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N Niederle

Publications and source records attributed to N Niederle.

At least 37 records · Page 2Linked to original sources
PubMed1996

Interferon therapy, but not busulfan restores normal-sized megakaryopoiesis in CML--a comparative histo- and immunomorphometric study.

To assess possible alterations of megakaryocytes associated with interferon (IFN) and busulfan (BU) therapy of Ph(1+)-CML, an immunohistochemical and morphometric study was performed on trephine biopsies of the bone marrow taken before and at varying intervals during treatment. For the identification of megakaryopoiesis and its endoreduplicative activity the monoclonal antibodies CD61 (anti-platelet glycoprotein IIIa) and PC10 raised against proliferating cell nuclear antigen (PCNA) were used. We compared 60 specimens from 20 patients following IFN alpha-2b administration (in combination with IFN gamma in seven patients) with 57 specimens from 22 patients after monotherapy with BU. A close correlation with clinical follow-up studies revealed that in the IFN-treated group the prevalence of atypical micro-megakaryocytes, usually characterizing CML, was conspicuously reduced in repeatedly taken bone marrow samples. Initially, even an increase in size which was levelled to normal values during maintenance therapy was observed. These features were most prominently expressed in the 13 patients with a complete hematologic and/or partial cytogenetic response. Associated with this phenomenon was a significant enhancement of the PCNA-labelling index which indicated a stimulation of endoreduplicative (endomitotic) activity necessary for achieving normal size and ploidy. In the second group of patients treated by BU these changes were absent. For this reason, our findings are in keeping with the assumption that during IFN treatment, there is at least partial recovery and expansion of a putative normal (Ph1-) megakaryopoiesis. In conclusion, megakaryocyte morphology, i.e. normalization in size, is thought to be a useful indicator to evaluate the response to IFN in CML patients.

Adult↗
PubMed1996

Paclitaxel and cisplatin in patients with non-small cell lung cancer: results of a phase II trial.

We performed a clinical phase II trial of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin in patients with locally advanced (stage IIIB) or metastatic non-small cell lung cancer (NSCLC), using a 3-hour infusion of paclitaxel followed by a 1-hour infusion of cisplatin. Treatment was repeated every 21 days, for a maximum of six cycles. The patients received paclitaxel 175 mg/m2 followed by cisplatin 75 mg/m2. At present, 52 chemotherapy-naive patients with stage IIIB (17.3%) or stage IV (82.7%) NSCLC have been entered into this ongoing trial. Ten (19%) of the patients are women and 42 (81%) are men. With 197 courses of chemotherapy given, all 52 patients are evaluable for toxicity. Hematologic toxicities were moderate: World Health Organization (WHO) grade 3 or 4 neutropenia occurred in 38.7% of the cycles (47.7% of patients), and WHO grade 3 or 4 thrombocytopenia was observed in 1.5% of cycles (3.8% of patients). Other toxicities consisted mainly of WHO grade 2 or 3 alopecia and nausea/vomiting. World Health Organization grade 1 or 2 polyneuropathy occurred in 30.4% and grade 3 or 4 only in 1% of all courses. Of 40 patients evaluable for response, a complete remission was noted in one patient, a partial remission occurred in 13 patients (32.5%), stable disease was seen in 14 patients (35%), and disease progressed in 12 patients (30%). These results suggest that the combination of paclitaxel and cisplatin is active and tolerable in the treatment of NSCLC. The efficacy of the combination seems high in this poor-prognosis population.

Adult↗
PubMed1996

Phase II study of paclitaxel and cisplatin in patients with non-small cell lung cancer.

Few cytotoxic agents tested in adequate phase II trials involving patients with non-small cell lung cancer have produced single-agent response rates greater than 15%. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of them, with reported response rates ranging from 21% to 36%. Platinum-based regimens have been key to the development of the most effective combination therapies for NSCLC. We are currently investigating the efficacy and toxicity of combining paclitaxel (175 mg/m2) given by 3-hour infusion, followed by cisplatin (75 mg/m2) via 1-hour infusion, on a 21-day schedule for the treatment of 75 chemotherapy-naive patients with stage IIIB (17.3%) or stage IV (82.6%) non-small cell lung cancer. Patient characteristics include a median age of 58 years (age range, 28 to 75 years) and a median Eastern Cooperative Oncology Group performance status of 2; 19 patients (25.3%) are women and 56 (74.7%) are men. All patients received standard prophylactic premedication as well as adequate hydration. To date, 75 subjects and 328 courses are evaluable for toxicity. Hematologic toxicities have been moderate; grade 3 or 4 neutropenia occurred in 37% of cycles (50% of patients), and grade 3 or 4 thrombocytopenia was observed in only 2% of cycles (2% of patients). Other notable toxicities were World Health Organization grade 2 or 3 alopecia and nausea/vomiting. Grade 1 or 2 peripheral neuropathy occurred in 26% and grade 3 or 4 in only 1% of all courses. Of 67 patients evaluable for response, complete remission was noted in three (5%) patients, partial remission in 25 (37%) patients, stable disease in 22 (33%) patients, and progressive disease in 17 (25%) patients. These results suggest that combination paclitaxel/cisplatin is active and well tolerated in the treatment of non-small cell lung cancer.

