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P Ferraresi

Publications and source records attributed to P Ferraresi.

At least 19 recordsLinked to original sources
PubMed2006

Intracellular readthrough of nonsense mutations by aminoglycosides in coagulation factor VII.

BACKGROUND: Nonsense mutations in coagulation factor (F) VII potentially cause a lethal hemorrhagic diathesis. Readthrough of nonsense mutations by aminoglycosides has been studied in a few human disease models with variable results. OBJECTIVES: We investigated the K316X and W364X FVII mutations, associated with intracranial hemorrhage, and their correction by aminoglycosides. The rare nonsense mutations in FVII represent favorite models to test this strategy, because even tiny increases in the amount of functional full-length protein in patients could ameliorate hemorrhagic phenotypes. RESULTS: A FVII-green fluorescent protein (GFP) chimaera provided us with a fluorescent model of FVII expression in living cells. Appreciable fluorescence in cells transfected with nonsense FVII-GFP mutants was detected upon geneticin treatment, thus demonstrating suppression of premature translation termination. To investigate the rescue of FVII function, nonsense variants of the native FVII without GFP (p316X-FVII and p364X-FVII) were transfected and found to secrete low amounts of FVII (approximately 1% of Wt-FVII activity), thus suggesting a spontaneous stop codon readthrough. Geneticin treatment of cells resulted in a significant and dose-dependent increase of secreted FVII molecules (p316X-FVII, 24 +/- 12 ng mL(-1), 3.6 +/- 0.8% of Wt-FVII activity; p364X-FVII, 26 +/- 10 ng mL(-1), 3.7+/-0.6%) characterized by reduced specific activity, thus indicating the synthesis of dysfunctional proteins. Similar results were observed with gentamicin, a commonly used aminoglycoside of potential interest for patient treatment. CONCLUSIONS: Our approach, extendable to other coagulation factors, represents an effective tool for a systematic study of the effects of aminoglycosides and neighboring sequences on nonsense codon readthrough. These results provide the rationale for a mutation-specific therapeutic approach in FVII deficiency.

Adolescent↗
PubMed2001

The heterozygous 20210 G/A genotype prevalence in patients affected by central and branch retinal vein occlusion: a pilot study.

BACKGROUND: Several inherited conditions have been associated with an increased or decreased incidence of retinal vein occlusion (RVO). The A allele in the 20210 G/A prothrombin gene has been found to be associated with systemic venous thrombosis. The aim of this study has been to verify the prevalence of this mutation in patients affected by central RVO (CRVO) or branch RVO (BRVO). METHODS: A retrospective study was carried out on 100 consecutive patients suffering from RVO, more than 50 years old, unaffected by systemic diseases known to be associated with markedly increased RVO occurrence. We determined the frequency of this mutation by performing mutagenised amplification of exon 14 followed by restriction analysis of the amplified DNA fragment. RESULTS: The overall frequency of prothrombin 20210A allele in RVO patients was 6.0%. All heterozygous patients had suffered from CRVO. In this study subgroup, the frequency of the 20210 G/A prothrombin heterozygosis was 12.0%. The difference in the frequency of this the genetic variant between the CRVO and BRVO groups was statistically significant. None of the conventional RVO risk factors were statistically related to the occurrence of the disease in either the CRVO or the BRVO subgroup. CONCLUSION: The prevalence of the prothrombin 20210A mutation observed in CRVO patients is significantly higher than in the normal Italian population. Moreover, the prevalence is significantly greater in CRVO than in BRVO patients. These results raise the possibility that the prothrombin 20210A variant may be considered as a risk factor for CRVO.

Aged↗
PubMed2001

Gamma knife radiosurgery in meningiomas of the posterior fossa. Experience with 62 treated lesions.

