Biomedical subjects
Publications and source records attributed to M Fiegl.
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AIMS: To analyse the entity specific incidence and disease specific survival (DSS) of non-Hodgkin lymphomas (NHLs) in Tyrol/Austria, 1991-2000. METHODS: Data from 1307 NHLs (excluding primary cutaneous lymphomas and monoclonal gammopathies of undetermined significance) were obtained. Current status was available for all patients. Except for 29 cases of small lymphocytic (CLL/SLL), lymphoblastic leukaemia (ALL), and myeloma (MM), which were diagnosed cytologically, diagnoses were reclassified on paraffin wax embedded archival material according to new World Health Organisation criteria. Sex specific age adjusted standardised incidence rates were computed using Segi's population weighting. Annual incidence changes were calculated by weighted least square regression analysis. Survival was estimated by the Kaplan-Meier method and compared by log rank test. RESULTS: NHL more frequently affected men (male/female ratio, 1.52). Mean age of occurrence was 61 and 66 years for men and women, respectively. The incidence rate of 14.3 remained constant. There was a significant increase in diffuse large B cell lymphoma (DLBCL) and decrease in CLL/SLL in men, and a decrease in MM in women. Overall DSS was 64% during the mean follow up (43 months). Age, T-NHL, lambda light chain restriction in MM, and male sex in CLL/SLL were associated with poor prognosis. In B-NHL, DSS decreased in the following order: hairy cell leukaemia, marginal zone lymphoma, follicular lymphoma, Burkitt lymphoma, ALL, DLBCL, CLL, MM, and mantle cell lymphoma. CONCLUSIONS: The incidence of NHL in Tyrol has changed in the past decade, with a significant increase in DLBCL, decrease in CLL/SLL in men, and decrease in MM in women.
Diagnosis of malignant cells in effusions is important for staging procedures and resulting therapeutic decisions. Cytodiagnostics in effusions is sometimes difficult since reactive mesothelial cells can mimic malignant cells. We used fluorescence in situ hybridisation (FISH) in single-colour or if appropriate in dual-colour evaluation to detect chromosomal aberrations in effusion cells as markers of malignancy, to raise the diagnostic yield. Cytologic and FISH evaluations--by using probes representing several chromosomes always including chromosomes 11 and 17--were performed in 358 effusion fluids. Cytology was positive for malignancy in 44.4% of all effusions, whereas FISH was positive in 53.9% (P=0.0001). The combination of cytology and FISH was diagnostic for malignancy in 60.9% of effusions. Diagnostic superiority of FISH was demonstrated in effusions from breast cancer, lung cancer, pancreatic cancer, and in effusions from the entire group of gynaecological and gastrointestinal carcinomas. In transudates (effusion protein <2.5 g dl(-1)), malignant cells were detectable by cytology, FISH, and combined use of both methods in 18.6, 30, and 37.1% of effusions, respectively, suggesting that cytologic and molecular analysis should be performed also with transudates. In conclusion, FISH in combination with conventional cytology is a highly sensitive and specific diagnostic tool for detecting malignant cells in effusions.
PURPOSE: To evaluate the efficacy and safety of the combination of ICE (ifosfamide 1.5 g m(-2), carboplatin 100 mg m(-2) and etoposide 150 mg m(-2), days 1-4, q 28 days, G-CSF 5 microg kg(-1) starting from day 6) alone and in combination with regional hyperthermia (RHT) in soft tissue sarcoma (STS) refractory to previous standard doxorubicin-ifosfamide-based chemotherapy. PATIENTS AND METHODS: Twenty patients with advanced STS of different histological sub-types were treated with the ICE regimen with 13 patients receiving additional RHT. A median of four courses of ICE were administered with RHT on days 1 and 3 (60 min, T(max) 42 degrees C). RESULTS: The objective response rate was 20%, with four partial responses (all treated with hyperthermia). In addition, two patients showed mixed responses and five patients stable disease. After a median follow-up time of 15 months, median time to progression was 6 months. Progression free rate estimates were 60% and 45% at 3 and 6 months, respectively. Median overall survival for all patients was 14.6 months. CONCLUSION: These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.