Adenocarcinoma↗
PubMed1996

Effects of interferon treatment on the macrophage population in the bone marrow of patients with Ph1+-CML.

In Ph1+-CML the abnormal function of bone marrow stroma was related to the presence of clonally transformed macrophages (MAs). Moreover, previous in vitro studies revealed that activation (phagocytosis, cytotoxicity) of MAs was associated with a pronounced increase in alpha-D-galactosyl residues on their membranes. Stimulation of this cell population has been shown to be easily accomplished by interferon (IFN) treatment. The latter caused an enhanced expression of binding sites for the lectin Griffonia simplicifolia isotype I-B4 (GSA-I), specific for this carbohydrate moiety. The present immuno- and lectinhistochemical study was designed to quantify MA subsets of the bone marrow in patients with Ph1+-CML under IFN therapy. For comparison a control group with monotherapy by busulfan (BU) was included. Identification of the total MA population was carried out by a monoclonal antibody against CD68 (PG-M1) and for the characterization of its activated fraction, the lectin GSA-I was employed. In both therapeutic groups morphometric analysis revealed a conspicuous increase in PG-M1-positive MAs in sequential trephine biopsies. However, following IFN therapy the relative amount of the GSA-I fraction was maintained or even increased and accompanied by enhanced apoptosis. On the other hand, BU generated a significant reduction of this subpopulation and the number of apoptotic cells as well. This finding is probably related to the immunomodulatory activity of IFN associated with MA activation and secretion of biogenic mediators. These are thought to belong partly to the so-called tumor necrosis factor superfamily, which is known to stimulate programmed cell death (apoptosis).

Adolescent↗
PubMed1995

Prolonged administration of interferon-alpha in patients with chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome.

To assess the influence of pretransplant cytoreductive therapy with special reference to interferon-alpha (IFN-alpha) treatment on major endpoints of allogeneic bone marrow transplantation (BMT), we studied 133 consecutive patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) in first chronic phase who received marrow grafts from HLA-identical family (n = 103) or alternative donors (n = 30) at a referral-based transplant center. Fifty of these patients (38%) were previously exposed to IFN-alpha for a median duration of 14 months (range, 1 to 61 months), whereas 83 patients (62%) exclusively received hydroxyurea and/or busulfan therapy between 1 and 129 months (median, 15 months) pretransplant. Using the categorized treatment duration with each pretransplant cytoreductive agent as a measure for individual patient exposure to each agent, prolonged ( > 12 months) IFN-alpha administration was identified as the sole significant pretransplant therapy-related predictor of transplant outcome by proportional hazards regression analysis. The adjusted risk ratio (RR) of transplant-related mortality (TRM) was 2.5-fold higher (95% confidence limits [95% CL], 1.4 to 4.5; P < .004) compared with other pretransplant therapy and this was mainly attributable to a 3.1-fold higher RR (95% CL, 1.4 to 6.4; P < .005) of fatal posttransplant infections after prolonged IFN-alpha treatment pretransplant. Marrow graft failure developed exclusively among 7 of 30 patients (23%) with donors other than HLA-identical family members and was further restricted to patients who had been previously exposed to IFN-alpha. The probability of graft failure was 49% +/- 28% in 17 patients pretreated with IFN-alpha compared with 0% for the other 13 patients with mismatched family or unrelated donors (P < .008). In addition, a significant delay in neutrophil and platelet count reconstitution was observed among patients with donors other than HLA-identical family members after pretransplant IFN-alpha exposure. No influence of pretransplant cytoreductive therapy on either acute and chronic graft-versus-host disease or leukemic relapse was detected in this study. As a consequence of its adverse effect on TRM, prolonged pretransplant IFN-alpha treatment was independently associated with a 2.5-fold lower likelihood (95% CL, 1.4 to 4.5; P < .003) of 5-year overall survival and with a 2.3-fold lower likelihood (95% CL, 1.3 to 4.2; P < .004) of 5-year disease-free survival postransplant after adjustment for other significant prognostic factors in multivariate analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Clinical and histological features retain their prognostic impact under interferon therapy of CML: a pilot study.