OBJECTIVES: This study was undertaken to assess the role of the gamma knife (GK) in the treatment of meningiomas of the posterior cranial fossa (PCF) and to statistically analyze the predictability of arbitrarily-selected prognostic factors in such treatment. METHODS: From February 1993 to November 1998, 57 patients underwent GK treatment for 62 meningiomas of the PCF (19 M/38 F; average age, 57.5 years, ranging from 25 - 82 years). Tumor sites included: foramen jugular-petrous bone (26/62), petroclival (23/62), cerebellar convexity (6/62), tentorium (6/62), and foramen magnum (1/62). Single lesions were treated in 44/62 cases while meningiomatosis was treated in the remaining 18. Post-operative residual or recurrent tumor was found in 27/62 patients and, in 7/27, histology documented characteristics of biological aggressiveness (GII/III). Indications for radiosurgery included: advanced age, high operative risk, tumor volume < 20 ml, inoperable or refused for additional surgery. The prognostic factors statistically analyzed included: meningiomatosis (yes/no), radiosurgery as primary or adjuvant treatment, GI vs. GII/III histology, and tumor volume (< or = 5 ml vs. > 5 ml). RESULTS: The observation periods varied from 6 to 64.3 months (median 28.7 months). At the end of the study, 53/57 patients were alive and reported to be in stable or improved neurological condition. The cause of death for the remaining 4 patients included: 2 deaths associated with tumor progression, while 2 died due to causes unrelated to the disease. Neuroradiological evaluation documented the disappearance or reduction of the meningioma mass in 34/62 (55 %) cases, a stable imaging picture in 25/62 (40 %), and a progression only in 3/62 (5 %). To date, there have been no reported cases of post-GK permanent morbidity or mortality. Side effects observed were of a transient nature due to post-radiosurgical edema (6.5 %). With regard to statistical analysis, the only factor to appear to significantly influence efficacy of radiosurgery for tumor growth control (TGC) was the biological nature of the meningioma (chi(2) = 2.708). The presence of meningiomatosis, SR as a primary or adjuvant treatment nor tumor volume were shown to statistically influence tumor behavior after GK. CONCLUSIONS: The excellent results obtained for TGC with minimal associated side effects suggest that GK is an effective therapeutic tool also for treatment of PCF meningiomas.

Adult↗
PubMed2000

Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease.

BACKGROUND: High plasma levels of coagulation factor VII have been suggested to be predictors of death due to coronary artery disease. Since polymorphisms in the factor VII gene contribute to variations in factor VII levels, such polymorphisms may be associated with the risk of myocardial infarction, which is precipitated by thrombosis. METHODS: We studied a total of 444 patients, 311 of whom had severe, angiographically documented coronary atherosclerosis. Of these 311 patients, 175 had documentation of a previous myocardial infarction. As a control group, 133 patients with normal coronary arteriograms were also included. We measured the levels of activated factor VII and assessed three polymorphisms in the factor VII gene, one involving the promoter (A1 and A2 alleles), one involving the catalytic region (R353Q), and one involving intron 7. RESULTS: Each of the polymorphisms influenced factor VII levels. Patients with the A2A2 and QQ genotypes had the lowest levels of activated factor VII (66 percent and 72 percent lower, respectively, than the levels in patients with the wild-type genotypes). The frequencies of the various genotypes in the patients free of coronary artery disease were similar to those in the entire population of patients with coronary artery disease. In the latter group, there were significantly more heterozygotes and homozygotes for the A2 and Q alleles among those who had not had a myocardial infarction than among those who had had an infarction (P=0.008 for the presence of the promoter polymorphism and P=0.01 for the presence of the R353Q polymorphism by chi-square analysis). The adjusted odds ratio for myocardial infarction among the patients with the A1A2 or RQ genotype was 0.47 (95 percent confidence interval, 0.27 to 0.81). CONCLUSIONS: Our findings suggest that certain factor VII genotypes have a role in protection against myocardial infarction. This may explain why some patients do not have myocardial infarction despite the presence of severe coronary atherosclerosis.

Case-Control Studies↗
PubMed2000

Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies.