This retrospective trial was performed to determine risk factors, incidence and severity of ifosfamide-induced encephalopathy in correlation with patient and treatment characteristics. Patients receiving ifosfamide were included consecutively with no restrictions concerning disease, prior chemotherapy or disease stage. Incidence and severity of encephalopathy were graduated according to common toxicity criteria. Between July 2001 and July 2002, 60 patients (32 male, 28 female, median age 47.5 years) were included; 26.6% of the patients (n = 16) developed neurological symptoms [grade 1: 6.7% (n = 4); grade 2: 3.3% (n = 2); grade 3: 11.7% (n = 7); grade 4: 5% (n = 3)]. Encephalopathy occurred for the first time in 87.5% (n = 14) in chemotherapy courses 1 and 2. In 56.25% (n = 9) of these 16 patients only one episode was observed. There was no significant difference concerning age (38 versus 50 years, p = 0.08) and dosage (median 2.9 versus 2.8 g, p = 0.74) between patients with and without encephalopathy. No risk factors could be identified by this study, suggesting an individual predisposition in each patient. On the other hand, ifosfamide can be administered in older patients without increased risk of neurotoxicity.
This multicenter randomized phase III study was designed to compare the efficacy and toxicity of IFN alpha-2c (3.5 MU/d) in combination with either araC (10 mg/m(2) d1-10) or hydroxyurea (HU: 25 mg/kg per day) in newly diagnosed CML patients. A total of 114 patients were randomized. Following a median observation period of 36 (range 1-73) months the major cytogenetic response rates were 25 and 27% and the 4-year survival probabilities 62.5 and 63% for the araC and HU group, respectively. While the overall toxicity profile was comparable between both groups, patients in the HU arm exhibited a slightly higher degree of WHO grades 3 and 4 non-hematological toxicities.
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Rarely lymphoproliferative disorders (LPD) may be associated with peripheral neuropathy, based on different mechanisms of pathogenesis. Here, we report a case of a primary extranodal diffuse large B-cell lymphoma which showed a prolonged course with several recurrences manifesting as neuropathies, and long term remissions achieved by chemotherapy and involved field radiation. Repeated pathohistologic evaluations showed spread of lymphoma growth predominantly along nerve structures, suggesting neurotropism of the lymphoma cells.
A patient is described who presented with pancytopenia, splenomegaly and excessively elevated lactate dehydrogenase levels in concurrence with signs of extramedullary hematopoiesis. Although initially considered in the differential diagnostic spectrum, a highly aggressive lymphoma could not be identified before the patient died, 6 weeks after admission. Even an intensive diagnostic work-up including splenectomy and repeated bone marrow biopsies was inconclusive. Finally, the diagnosis of an intravascular large B-cell lymphoma, a highly aggressive clinical subtype of a diffuse large B-cell lymphoma, spreading within vascular structures of multiple organs was established by autopsy. Intravascular large B-cell lymphoma is often not diagnosed before death due to the exclusive intravascular growth pattern of the tumor cells and a fulminant clinical course. The heterogeneous clinical features of this lymphoma subtype are discussed.