In 55 patients with Ph1+ CML under interferon (IFN) monotherapy, an immunohistochemical and morphometric study on pretreatment bone marrow biopsies was performed to evaluate the prognostic impact of clinical as well as histological disease features. For identification of megakaryocytes we used the PAS stain and CD61 to calculate the subfraction of precursors (pro- and megakaryoblasts). Demonstration of macrophages and their different subsets was carried out by PG-M1 (CD68) and the GSA-1 lectin. The erythroid precursors were stained by Ret40f (anti-glycophorin C). Density of argyrophilic (reticulin plus collagen) fibers was determined by applying Gomori's silver impregnation method. Clinical variables like state of hematological response to IFN administration, age, spleen and liver size, myeloblasts plus promyelocytes, basophils as well as basophils and eosinophils exerted a predictive capacity by univariate statistical analysis. However, when entering these factors into previously published risk models, i.e., the so-called Sokal score and its modifications, to assess subgroups with different survival patterns or relative risk groups, a clear-cut discrimination was not feasible. Bone marrow features of prognostic value consisted of megakaryocytes and their precursors, fibers, and pro- and erythroblasts. Only when including histological variables into a formerly reported Cox model, could a significant separation of patients into the different categories or relative risk groups be computated. In conclusion, the present data emphasize the prognostic impact of histological parameters to be considered in all clinical trials on CML.

Adult↗
PubMed1995

The impact of interferon versus busulfan therapy on the reticulin stain-measured fibrosis in CML--a comparative morphometric study on sequential trephine biopsies.

To evaluate treatment-related changes of the reticulin stain-measured fibrosis in Ph(1+)-CML, a clinicopathological study was performed on sequential trephine biopsies of the bone marrow following either interferon (IFN) or busulfan (BU) monotherapy. Using the monoclonal antibody CD61 for the identification of megakaryopoiesis and Gomori's silver impregnation method, number of megakaryocytes and density of argyrophilic (reticulin and collagen) fibers were determined by morphometry. We studied specimens from 26 patients with IFN-alpha 2b (including nine patients with additional IFN gamma) therapy and from 23 patients who had received BU. In both groups, repeated bone marrow biopsies (total 125) revealed a significant increase in the fiber content, as well as in the number of megakaryocytes during treatment. To assess the dynamics of myelofibrosis more precisely, computation of differences in the degree of fiber density between the first and last examination was carried out. Regarding the considerable variations in the biopsy intervals, a so-called myelofibrosis progression index (MPI) was calculated. Following this rationale, we were able to demonstrate that, in comparison to the BU-group, speed of progression of bone marrow fibrosis was significantly increased in CML patients treated with IFN. Preliminary statistical analysis indicated a relationship between myelofibrosis on admission, which was always associated with increased growth of megakaryocytes, and the MPI with survival. Even when these parameters were regarded, prognosis was significantly more favorable in the IFN-treated patients. The failure of IFN and BU to inhibit the evolution of myelofibrosis may be related to several conversely acting pathomechanisms. Among others, the inability of both therapeutic agents to reduce the number of megakaryocytes more effectively should be taken into consideration.

Adolescent↗
PubMed1994

Hypersensitivity reactions to carboplatin. Report of two patients, review of the literature, and discussion of diagnostic procedures and management.

