Biomedical subjects
Publications and source records attributed to R Spanedda.
Tumor necrosis factor alpha (TNF-alpha) seems to play a key role in the pathogenesis of Langerhans' cell histiocytosis (LCH). Thalidomide is an immunomodulator agent of inflammatory cytokines including TNF-alpha. To our knowledge this is the first case of disseminated LCH successfully treated with thalidomide.
In this study we evaluated whether a good response to conventional chemotherapy, i.e. a significant tumour reduction, is a prerequisite for improved survival in multiple myeloma (MM). Between January 1987 and March 1990, 341 consecutive previously untreated patients with MM received chemotherapy within the prospective, multicentre, randomised Protocol MM87. Of these, 258 patients were evaluable for both response and long-term survival and 244 (94.6%) have died. The median survival of all patients was 40 months (6-162 months). The median survival did not differ between patients who had complete response (CR) (50 months (9-162 months)), partial response (PR) (46 months (8-147 months)) or stable disease (SD) (41 months (7-135 months)). The median survival was shorter (13.6 months (6-135 months)) (P<0.0001) in patients whose disease progressed while they were receiving first induction chemotherapy. Causes of death were more frequently (P=0.04) related to MM in patients who had progressive disease (PD) than in patients who had a CR or PR or SD. The main clinical and laboratory characteristics were similar in the four groups. These data indicate that patients who maintain SD during first-line chemotherapy have a prognosis similar to that of patients who attain a response. Only patients whose disease progresses have a distinctly worse outcome.
The distribution and functional characteristics of in vitro bone marrow (BM) endothelial colonies (CFU-En) were studied in 70 non-Hodgkin's lymphoma (NHL) patients in different phases of the disease to explore the association between CFU-En growth and angiogenesis, and between the number of CFU-En and the presence of hematopoietic and mesenchymal progenitor cells. The mean number of CFU-En/10(6) BM mononuclear cells seen in remission patients was significantly higher than that seen in newly diagnosed patients (P=0.04), and in normal subjects (P=0.008). Patients with low-grade NHL in remission displayed a higher CFU-En value compared with high-grade NHL (P=0.04). In the autograft group (40 patients), a significant reduction of CFU-En number was detected in the first 4-6 months after transplantation. In remission patients, the CFU-En number positively correlated with the incidence of BM colony-forming unit granulocyte-macrophage (CFU-GM) (P=0.013) and CFU-multilineage (CFU-GEMM) hematopoietic colonies (P=0.044). These in vitro data show that CFU-En numbers increase following standard-dose chemotherapy, thus providing a rationale for further investigating the effects of different cytostatic drugs on BM endothelial cells growth and function.
The possibility has been raised that either a human herpesvirus-8 (HHV-8) variant or a novel, unidentified, gamma-herpesvirus related to HHV-8 is frequently associated with multiple myeloma (MM), which could explain the lack of antibodies to HHV-8 antigens and the discordant results from polymerase chain reaction (PCR) studies of HHV-8-specific sequences in MM patients. Thus, we used a sensitive PCR assay with degenerate primers targeting the highly conserved DNA polymerase gene of the herpesvirus family to examine the long-term cultures of bone marrow stromal cells (BMSCs) from 19 MM, 3 monoclonal gammopathies of undetermined significance and 6 control patients. Both the culture supernatant and the adherent stromal layer were examined from the 2nd until the 8th week of culture to assess the immunophenotype of the various cell types harvested for the molecular analysis. BMSCs consisted of a mixed population of fibroblast, macrophage, dendritic and endothelial cells. An amplified product of the expected size was obtained only in 3 MM cases, both in the adherent and nonadherent fractions. Direct sequencing and alignment of the nucleotide and amino acid sequences showed that the DNA sequences were 100% identical to Epstein-Barr virus (EBV) DNA. The PCR positivity was due to the presence of EBV-infected lymphoblastoid cells with plasmacytoid features, expressing the EBV-encoded latent membrane protein-1 and detectable either in the stromal cells or in the culture supernatant. Our data do not support a causal role of either HHV-8 or a novel herpesviral variant related to HHV-8 in MM.