Previous studies have established that factor VII gene (F7) polymorphisms (5'F7 and R353Q) contribute about one-third of factor VII (FVII) level variation in plasma. However, F7 genotyping in patients with cardiovascular disease has produced conflicting results. Population and expression studies were used to investigate the role of intron 7 (IVS7 ) polymorphisms, including repeat and sequence variations, in controlling activated FVII (FVIIa) and antigen (FVIIag) levels. Genotype-phenotype studies performed in 438 Italian subjects suggested a positive relation between the IVS7 repeat number and FVII levels. The lowest values were associated with the IVS7 + 7G allele. The screening of 52 patients with mild FVII deficiency showed an 8-fold increase in frequency (8%) of this allele, and among heterozygotes for identical mutations, lower FVII levels were observed in the IVS7 + 7G carriers. This frequent genetic component participates in the phenotypic heterogeneity of FVII deficiency. The evaluation of the individual contribution of polymorphisms was assisted by the expression of each IVS7 variant, as a minigene, in eukaryotic cells. The novel quantitative analysis revealed that higher numbers of repeats were associated with higher mRNA expression levels and that the IVS7 + 7G allele, previously defined as a functionally silent polymorphism, was responsible for the lowest relative mRNA expression. Taken together, these findings indicate that the IVS7 polymorphisms contribute to the plasmatic variance of FVII levels via differential efficiency of mRNA splicing. These studies provide further elements to understand the control of FVII levels, which could be of importance to ensure the hemostatic balance under pathologic conditions.

Amino Acid Substitution↗
PubMed2000

Gamma knife radiosurgery as a primary treatment for prolactinomas.

OBJECT: The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. METHODS: Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6-72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. CONCLUSIONS: Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (> or = 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.

Humans↗
PubMed2000

Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma.

Molecular genetics and biochemical studies were performed in homozygotes for the R2 allele (4070G) in the factor V gene, most of them affected by coronary artery disease. Novel polymorphisms (G642T, 156Ser; T1328C, 385Met/Thr), among which a functional candidate (A6755G, 2194Asp/Gly) located in the C2 domain of FV, were identified in the R2 gene. In chromatographic studies R2 FV appeared qualitatively identical to normal FV. However, a relative increase of the more thrombogenic and more glycosylated FV isoform (FV1) was observed in plasma of 2194Gly homozygotes (mean FV1/FV2 ratio 0.71, 95% CI 0.66-0.77) as compared to R2-free controls (0.37, 95% CI 0.34-0.40). We conclude that carriership of the R2 FV gene is associated with an imbalance between the two functionally different FV isoforms, and propose that genetically determined differential glycosylation of FV could represent a novel mechanism of thrombotic disease.

Aged↗
PubMed1999

Idiopathic central retinal vein occlusion in a thrombophilic patient with the heterozygous 20210 G/A prothrombin genotype.

PURPOSE: To report the occurrence of monolateral central retinal vein occlusion in a patient with heterozygous 20210 G/A prothrombin genotype, known to be associated with high thrombophilic risk. METHODS: A monolateral central retinal vein occlusion was diagnosed in a 71-year-old woman, who had suffered from a deep vein thrombosis in her left leg at the age of 36 years. Mutations of the genes involved in the coagulation process were investigated by DNA polymerase chain reaction. RESULT: DNA analysis showed the patient to be heterozygous for the prothrombin 20210 G/A genetic variation. CONCLUSION: The 20210 G/A prothrombin gene mutation may be associated with central retinal vein occlusion.

Aged↗
PubMed1997

Visual control of hand-reaching movement: activity in parietal area 7m.

The activity of single neurons was studied in parietal area 7m while monkeys performed an instructed-delay reaching task to visual targets under normal light conditions and in darkness. The task was aimed at assessing the influence of vision of hand position on the neural activity of 7m related either to static posture and movement of the hand or to eye position in the orbit. The results show the existence of preparatory, movement-related and postural activity for the control of reaching, all of which are strongly modulated by vision. The activity of many 7m neurons, otherwise insensitive to pure visual stimuli, seems to reflect complex interactions between gaze angle and hand position in the visual field.

Animals↗
PubMed1997

The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease.