BACKGROUND: Hypersensitivity reactions are rare but sometimes life-threatening complications of cytostatic combinations containing platinum compounds. Only approximately 40 instances of such hypersensitivity have been reported in association with carboplatin treatment. However, the symptoms probably often are misinterpreted. METHOD: Signs and symptoms of two patients with severe hypersensitivity reactions to carboplatin are presented. Intracutaneous tests with carboplatin were performed in these two patients and in five control patients receiving carboplatin therapy without unexpected side effects. RESULTS: Both patients had received several cycles of a carboplatin-containing combination chemotherapy. In both patients, hypersensitivity reactions became manifest for the first time after cumulative doses of 3900 and 5400 mg, respectively. Symptoms included dyspnea, tachycardia, angina pectoris, hypotension, diarrhea, edema, and rash. In both patients, a positive urticarial reaction to intracutaneous carboplatin (diluted 1:10 with normal saline) was observed, whereas five control patients undergoing carboplatin therapy without adverse reaction had negative test results. There were no signs of delayed hypersensitivity. Serum immunoglobulin E levels were normal. Symptoms were ameliorated but not suppressed when one patient was reexposed after premedication with corticosteroids and histamine antagonists. Both patients tolerated high doses of cisplatin without allergic reactions. CONCLUSIONS: Although they are rare, hypersensitivity reactions can be serious complications of carboplatin therapy. Simple intracutaneous tests might help to establish the diagnosis to avoid dangerous reexposures. Although the pathogenetic mechanisms are not fully understood, the clinical and experimental findings suggest an anaphylactic type of hypersensitivity, perhaps aggravated to some extent by nonspecific histamine liberation. There seems to be no general cross-reactivity to cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Soluble HLA class I and beta-2-microglobulin plasma concentrations during interferon treatment of chronic myelogenous leukemia.

Soluble class I molecules (sHLA-ABC) were measured by an enzyme-linked immunosorbent assay (ELISA) in plasma samples of 13 patients with chronic-phase Ph1-positive chronic myelogenous leukemia (CML). The patients were treated once daily with interferon (IFN) s.c. at a dosage of 4 x 10(6) IU/m2 IFN-alpha-2b or in combination with 50 micrograms IFN-gamma. Measurements were performed before 2, 4, 6, 8, 24, 48, and 72 h after the start of treatment and thereafter every 2-4 weeks. Baseline sHLA-ABC levels were within normal limits (mean 22.1 +/- 8.8 mg/l). An initial decrease of sHLA-ABC (mean 3.2 +/- 2.7 mg/l) was seen in all patients during the first 2-8 h of IFN treatment. Thereafter, sHLA-ABC levels increased steadily reaching maximum values within 2-5 weeks. The overall increase was 12.7 +/- 12.4 mg/l. During the following 2-4 months of IFN treatment sHLA-ABC decreased to near baseline levels in 12 of 13 patients. No difference was detected between IFN-alpha and IFN-alpha plus IFN-gamma treatment. beta 2-Microglobulin values were measured in 8 patients and were found to be correlated to sHLA-ABC concentrations (r = 0.48).

Adult↗
PubMed1994

Bcr-abl-positive and -negative clonogenic cells in CML patients undergoing long-term interferon treatment.

Bone marrow (BM) and peripheral blood cell (PBC) samples of 11 Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) patients in long-lasting hematologic remission induced by interferon (IFN) treatment were examined for the presence of leukemic hematopoietic precursor cells. Southern blot analysis revealed residual leukemic cells in BM samples of four patients, whereas seven patients showed no aberrant bands. Reverse transcription polymerase chain reaction (RT-PCR), however, amplified bcr-abl-specific cDNA in unfractionated BM or PBC samples in all 11 patients. The patients demonstrating bcr rearrangements in Southern blots had either a mosaic pattern (three patients) of bcr-abl-negative and positive colony-forming precursors (CFU-GEMM, BFU-E, CFU-GM, CFU-Mega), or all colonies were derived from leukemic precursors (one patient). However, in soft agar cultures of four patients without aberrant bands in Southern blots, only colonies without amplifiable bcr-abl transcripts were detectable. In another patient, few bcr-abl-positive colonies were found after 44 months of treatment, but not after 53 and 56 months of therapy. In these patients, therefore, residual disease detectable by PCR analysis of unfractionated cell samples does not appear to reside in the colony-forming cell compartment. The prognostic implications of these observations and the nature of the remaining bcr-abl-positive cells within unfractionated cell samples remain to be determined.

Adult↗
PubMed1993

[Hypersalivation as a leading symptom of neoplastic meningiosis in highly malignant non-Hodgkin's lymphoma].

Partial remission of a centroblastic non-Hodgkin's lymphoma, clinical stage IV A, in a 79-year-old man was achieved by six courses of chemotherapy with epirubicin, cyclophosphamide and vincristine. The only residual finding was a palpable small cervical lymphoma. After a treatment pause of about 6 weeks increasing hypersalivation set in which ultimately made food intake impossible and led to a breakdown in the patient's general state. Findings in the region of the head, neck, throat and the base of the skull were unremarkable, but cerebrospinal fluid contained 1300/3 cells, almost all of them lymphoblasts. After five intrathecal injections of at first 15 mg methotrexate and 4 mg dexamethasone each, followed by five more with 40 mg cytarabine added to them, the CSF cell count became normal. At the same time salivation clearly decreased and food intake became once again possible. The patient died 5 months later from hypercalcaemia due to osseous infiltrations. Until his death there was no recurrence of the hypersalivation as the cardinal sign of meningeal carcinomatosis.