We conducted a randomized trial to evaluate whether melphalan-prednisone (MPH-P) treatment administered just after diagnosis improves survival of stage I multiple myeloma (MM). Between January 1987 and March 1993, 145 consecutive previously untreated patients with stage I MM were randomized between treatment with MPH-P (administered for 4 days every 6 weeks) just after diagnosis and treatment only at disease progression. Survival was not influenced by MPH-P treatment either administered just after diagnosis or at disease progression (64 vs 71 months respectively). Comparing the first with the second group the odds ratio of death is 1.17 (95% confidence interval 0.57-2.42; P = 0.64). Disease progression occurred within a year in about 50% of patients who were initially untreated. Response rate was similar in both groups, but duration of response was shorter in patients who were treated at disease progression (48 vs 79 months, P = 0.044). Patients actually treated at disease progression (34/70) survived shorter than those who had neither disease progression nor treatment (56 vs > 92 months; P = 0.005). Starting MPH-P just after diagnosis does not improve survival and response rate in stage I MM, with respect to deferring therapy until disease progression. However, patients with stage I MM randomized to have treatment delayed and who actually progressed and were treated had shorter survival than those with stable disease and no treatment. Biologic or other disease features could identify these subgroups of patients.
PURPOSE: To evaluate the diagnostic workup proposed by the UICC (International Union against Cancer) Flow charts for diagnosis and staging of lymphomas in developed and developing countries (1998). MATERIAL AND METHODS: Our series consists of 134 patients with early non-Hodgkin's lymphoma (NHL). The patients, 75 men (56%) and 59 women (44%), ranging in age 14-80 years (mean: 56.8), were examined with chest radiography and thoracoabdominal CT. Abdominal US was used only in the follow-up of low-grade NHL. The patients were classified according to the Working Formulation criteria (1981) and staged as proposed by the Ann Arbor Conference guidelines (1971). RESULTS: At diagnosis, 5 patients (3.7%) were in stage I, 32 (23.8%) in stage II, 46 (34%) in stage III and 51 (38%) in stage IV. Extranodal involvement was seen in 59 patients (44%), which was present at disease onset in 49 of them (80%) and developed later on in 10 (20%). Gastrointestinal tract and respiratory system were the most frequent sites of extranodal involvement (15 cases, 25%), followed by liver (12%), genitourinary system (including the ovary), adrenal glands, the craniocervical region, muscles and finally the breast. The parotid gland, thyroid and bone were involved in one case only each. DISCUSSION AND CONCLUSION: In agreement with previous literature reports, our study confirms that the best technique currently available for diagnosis, staging and follow-up of malignant lymphoma is chest-abdomen CT. Indeed, even though extranodal involvement exhibits extremely variable patterns, there are some typical findings at CT, such as homogenous structural hypodensity, low contrast enhancement, frequent plurivisceral involvement and/or local lymph node involvement. Our study followed the 1998 UICC guidelines for cancer diagnosis and staging in developed countries, based on the histology of lymph node biopsy material and on imaging techniques such as CT, MRI and PET. As for developing countries, lymph node biopsy is the most easily available, and thus preferred, examination, while imaging diagnosis features chest radiography and abdominal US.
Age could influence the prognosis of multiple myeloma patients treated with conventional chemotherapy. Between January 1987 and March 1990, 341 consecutive previously untreated patients with multiple myeloma received chemotherapy within the prospective, multicentre, randomized Protocol MM87. Survival was evaluated in patients aged > or < or = 66 years (the median age for the whole series) and in a subgroup of patients aged < 55 years. These groups were similar for main clinical characteristics, including results of cytostatic treatment. As of May 1996, 271 (79%) of the 341 patients had died, and median follow-up of the 70 (21%) living patients was 82 months. Overall, younger patients survived longer than older ones. In fact, in patients > and < or = 66 years, median survival was 31 and 44 months (P < 0.00095) and the percentage of patients surviving over 72 months was 17% and 32% (P = 0.0018) respectively; in patients < 55 years, these figures were 57 months and 35% respectively (P = 0.02 and 0.01, with respect to patients aged > 55 years). In all groups, about 50% of the patients surviving over 72 months had stage I disease. For multiple myeloma patients treated with chemotherapy, survival is favourably affected by relatively young age and early stage of disease.