A genetic variation in the 3'-untranslated region of the prothrombin mRNA (20210 G/A) has recently been reported to be associated with elevated plasma prothrombin levels and with an increased incidence of venous thrombosis. We determined the frequency of this mutation, the detection of which was improved by allele-specific amplification of exon 14 and by denaturing gradients (denaturing gradient gel electrophoresis), in cohorts of patients affected by venous thrombosis (n = 132) or by coronary or cerebrovascular diseases (n = 195) and in normal subjects from various populations. An overlapping frequency of the heterozygous genotype (4%) was found in normal subjects from Italy and Cyprus, and no carrier was detected in 40 subjects of Indian or Somali origin. The 20210 GA heterozygous genotype was not increased in frequency in patients with arterial disease. In contrast, the GA genotype was associated (P = .007) with venous thrombosis both in simple heterozygotes (16%) with a family history of thrombosis as well as in double heterozygotes (14%) for other known thrombophilic defects. A synergic interaction between the prothrombin 20210 GA genotype and the factor V Leiden mutation, both potentially affecting the prothrombinase complex, was suggested by the early onset of thrombosis (median age 22 years) in doubly heterozygous patients. The association of the 20210 A allele with higher prothrombin levels was confirmed in the Italian population. However, the prothrombin assay does not allow an efficient preselection of patients for the DNA analysis.

Adolescent↗
PubMed1997

Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation (Ala223Val MTHFR) in patients with inherited thrombophilic coagulation defects.

To assess whether certain abnormalities of the sulfated amino acid metabolism are associated with the occurrence of thromboembolic events in patients with inherited thrombophilic conditions, the levels of homocyst(e)ine, before or after methionine load, and the presence of the Ala223Val substitution in the 5,10-methylenetetrahydrofolate reductase (MTHFR) were evaluated in 119 subjects with a congenital single thrombophilic condition (type I deficiency of antithrombin n = 10, protein C n = 24, protein S n = 16; activated protein C resistance due to factor V Leiden mutation n = 69). Sixty-three subjects had experienced at least one documented thrombotic event, while the remaining 56 subjects were still free from any thrombotic symptom. Our results show that (1) high homocyst(e)ine levels, either in fasting condition or after methionine load, were not more frequent in subjects with inherited thrombophilic alterations (14.4%) than in normal control subjects (10% by definition) and (2) the frequency of hyperhomocyst(e)inemia was similar in thrombophilic subjects, who already have (14.3%) or have not (14.6%) experienced thrombotic events. As regards the MTHFR mutation, the homozygous condition was present in 23.2% of the thrombophilic patients versus 17.5% in the control subjects, a nonsignificant difference. The mutation was slightly more frequent in those thrombophilic subjects who had suffered a thrombotic episode (25.5%) versus those with no thrombosis (20.8%), with odds ratios of 1.61 (confidence interval (CI) = 0.58-4.52) and 1.24 (CI = 0.42-3.43), respectively. These differences were also nonsignificant. It is concluded that in subjects with inherited thrombophilias, a condition of hyperhomocyst(e)inemia "per se" is not a factor increasing the risk of thrombosis. The risk enhancement conferred by the MTHFR mutation, if any, seems to be slight or limited, and its significance could be ascertained only in a large multicenter trial.

Adult↗
PubMed1997

Stereotactic radiosurgery for the treatment of arteriovenous malformations in childhood.

