Incidence and prevalence of idiopathic pulmonary fibrosis

RATIONALE: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease of unknown etiology; its epidemiology in the United States has not been well characterized. OBJECTIVE: To estimate the annual incidence and prevalence of idiopathic pulmonary fibrosis in the United States. METHODS: Retrospective cohort design utilizing a large health care claims database spanning the period January 1996 through December 2000. MEASUREMENTS AND MAIN RESULTS: Persons with idiopathic pulmonary fibrosis were identified based on diagnosis and procedure codes. Using broad case-finding criteria, prevalence was estimated to range from 4.0 per 100,000 persons aged 18 to 34 yr to 227.2 per 100,000 among those 75 yr or older; annual incidence was estimated to range from 1.2 to 76.4 per 100,000. Using narrow case-finding criteria, prevalence ranged from 0.8 to 64.7 per 100,000 persons; comparable figures for incidence were 0.4 to 27.1 per 100,000 persons. Extrapolating these rates to the overall United States' population, prevalence was estimated to be 42.7 per 100,000 (incidence, 16.3 per 100,000) using broad criteria; with narrow criteria, prevalence was estimated to be 14.0 per 100,000 (incidence, 6.8 per 100,000). CONCLUSIONS: Our results suggest that idiopathic pulmonary fibrosis is probably more common in the United States than previously reported.     

Trends in the incidence of chronic Philadelphia chromosome negative (Ph-) myeloproliferative disorders in the city of Göteborg, Sweden, during 1983-99

Objective. In the literature the incidence rates for the chronic Philadelphia chromosome negative (Ph‐) myeloproliferative disorders (MPD) are known to vary extensively; only a few studies have, however, been concerned with incidence trends over time. Therefore, the aim of the present work was to investigate possible trends as regards incidence rates over time for Ph‐MPD. Design. Herein, we carried out a retrospective population‐based survey on the incidence of polycythaemia vera (PV), essential thrombocythae‐mia (ET) and chronic idiopathic myelofibrosis (IMF), in the city of Göteborg (Sweden), covering the years 1983–99. Results. The study comprised 416 patients with Ph‐MPD. There were 205 patients with PV, 153 patients with ET, 34 with IMF and 24 with unclassified MPD. The annual incidence for PV was 1.97 per 10⁵ inhabitants; the corresponding figures for ET and IMF were 1.55 per 10⁵ and 0.30 per 10⁵ inhabitants, respectively. There was a significant increase in the annual incidence rate for ET (P = 0.008); this increase was significant for male subjects (P = 0.015) but did not reach significance for females (P = 0.118). No such increase over time was recorded as regards PV and IMF. Conclusions. The increasing annual incidence rate for ET is most possibly explained by the more frequent use of automated platelet counts whenever a patient consults a doctor. Thereby, an increasing number of patients with overt thrombocytosis of unknown origin are discovered and will be referred to specialists within the field of haematology for a correct diagnosis.     

Myeloproliferative disorders: complications, survival and causes of death

This retrospective single-center study compared thromboembolic and hemorrhagic complications, survival and causes of death in a cohort of 102 consecutive patients with myeloproliferative disorders (MPD). We included 17 patients with essential thrombocythemia (ET), 59 with polycythemia vera (PV), and 26 with osteomyelofibrosis (OMF). The median follow-up was 3.7 years. Estimated 8-year probability of complications for the entire cohort was 80 ±11% (95% confidence interval), without significant differences among MPD subgroups. The rate of thromboembolic complications, expressed as the number of events per 100 patient years, was 16.7 for patients with PV, 13.8 for OMF, and 7.5 for ET. Fifty-four percent of thromboembolic events in PV involved cerebral or limb arteries. The rate of bleeding complications was highest in patients with OMF (31.8 per 100 patient years), followed by ET and PV (11.8). Ninety percent of bleeding episodes affected the skin, mucosal membranes, and the gastrointestinal tract. Eight-year survival was highest in ET with 91±17%, followed by PV (66±18%) and OMF (40±31%) (P<0.01). Twenty-four patients died during the observation period, and fatal thrombosis (in five patients) represented the leading cause of death. Only two patients with MPD died from fatal hemorrhage and one from acute leukemia. We conclude that survival is highest in ET and lowest in OMF. Both thromboembolic and hemorrhagic complications are frequent. However, thrombosis appears to be more often fatal than bleeding complications. Prophylaxis of thromboembolic events remains a key issue in the management of MPD. Received: 9 April 1999 / Accepted: 22 October 1999     