To better define the role of exposure to myelotoxic agents in the genesis of myelodysplastic syndrome (MDS), we carried out (a) a case-control study for the determination of the relative risk (RR) of developing MDS, including 178 consecutive patients and 178 sex- and age-matched controls: (b) a study of clinicobiological features in MDS arising after occupational exposure to myelotoxic agents and in MDS in 'non-exposed' patients. The definition of the 'exposure' status was based on a predetermined questionnaire, with calculation of an 'exposure' index (hours/day x days/year x years). Cumulative exposure to pesticides or to organic solvents, for >2400 h, was recorded in 48 and 25 MDS patients, respectively, compared to 27 and four controls (P<0.00001; RR 3.74; 95% confidence interval 2.02-5.37). Older age and an excess of refractory anaemia with ringed sideroblasts and refractory anaemia with excess of blasts was noted among 'exposed' MDS-patients (group 1), compared to non-exposed MDS-patients (group 2). 68.3% patients in group 1 had clonal chromosome changes, compared with 43.2% patients in group 2. Complex karyotypes, -7/7q-, -5/5q-, +8, 7p and 17p aberrations were seen more frequently in group 1, whereas a normal karyotype, isolated 5q- or 20q- occurred more frequently in group 2. The association of exposure to myelotoxic agents with older age at presentation and with unfavourable chromosome changes accounted for the shorter survival observed in 'exposed' patients. These data show that occupational exposure to pesticides and organic solvents in our region resulted in an increased RR of developing MDS and that a distinct cytogenetic profile was associated with MDS in 'exposed' patients. These findings provide strong indirect evidence that these agents may play a role in the pathogenesis of MDS, preferentially targeting some of the chromosome regions which are frequently involved in therapy-related myeloid neoplasias.
To define better the chromosomal profile of atypical chronic lymphocytic leukemia (aCLL), cytogenetic and interphase cytogenetic studies were performed in 43 cases, using mitogen-stimulated cultures and DNA probes detecting the two most frequently occurring aberrations in CLL, ie +12 and 13q14 deletions. All cases showed monoclonal CD5/CD19-positive lymphocytosis, with more than 10% large lymphocytes and/or prolymphocytes in peripheral blood smears and reactivity with FMC7, or bright expression of surface immunoglobulins in a fraction of the cases. Karyotype aberrations were detected in 27 of 43 cases (62.8%). Recurrent chromosome changes were +12 (nine cases), 13q14 aberrations (five cases), 11q anomalies (three cases), 6q21-q23 abnormalities and 4q anomalies with different breakpoints (two cases each). Additional chromosome changes were seen in four cases with +12, in three cases with 13q14 anomalies, in two cases with 11q anomalies, in one case with 6q and 4q anomalies. Trisomy 12 was associated with 13q14 anomalies in three cases, one of which also had an 11q abnormality; other associations, found in one case each, were: 13q14 deletion with a 6q anomaly, 11q anomaly with 13q- and 7q-, a 6q anomaly with 7q- and +12. Interphase cytogenetics confirmed the results of chromosome banding analysis and showed that six patients with normal karyotype or no mitosis in fact had concomitant +12 and 13q14 deletion in four cases and isolated +12 or 13q14 deletion in one case each, with a resultant 76% overall incidence of cytogenetic abnormalities. The presence of +12, 13q14 deletions, 11q, and 6q21-q23 anomalies in 19 cases was associated with a 2-month median interval between diagnosis and start of treatment, as compared with a 24-month median interval in 14 cases with normal karyotype or non-recurrent chromosome changes (P = 0.003). We conclude that aCLL is characterized by a relatively high incidence of chromosome anomalies, with recurrent chromosome changes, involving chromosomes 12, 13q14, 6q21q23, 11q, and, possibly, 4q. The presence of complex karyotypes, with concomitant abnormalities of 13q, +12, 6q, 11q, suggests that the development of sequential chromosome changes, rather than any single specific anomaly, may underlie leukemogenesis in this cytologic subset of CLL, partially accounting for the relatively aggressive clinical course.