Aged↗
PubMed1993

Impact of interferon alpha-induced cytogenetic improvement on survival in chronic myelogenous leukaemia.

The objective of this study was to investigate the prognostic impact of the reduction of Philadelphia chromosome (Ph) positive metaphases by treatment of chronic myelogenous leukaemia (CML) with interferon (IFN) alpha. Therefore, we evaluated the outcome of patients with previously untreated chronic phase Ph-positive CML, enrolled from 1984 to 1990 into two consecutive IFN trials at our institution. Of a total of 71 patients, 62 (87%) were evaluable for cytogenetic response. No cytogenetic improvement was seen in 16 patients (23%), 28 patients (38%) had a decrease in Ph-positive bone marrow metaphases to levels ranging from 35% to 95%, and nine patients (13%) to levels between 5% and 34%. In nine patients (13%), Ph-positive metaphases were no longer detectable. After a median follow-up period of 33 months, the projected 5-year survival is 55% for the 62 patients evaluable for cytogenetic response. In this patient population there was no significant difference in the survival probability according to patients' risk status as defined by the Sokal score. Categorization according to the extent of Ph reduction, however, allowed three groups with significantly different prognoses to be identified. Patients achieving a Ph reduction to less than 35% were found to constitute a low risk group with a median survival not yet known and a projected 5-year survival of 90%. The 5-year survival rate was 55% for patients with a Ph reduction to levels between 35% and 95%, and less than 10% for those without any cytogenetic improvement. Thus, this study demonstrates that cytogenetic improvement on IFN treatment is an important prognostic factor for survival.

Adolescent↗
PubMed1993

Long-term treatment of chronic myelogenous leukemia with different interferons: results from three studies.

131 patients with Philadelphia (Ph') chromosome positive chronic myelogenous leukemia (CML) were treated with interferon (IFN) alpha or a combination of IFN alpha and IFN gamma. In study, 1, 13 not pretreated and 41 pretreated patients, 48 in chronic phase disease, 6 in accelerated phase, received 4 x 10(6) U/m2 IFN alfa-2b initially. After achievement of hematologic remission, the individually minimum effective dose was used for maintenance. There was no response in acute phase disease. Of the 48 patients with chronic phase disease, 22 achieved a hematologic remission (HR), 13 a partial HR (PHR), and 13 did not respond (NR) to IFN. No major cytogenetic response occurred in these patients, but two patients achieved a major molecular response in Southern blots, whereas PCR tests were positive. In a further randomized study, CML patients without prior therapy were treated initially with 4 x 10(6) U/m2 IFN alpha alone (arm A) or in combination with 50 micrograms IFN gamma (arm B). For maintenance, the maximum tolerable dose of IFN alpha was given (up to 10 x 10(6) U/day). Thirteen patients in arm A (54%) and 14 (56%) patients in arm B achieved a HR, 7 patients (29%) in arm A and 6 patients (24%) in arm B a PHR. No response could be induced in 4 patients (17%) of arm A and 5 patients (21%) of arm B. Major cytogenetic responses were observed in 5 (20%) patients of arm A and 5 patients (20%) of arm B. Major molecular responses were observed in 3 patients of arm A and 5 patients of arm B.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

[The clinical picture and therapy of aggressive fibromatosis (desmoids)].

Desmoid tumors are accounted among histologically benign soft tissue tumors. Though metastases do not occur the clinical course of the disease with their tendency to grow locally aggressive and to relapse after curative intended surgery is similar to sarcomas. After surgical excision adjuvant therapy of desmoid tumors is necessary in such cases, where a radical excision with a wide margin is not possible, or must be doubted or after the surgical excision of a locally recurrent tumor. Radiation doses of 50 to 60 Gy reduce the risk of local recurrence of desmoid tumors to 18%. In such cases, where surgery and radiotherapy have been leading to incomplete responses, systemic therapy with hormones (tamoxifen or progesterone), with alkylating agents (e. g. ifosfamide) or with prostaglandin antagonists (indomethacin) is possible. The published data on therapeutic responses to the treatment of desmoid tumors are scarce. We are reporting on seven of our own cases, treated with surgery and radiotherapy (four) or with a combination of surgery, radiotherapy, hormones and chemotherapy (three).

Adult↗