The biological mechanisms responsible for the association of specific karyotypes with prognosis in acute myeloid leukaemia (AML) remain largely unclear. A prospective study was performed to evaluate how far cytogenetically defined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S-phase-specific induction chemotherapy comprising cytosine arabinoside (AraC). One hundred and eighty-seven patients with de novo AML were included in the study; 25 patients with a favourable [inv(16), t(8;21), t(15;17)] karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (-5, 5q-, -7, 7q-, complex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others). The favourable group demonstrated the highest ex vivo proliferative activity (PA) (3.41 pmol/105 cells), significantly (P = 0.02) exceeding the unfavourable group with the lowest PA (0.72) and the group with a normal karyotype (1.06) or with karyotype of unknown significance (1.05) that both demonstrated an intermediate PA. Samples with a high PA (> median of the whole group) were more likely to produce interleukin 3, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF) (56%, 43% and 50%) than cells with a low PA (33%, 36% and 36%; n.s.). The effect of priming by exogenous GM-CSF or G-CSF was significantly more pronounced in samples with a low PA than in rapidly proliferating samples (P < 0.01). For the whole group, a high PA was closely associated with an increased incorporation of AraC triphosphate (AraCTP) into the DNA (P < 0.0001). Clinically, a high PA was associated with a better complete remission (CR) rate in the normal (95% versus 62%) and the unfavourable group (75% versus 33%). The significant differences in proliferative activity between cytogenetic subgroups of AML are associated with increased cytosine arabinoside pharmacodynamics and constitute one potential mechanism for the different response of cytogenetic subgroups to AraC-based induction therapy.
In the present study the chromosomal status of seven invasive non small cell lung cancer specimens and associated premalignant lesions was investigated. By fluorescence in situ hybridisation (FISH) with centromere specific probes, an increase in the percentage of aneuploid cells from pre-invasive to invasive lesions could be demonstrated (mean 8.5 and 59%, respectively, for chromosome 7). Furthermore, mean chromosome copy numbers were higher in invasive carcinomas as compared to premalignant lesions, indicating polyploidization during tumor development. Increasing evidence suggests that aberrations of chromosome 7 occur early in the development of lung cancer. Whether these aberrations can be used as a biomarker for future neoplastic progression remains to be determined.
Various molecular markers have been used for the detection of circulating breast cancer cells in blood by reverse transcriptase-polymerase chain reaction (RT-PCR). Using nested RT-PCR, we compared the specificity and sensitivity of human mammaglobin (hMAM), epidermal-growth-factor receptor (EGF-R), and cytokeratin 19 (CK-19) expression as markers for circulating carcinoma cells in the peripheral blood of patients with breast cancer. Blood samples from 12 patients with ductal carcinoma in situ, 133 patients with invasive breast cancer, 20 patients with hematological malignancies, 31 healthy volunteers, and tumor tissues from 40 patients with invasive breast cancer were screened for mRNA encoding hMAM, EGF-R, or CK-19 by nested RT-PCR. In all breast cancer tissues, mRNA for hMAM, EGF-R, and CK-19 was detectable. In blood samples from patients with invasive breast cancer, 11 (8%), 13 (10%), and 64 (48%) were positive for mRNA encoding hMAM, EGF-R, or CK-19, respectively. Blood samples from none of the healthy volunteers and patients with hematological disorders were positive for hMAM, while CK-19 mRNA was found in the blood of 12 (39%) healthy volunteers and transcripts for EGF-R and CK-19 were detectable in 5 (25%) and 2 (10%), respectively, of the patients with hematological malignancies. Only hMAM mRNA expression in blood correlated with clinical parameters such as nodal status, metastasis, and CA 15-3 serum levels. In summary, hMAM transcripts detectable in blood by RT-PCR represent the most specific molecular marker for hematogenous spread of breast cancer cells. With the nested RT-PCR method, aberrant EGF-R mRNA expression might occasionally be found in hematological malignancies, whereas CK-19 mRNA expression proved to be rather nonspecific. The prognostic value of hMAM RT-PCR-based tumor cell detection in peripheral blood should be further tested and validated in prospective studies.