PURPOSE: To assess the role of CT in the diagnosis and management of multiple myeloma (MM) and to investigate if CT findings can influence the clinical approach, prognosis and treatment. STUDY DESIGN AND PATIENTS: We reviewed the findings relative to 273 MM patients submitted to CT June, 1994, to December, 1996. The patients were 143 men and 130 women (mean age: 65 years): 143 were stage I, 38 stage II and 92 stage III according to Durie and Salmon's clinical classification. All patients were submitted to blood tests, spinal radiography and CT, the latter with serial 5-mm scans on several vertebral bodies. The CT unit was a Philips Tomoscan SR 7000. RESULTS: CT showed lysis foci in some vertebral bodies (4 cases) where conventional radiography had shown only aspecific osteopenia. CT also depicted vertebral arch and process involvement in 3 cases with the vertebral pedicle sign. Moreover, CT proved superior to radiography in showing the spread of myelomatous masses into the soft tissues in a case with solitary permeative lesion in the left pubic bone, which facilitated subsequent biopsy. As for extraosseous localizations, CT demonstrated thoracic soft tissue (1 woman) and pelvic (1 man) involvement by myelomatous masses penetrating into surrounding tissues. In our series, only a case of osteosclerotic bone myeloma was observed in the pelvis, associated with lytic abnormalities. DISCUSSION AND CONCLUSIONS: The role of CT in the diagnosis and management of MM has not been assessed, because this technique demonstrates tumor extent more accurately than radiography but CT findings do not seem to improve the clinical approach and therapeutic management of the disease. Nevertheless, we recommend CT for some myelomatous conditions, namely: a) in the patients with focal bone pain but normal skeletal radiographs; b) in the patients with M protein, bone marrow plasmocytosis and back pain, but with an inconclusive MM diagnosis; c) to assess bone spread in the regions which are anatomically complex or difficult to study with radiography and to depict soft tissue involvement; d) for bone biopsy.
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The purpose of the study was to ascertain whether the prognostic significance of staging in multiple myeloma (MM) is influenced by the aggressiveness of effective induction treatment and/or by continuing or discontinuing maintenance chemotherapy. Patients with untreated stage I MM (defined according to Durie and Salmon) were randomised between being followed without cytostatics until the disease progressed and receiving six courses of melphalan and prednisone (MP-P) just after diagnosis; stage II patients were uniformly treated with MPH-P and stage III patients were randomised between MPH-P and four courses of combination chemotherapy with Peptichemio, vincristine and prednisone (PTC-VCR-P). Within each stage, responsive patients were randomised between receiving additional therapy only until maximal tumour reduction was reached (plateau phase) and continuing induction therapy indefinitely until relapse. With resistant, progressive or relapsing disease, patients originally treated with MPH-P for induction received combination chemotherapy and vice versa. The overall first response rate was 43.8% (42.2% in 206 stage I, II and III patients treated with MPH-P and 48.0% in 75 stage III patients treated with combination chemotherapy, P = NS). Combination chemotherapy was more myelotoxic than MPH-P and, in particular, caused more non-haematological side-effects. Both the less and the more aggressive induction policies gave the same disease control. Progression of disease was statistically similar in stage I patients who were initially left untreated and in t hose who received MPH-P just after diagnosis; median duration of first response was similar in stage III patients receiving MPH-P and in those on combination chemotherapy. In all stages, discontinuing or continuing maintenance did not alter the median duration of first response. The overall second response rate was 28.5% (34.0% to MPH-P and 25.3% to combination chemotherapy, P = NS). Median survival was greater than 78 months in stage I, was 46.3 months in stage II and was 24.3 months in stage III patients, still independent of both induction and post-induction policies. In MM, the significance of staging for survival is independent of both the aggressiveness of induction and of continuing or discontinuing maintenance chemotherapy after the maximal tumor reduction has been achieved. Both MPH-P and and the association of PTC, VCR and P are effective in inducing first response and also second response in patients failing on the alternative regimen, but PTC-VCR-P causes more side effects. Thus, the overwhelming majority of patients with MM can safely be given MPH-P as first therapy, and this treatment may be delayed in early diseases.
