes (28%), discontinuation of dialysis treatment (28%) or infection (19%). CONCLUSIONS: We think that both survival and quality of life in elderly patients during RRT are acceptable, and that neither age nor comorbidity should be a contraindication to RRT.

A long-lasting, complete hematologic and cytogenetic remission of chronic myelogenous leukemia after treatment with busulfan alone.

A 44-year-old man suffering from cytogenetically and molecularly proven Philadelphia translocation-positive chronic myelogenous leukemia in chronic phase was treated with busulfan for 18 months and studied during a follow-up period of 13 years. Hematologically and cytogenetically, he attained a continuing complete remission, although at one point (9.5 years) at least, after attaining complete remission molecular analysis indicated the presence of minimal residual disease.

Carcinoid tumor of the jugulo-tympanic region.

Increased levels of 5-hydroxyindole acetic acid (5-HIAA) were found in a patient with a tumor arising in the middle ear. Iodine-123-metaiodobenzylguanidine ([123I]MIBG) scintigraphy and biochemical analysis showed evidence of serotonin production by the tumor. Immunohistochemistry of the tumor showed reactivity with antibodies directed against serotonin, chromogranin, leu-7 and neuron-specific enolase; S-100, met-enkephalin, leu-enkephalin and glial fibrillary acid protein were negative. This case suggests a close relationship between functioning paragangliomas and carcinoid tumors because a strong clinical and endocrinological resemblance exists. The hormonal activity found is discussed in relation to extra-adrenal paragangliomas. We recommend urinary screening not only for detection of increased levels of catecholamines, but also of 5-HIAA in all patients with paragangliomas of the head and neck. When elevated levels are found, [123I]MIBG scintigraphy should be performed to localize the areas of increased uptake in or outside the head and neck region.

Rounded atelectasis of the lung, just a benign disorder.

Three patients with rounded atelectases are described. One of them developed a malignant non-Hodgkin lymphoma 6 months after presentation with rounded atelectasis. His rounded atelectasis could be followed during 20 months and was unrelated to the appearance, complete remission after chemotherapy and relapse of a malignant non-Hodgkin lymphoma. Rounded atelectasis of the lung is a little-known form of peripheral pulmonary collapse which may mimic a neoplastic tumour. It might be formed either because of a folding in a basal lung segment caused by temporarily pleural effusion, or because of initial damage to the pleura which leads to fibrosis and thus to challenge to the clinician, it should be emphasized that the benign nature of rounded atelectasis should be recognized by radiological techniques.

A hospital outbreak of penicillin-resistant pneumococci in The Netherlands.

Respiratory infections with penicillin resistant pneumococci constitute an increasing health care problem. This paper describes the nosocomial spread of penicillin resistant pneumococci (PRP) on a pulmonary ward. During an eight-month period, minimal inhibitory concentrations (MICs) for penicillin and several other antibiotics were performed on all Streptococcus pneumoniae isolates that were shown to be penicillin resistant by a screening assay. The personal data and case history of all patients with penicillin resistant pneumococci were evaluated. Penicillin Resistant Pneumococci were cultured from 18 patients, 16 men (mean age 74 +/- 8 yrs) and 2 women (aged 54 and 60 yrs). Chronic obstructive pulmonary disease was diagnosed in 16 patients, 10 of which had an additional underlying disease (2 diabetes mellitus, 2 heart failure, 2 malignancy). Prior to culture of Penicillin Resistant Pneumococci, 11 out of 18 patients were treated with antibiotics, a beta-lactam in most instances. Ten out of 18 patients died during or shortly after hospitalization. The death of one patient seems to be directly related to infection with Penicillin Resistant Pneumococci. The five Penicillin Resistant Pneumococci isolates available for serotyping were all type 9. The minimal inhibitory concentrations for penicillin varied from 0.5 to 2.0 mg.l-1. High minimal inhibitory concentrations were also noted for cefixime (all over 4.0 mg.l-1) and ceftriaxone (0.5-1.0 mg.l-1). It is concluded that penicillin resistant pneumococci can spread rapidly among old and debilitated patients. Thus, patients with this infection should be barrier nursed.

Astrocytoma in childhood: survival and performance.

Seventy-nine children (35 female, 44 male) with proven or presumed astrocytoma were treated from 1967 to 1987. The tumors were supratentorial located in 24 children, cerebellar in 21 children, and pontine in 34 children. If possible, a radical tumor resection (4%), a subtotal tumor resection (51%), or a biopsy (8%) was performed. The predominant pathological Kernohan grading for the supratentorial, cerebellar, and pontine located tumors were grades II, II, and IV respectively. Histology was unknown in 15 out of 34 pontine tumors and in 1 out of 24 supratentorial tumors. Low-graded tumors (46%) were irradiated with a local field (1.8/45-50 Gy) and children with high-graded tumors (34%) received a total brain irradiation (1.8/40 Gy) followed by a boost irradiation (10 Gy) in 5 or 6 fractions. Overall 1-, 5-, and 10-year survivals of children with supratentorial, cerebellar, and pontine located tumors were 96%-91%-46%, 95%-95%-95%, and 35%-20%-20% respectively. For all tumor locations, 77% of deaths occurred within 2 years of treatment. The performance status of both children with supratentorial and cerebellar astrocytoma showed an increase during the first year of treatment and then stabilized on a rather high level (mean performance after 5 years of 60% and 70% respectively). Children with pontine tumors showed a steep decrease in performance status during the first year of treatment and then stabilized on a low level (mean performance after 5 years of 15%). In our study, children with supratentorial astrocytoma showed improvement in both survival and performance status after irradiation following surgical removal of the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)