Cytological diagnosis of malignant cells in effusions is hampered by difficulties in the differentiation from reactive mesothelial cells. Because interphase cytogenetics by fluorescence in situ hybridization (FISH) might complement cytological evaluation, we determined the power of tumor cell detection using FISH and cytology in 201 effusions from patients with advanced cancer. Furthermore, 9 primary breast tumors were FISH-karyotyped, and chromosomal aberrations were compared with those of corresponding metastatic effusion cells. By using centromeric probes representing chromosomes 7, 8, 11, 12, 17, and 18, a rate of malignancy-associated aneusomy combined for the 6 chromosomes was detected in an overall of 44.8% of effusion specimens (range, 31.8% to 39.3% for the individual chromosome), comparable to cytology (43.3%). The combination of just 2 FISH probes (namely, representing chromosome pairs 8/11 and 8/17) was almost equally efficient in the identification of aneusomy. Approximately one fourth of the cytologically negative effusions were FISH positive and vice versa. From the initially FISH-negative effusions, 18.9% could be subsequently classified positive with dual-color FISH by visualization of intranuclear chromosomal complexity in rare aneuploid cells. Thus, "overall FISH analysis," including dual-color evaluation, identified tumor cells in significantly more effusions (55.2%, P = .001) than conventional cytology, implying greater sensitivity. Finally, our finding that numerical aberration patterns in primary breast tumors and corresponding metastatic effusions are comparable indicates that FISH examination of primary tumors will indicate the centromeric probe(s) best suited for an efficient search for metastasis in the individual case.
Interphase cytogenetics by fluorescence in situ hybridization (FISH) can be used to detect malignant cells characterized by chromosomal aneuploidy. However, apparent aneusomy in normal "control" tissues has to be considered when using FISH as diagnostic tool. In effusions as model tissue exposed to metastasis, the definition of cut-off levels for background aneusomy by FISH was aimed in this study. Using centromeric probes representing chromosomes 7, 8, 11, 12, 17 and 18, extensive chromosome copy number enumeration by single-color FISH analysis was performed in pleural and ascitic effusions derived from 15 patients with various, non-malignant diseases. In all effusions, cells with gain of hybridization signals for several or all chromosomes tested were found (in up to 1.94% of cells). A consistent finding was high grade hyperdiploidy (>4 centromeric signals). Mesothelial elements mainly contributed to hyperdiploidy in effusions, as demonstrated by a combined analysis of FISH and immunocytochemistry with staining for cytokeratin. Dual-color FISH analysis showed that hyperdiploidy was predominantly corresponding to polyploidization; however, there were always minor cell populations classified as aneuploid by dual-color FISH. In conclusion, stringent criteria have to be applied to distinguish malignancy-related aneuploidy from background aneusomy by FISH.
A 68-year-old woman presented with profuse hemorrhage and other signs suggesting an acute leukemia. Histologic and cytogenetic evaluation of her bone marrow revealed alveolar rhabdomyosarcoma as the underlying cause of massive disseminated intravascular coagulation and hyperfibrinolysis. A review of the literature reveals that coagulopathy appears to be a common feature of alveolar rhabdomyosarcoma.
A 37-year-old man with a newly diagnosed chronic myelogenous leukemia received induction therapy with hydroxyurea and interferon-alpha, and maintenance therapy with low-dose ara-C and interferon-alpha. Subsequent to a rapid hematological remission, a continuously aggravating pancytopenia with bone marrow aplasia developed which persisted after withdrawal of maintenance therapy. Bone marrow examination exhibited aplastic areas and residual hematopoiesis with impaired maturation; cytogenetically, there was a 100% persistence of Philadelphia chromosome-positive metaphases. By allogeneic bone marrow transplantation, a complete reconstitution of hematopoiesis was achieved.
Philadelphia chromosome-positive chronic myelogenous leukemia was diagnosed in a now 37-year old woman 16 years ago. Induction therapy with hydroxyurea and busulphan led to hematological remission lasting for about 4 months without treatment. Then, intermittent busulphan over a 7 years' period, and subsequently, alpha-interferon was given, of which ever decreasing doses (currently 3.5 megaunits interferon-alpha-2c once every 14 days) have been required to keep leukocyte counts in the target range. Although no major cytogenetic response was achieved by maintenance therapy, the patient has now been in an ongoing chronic phase of disease for 16 years. This is a rare case of indolent chronic myelogenous leukemia, in which, for undefined reasons, the leukemic cells have not acquired the capacity to transform leading to disease acceleration, which usually is imminent after a few years.