Morphologic, immunologic, and cytogenetic features were studied in 30 newly diagnosed patients with CD34-positive (CD34+) de novo acute myeloid leukemia (AML) in comparison with 30 patients with CD34-negative (CD34-) AML. Karyotype at diagnosis was abnormal in 25/30 CD34+ AML patients, of which nine had major karyotype aberrations (MAKA). Clonal chromosome changes were detected in 9/30 patients with CD34- AML. The most frequent chromosome aberration in CD34+ patients was -5/5q-, an aberration showing a strong association with the M2 FAB subtype of AML. Other recurring chromosome changes involved chromosome 16q (four cases) and chromosome 17p (three cases). Total or partial monosomy 7q was detected in three cases. Among CD34- AML, two patients had the classical t(15;17) and two had structural aberrations of 6q. Among patients with CD34+ AML, nine had MAKA in association with trilineage myelodysplasia (TMDS). TMDS was infrequent in CD34+ AML without MAKA and in CD34- AML. Complete remission (CR) was achieved in 8/30 CD34+ AML (26%), as compared with 22/30 CD34- AML (73%), and median survival was 2 months in the former group and 8 months in the latter. No patient with CD34+ AML and MAKA achieved CR, whereas 8/21 CD34+ AML without complex chromosome changes or with normal karyotype achieved CR. In conclusion, a distinct cytogenetic profile may be associated with CD34+ AML. Cytogenetic findings in CD34+ AML may be clinically relevant in that they may disclose a subset of patients with MAKA with a low CR rate.
From 1984 to 1990 the authors reviewed the radiologic-clinical charts of 237 patients affected with multiple myeloma (MM). The series included 127 males and 110 females (mean age: 66 years) who had been classified according to Durie and Salmon clinical criteria. All the patients underwent X-rays of the skeleton, as recommended in international literature; moreover, 148 subjects underwent whole-body bone scintigraphy, and 130 bone marrow scintigraphy. A selected group of cases (18 male/female patients) were submitted to bone densitometry employing both quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA). The results follow: 1) in the first stage of the disease, a high number of patients (29.5%) exhibits no skeletal abnormalities on X-rays; the most common lesion locations include the spine (49%), skull (35%), pelvis (34%), ribs (33%), humeri (22%), femora (13%) and mandible (10%); 2) the most frequent pattern is osteolysis, as a characteristic "punched-out" multiple lesion; the second most frequent lesion is osteopenia (43%), especially in the spine; pathologic fractures are common (54%) in the ribs, vertebral bodies, limbs; typical associations of features and sites are seen on X-ray images, which sometime make diagnosis easier; 3) whole-body scintigraphy, revealing aspecific uptake only in the presence of pathological fractures, is not recommended in the first staging of the disease, but is considered as a valuable technique in the follow-up, when the patients become symptomatic; 4) bone marrow scintigraphy, especially in the "marrow expansion" pattern, might be considered as an attempt made by the body to recover the central space which was destroyed by myelomatous involvement. The prognostic value of this technique is still to be assessed; 5) bone densitometry, by confirming the grade of osteopenia, reveals that osteoporosis is a peculiar pattern of bone disease in MM, which is not related to age only; 6) conventional radiography of the skeleton is the method of choice in the diagnosis of lytic areas of MM, and remains, as yet, irreplaceable. The other diagnostic techniques--i.e., CT and MRI--can be used to evaluate the extent of bone and soft tissue involvement, in the cases with questionable diagnosis, and to assess the degree of marrow involvement.