BACKGROUND: The main techniques and results in stereotactic radiosurgical treatment of endocranial AVM's are described and compared. The authors also report their preliminary experience in the treatment of 6 consecutive pediatric patients with intracerebral vascular malformations using gamma knife (GK) radiosurgery. METHODS: The various stereotactic radiosurgery methods currently used (charged-particle beam, modified linear accelerator, and GK) are described. At the Department of Neurosurgery in Verona, from February 1993 to February 1996, stereotactic GK radiosurgery was performed on 721 patients, including 20 of pediatric age (3%). Of the 78 AVMs, 7 (9%) were diagnosed in children. One patient was lost at follow-up. Among the remaining 6 children, there were 3 males and 3 females with a mean age of 12.3 years (range, 5-16 years). Treatment general anesthesia was needed only in 1 case. The AVM volume was always less than 10 cc. After completion of the procedure, children were discharged from the hospital the following day. RESULTS: The follow-up period ranged from 4 months to 29 months (median 18.8 months). The angiographic confirmed total obliteration is used as the end point of an AVM treated radiosurgically, and usually requires 2 to 3 years. All the patients are alive; four of the treated children are neurologically normal and one patient has clinically improved to a normal neurological status. The sixth patient has fixed neurological deficits that existed prior to treatment. Among the three cases with a follow-up period of over 2 years, complete obliteration has been angiographically confirmed in 2 patients and subtotal in 1 patient. In the three remaining patients with follow-up periods less than 2 years, serial MR images suggest subtotal obliteration in 2 cases and no significant change in one patient who had undergone treatment within the current year. To date, neither persistent GK radiosurgery-related complications nor bleeding following stereotactic radiosurgery has been described. CONCLUSIONS: The review of literature and our preliminary results suggest that also in children, as in adults, the use of stereotactically delivered irradiation represents a safe and effective technique obtaining complete obliteration of AVMs previously considered surgically inaccessible due to their location and poor response to resection and/or embolization.

Adolescent↗
PubMed1996

Mutation pattern in clinically asymptomatic coagulation factor VII deficiency.

A total of 122 subjects, referred after presurgery screening or checkup for prolonged prothrombin time, were characterized for the presence of coagulation factor VII deficiency. Fourteen subjects carried a partial and asymptomatic deficiency, and in half of them dysfunctional molecules were detected in plasma. In nine subjects we found five missense mutations differing from those previously found in factor VII deficient patients. The others were homozygous for a common polymorphism (R353Q) that affects factor VII levels. A new codon dimorphism (A330) was also found in exon 8. Four mutations (R223W, M298I, R304Q, and R353Q) located at FVII-specific residues point out protein regions that are important for coagulation factor evolution, and two mutations (G342E and E265K) affect generic or partially generic residues. The newly reported mutations were combined with those we previously found, totalling 17 independent mutations responsible for FVII deficiency in 27 Italian pedigrees. We observed several similarities with the mutation pattern determined in factor IX, which include a high percentage of transitions at CpG doublets, the presence of hot spot sites affected by multiple substitutions, and of several topologically equivalent mutations.

Factor VII Deficiency↗
PubMed1996

Gamma Knife radiosurgery in skull base meningiomas. Preliminary experience with 50 cases.

Gamma Knife radiosurgery was performed on 50 patients (10 males and 40 females) with skull base meningiomas (SBMs) between February 1993 and September 1995. The patients ranged in age from 25 to 78 years (mean age 56 years). The location of the tumors was anterior fossa (n = 4), sphenoorbital (n = 2), sellar region (n = 5), cavernous sinus (n = 26), petroclival (n = 12), and occipital foramen (n = 1). The tumor volume ranged from 0.6 to 20 cm3 (mean 8.6 cm3). The mean values for dose planning were edge isodose (EI) 46.7%, edge dose (ED) 18.0 Gy, maximum dose 39.8 Gy, average dose (AD) 25.4 Gy, and average number of isocentres 5.7. The patients were analyzed for five parameters: tumor volume (< 7.5 vs. > or = 7.5 cm3); EI (< 50 vs. > or = 50%); ED (< 18 vs. > or = 18 Gy); AD (< 25 vs. > or = 25 Gy), and primary versus residual or recurrent tumors. The overall frequency of tumor growth control (TGC) was 98%, with 1- and 2-year TGC rates of 97% and 100%, respectively. The most favorable neurological results were obtained with a tumor volume < 7.5 cm3 (p < 0.05), EI > or = 50% (NS), ED > or = 18 Gy (NS) and with primary SBMs (p < 0.01). A favorable TGC was demonstrated at follow-up imaging examinations when the tumor volume was > or = 7.5 cm3 (100% TGC rate), EI < 50% (100%), ED > or = 18 Gy (100%), AD > 25 Gy (100%), in both primary SBMs (100%) and residual or recurrent SBMs (96.5%). To date, only 3 (6%) of the 50 patients have presented signs of neurological worsening related to the Gamma Knife radiosurgery. While no early complications were noted, neuroradiological follow-up did show delayed transient imaging complications (3 edema and 1 radionecrosis; 8% of all patients). In conclusion, our preliminary results seem to confirm that Gamma Knife radiosurgery is an effective and safe adjuvant or a feasible alternative primary treatment in controlling or preventing SBM progression.