The radiologic staging of a series of 144 patients (88 males and 56 females) affected with plasma-cell dyscrasias and observed over a 26-month period, revealed both the well-known bone myeloma-related abnormalities and hyperostotic lesions similar to those described in diffuse idiopathic skeletal hyperostosis. The incidence of skeletal hyperostosis was 31.94%, much higher than that reported in literature for the general population (5%). Typically, the axial skeleton is the most common location for abnormalities in multiple myeloma (MM) as well as in DISH: involvement of the dorsal spine was observed in 65% of cases, the cervical spine was involved in 34.8% of patients, and the lumbar spine in 28.3%. Peripheral ossifying enthesopathy, considered as "whiskering" in the pelvis, was found in 12 cases (8.2%), 7 males and 5 females. DISH was indifferently present in both MM (23 cases), with severe osteolysis (stage III) or simple osteoporosis (stage I), and monoclonal gammopathy of undetermined significance (MGUS) (17 cases), usually without any myeloma-related bone lesions, and in Waldenström disease (4 cases). Many hypotheses are discussed as to the possible pathogenesis (e.g.: accidental, dysmetabolic, or degenerative) of hyperostosis in dysgammaglobulinemias, but, to date, they are no more than mere guesses. DISH is a disorder the etiology of which is still unknown: it is likely to be an ossifying diathesis, but its incidence in both illnesses--which are both plasma-cell dyscarsias--is too high for the association to be accidental. Thus, a pathogenetic factor produced by multiple myeloma can be hypothesized, capable of increasing the so-called idiopathic hyperostosis.
Bone lesions are the main sign of neoplastic proliferation of multiple myeloma (MM), a disseminated malignant disease which originates in, invades and replaces normal bone marrow. The most characteristic radiographic pattern is a focal lytic lesion, well-defined or "punched-out", generally with no surrounding bone reaction. The association is confirmed between MM and osteoporosis, as reduced bone density (osteopenia) and pathologic fractures (ribs, spine). This paper is aimed at evaluating the importance of osteopenia in both diagnosis and prognosis of MM. Eighteen patients affected with MM were examined with quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DEXA) for bone densitometry in lumbar spine and proximal femur. The patients (12 males and 6 females) were classified according to Durie's clinical criteria and to the radiographic patterns suggested by Merlini. The results indicate the patients with an advanced clinical stage (III) and scintigraphic expansion of bone marrow to have low densitometric values on both QCT and DEXA. There was substantial agreement between the 2 methods, but DEXA had a higher number of false positives. Instrumental diagnostic protocol may be thus planned as follows: 1) conventional radiography; 2) bone marrow scintigraphy; 3) bone densitometry of lumbar spine, with QCT. The patient is then to be followed with conventional and/or digital radiography in symptomatic locations, and with bone scintigraphy.
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The radiographic patterns of the skeleton of 73 patients affected by multiple myeloma (MM) were compared to the correspondent scintigraphic findings. Whole body scans were performed using 99m Tc-diphosphonates (bone scintigraphy), and 99m Tc-microcolloids (bone marrow scintigraphy). The results indicate that: a) radiography is more sensitive and accurate than scintigraphy in detecting typical myeloma-related bone lesions; b) bone scintigraphy is useful in detecting alterations in particular locations--i.e., sternum, ribs, scapulae, etc.--which are difficult to demonstrate by plain X-rays; moreover, the recovery of the fractures can be visualized; c) bone marrow scintigraphy is employed to demonstrate the presence of marrow expansion, of cold/hot spots, and relative marrow uptake, related to phagocytic activity. Since in adult men red marrow is confined to the epiphysis of long bones and to the spine, all the diseases affecting bone marrow cause medullary expansion/reduction, which are both easily detected by specific radiopharmaceuticals. The peripheral expansion is clearly documented especially in distal humeri and femora since marrow uptake is included, in healthy adults, in the axial and proximal appendicular skeleton. In spite of its yielding unique information, bone marrow scintigraphy remains an additional technique of bone scan, because of its low diagnostic accuracy.