Adult↗
PubMed1996

Gamma Knife radiosurgery for intracranial metastases: from local tumor control to increased survival.

We have analyzed a series of 225 patients with intracranial metastases (343 lesions), treated in our department by Gamma Knife radiosurgery over a 30-month period. We have used a modified Pittsburgh protocol and performed 242 procedures on 164 single/78 multiple lesions. Primary tumors were mostly carcinomas of the lung (52%) and breast (11.6%). Neuroradiological localization of the target was usually performed by stereotactic computed tomography. Magnetic resonance imaging was only used in special circumstances. Routine dose planning was assisted by three-dimensional reconstruction programs. Mean tumor volume was larger than expected (5.7 ml). Mean prescription dose and average dose were 21.1 and 29.9 Gy, respectively. Middle- and long-term results were evaluated in a subset of 152 patients (236 lesions) with adequate (> 4 months) follow-up. Mean follow-up was 53.1 weeks with 61/152 patients still living. There was a predominance of retrospectively classified 'not fully eligible cases' among the survivors, mainly because of uncontrolled primary tumor. The 1-year local tumor control rate was 88.2%. Treatment-related radiological (3.9%) and clinical (1.6%) sequelae were minimal. Overall mean survival in these patients (40 weeks) turned out to be higher than that commonly reported after conventional surgical-radiation treatments. It was encouraging that the mean survival of 'fully' eligible patients was 51 weeks. Karnofsky performance status and neurological (Order Grading) performance scores were consistently high for most of the follow-up period. Functional Independence and the Palliative Index were not far from the value of mean survival. The main cause of death remains uncontrolled systemic disease (64.8%). On the other hand, the relative incidence of intracranial tumor progression was considerably decreased. This indicated that these patients should perhaps be treated more aggressively and underlines the need for randomized trials to determine the optimal treatment.

Adult↗
PubMed1996

A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects.

305 patients with juvenile thromboembolic episodes were screened for the presence of heparin cofactor II deficiency. The heterozygous deletion of two bases was found in the exon 5 of the heparin cofactor II gene in two unrelated patients, very likely due to a founder effect. This molecular lesion, causing a frameshift and elongated translation, affects the core of the molecule and should cause the complete unfolding of the protein, which is in accordance with the observed type I deficiency. The corresponding region of antithrombin III gene is affected by a cluster of frameshift mutations suggesting that heparin cofactor II and antithrombin III could share similar mutational patterns. The heparin cofactor II gene alteration was associated with, in one patient, the factor V Leiden mutation and, in the other, type I protein C deficiency. The tracing of the single defects in several family members indicated that the mutations became clinically manifest only when present in the doubly heterozygous condition. This study provides two examples, based on molecular findings, of the interplay of risk factors which is potentially useful to define a role for heparin cofactor II deficiency in inherited thrombophilia.

Adult↗
PubMed1985

Further cytogenetic evidence for a multistep pathogenesis of Ph-positive chronic myelogenous leukemia.

A case of Ph-positive chronic myelogenous leukemia in blastic crisis was studied extensively by means of cytogenetic techniques. Karyotypic features, as well as growth patterns, kinetic data, and rates of sister chromatid exchange, were examined in bone marrow, blood, and pleural effusion cells. The data provide strong evidence for a multistep pathogenesis of the disease, the development of which appears to be linked to mechanisms of clonal selection and genetic imbalance in the malignant cell population.

Aged↗