JAK2V617F点突变在BCR-ABL阴性骨髓增殖性疾病中的意义

目的研究JAK2V617F点突变在诊断BCR—ABL融合基因阴性的骨髓增殖性疾病（MPD）患者中的意义。方法选择51例BCR—ABL阴性MPD患者,采用等位基因特异PCR法检测各组患者JAK2V617F的突变情况。结果51例BCR—ABL融合基因阴性的MPD患者中,34例JAK2V617F突变阳性,其中原发性血小板增多症（ET）18例（69．23％）,真性红细胞增多症（PV）16例（66．67％）,特发性骨髓纤维化（IMF）1例为阴性;PV与ET患者相比更容易发生肝脾肿大、脑梗死、静脉血栓形成、高尿酸血症等并发症（P〈0．05）。ET患者中,JAK2V617F突变阳性组白细胞计数较阴性组高（P〈0．05）。ET患者中,JAK2V617F突变阳性组白细胞计数较阴性组高（P〈0．05）,ET和PV患者中JAK2V617F突变阳性组都比阴性组更容易发生上述并发症等（P均〈0．05）。结论JAK2V617F点突变在BCR—ABL融合基因阴性MPD中有较高的发生率,具有明确的诊断学意义;ET及PV患者中此突变阳性者更易发生血栓形成等并发症。     

Prevalence of active hepatitis C virus infection in patients with systemic lupus erythematosus

OBJECTIVE: Hepatitis C virus (HCV) infection is associated with various autoimmune disorders and can mimic systemic lupus erythematosus (SLE) clinically and serologically. There are few reports of prevalence of HCV infection in patients with SLE. The aim of this study was to determine the prevalence of HCV viremia by polymerase chain reaction (PCR) in patients with SLE. METHODS: We tested sera from 40 consecutive patients with SLE collected from 1993 to 2000. All of the patients had HCV viral load measured by PCR. The results were compared with the prevalence of HCV viremia in a control group of blood donors in our geographic area as well as in United States general population. RESULTS: HCV was detected in 4 of 40 patients (10%). The prevalence of HCV in our area blood donors is 130 cases per 100,000 persons (0.13%; P<0.0001). The prevalence of HCV infection in the United States general population, screened by PCR, is 1330 cases per 100,000 people (1.33%; P=0.002). The prevalence of HCV infection was significantly higher in our SLE patients than in our area blood donors. The frequency of HCV infection was also higher than that of the United States general population. CONCLUSION: Our observations support those of other investigators who have reported an increased prevalence of HCV infection in SLE patients. Further detailed investigation of this association may help in understanding the pathogenesis of SLE. HCV infection should be tested when the diagnosis of SLE is considered.     

骨髓增殖性疾病137例患者JAK2基因突变的研究

目的探讨信号分子JAK2基因突变——JAK2V617F在骨髓增殖性疾病（MPD）患者中的发生情况及诊断价值。方法采用等位基因特异性PCR方法及序列测定,检测137例MPD患者骨髓及外周血单个核细胞JAK2基因第12号外显子,研究JAK2V617F的发生情况,并结合细胞遗传学及分子生物学等检查结果分析其诊断价值。结果137例MPD患者共检出90例JAK2V617F阳性,总阳性率65．7％;其中真性红细胞增多症（PV）57例,阳性率73．7％（42／57）;原发性血小板增多症（ET）68例,阳性率58．8％（40／68）;特发性骨髓纤维化（IMF）12例,阳性率66．7％（8／12）;PV及ET患者突变型平均年龄高于野生型（P〈0．05）。115例进行过染色体检查,其中7例存在核型异常,突变型5例,阳性率为71．4％（5／7）;染色体核型正常者108例,突变型74例,阳性率68．5％;两组差异无统计学意义。结论MPD患者中JAK2V617F发生率较高,其发生与年龄相关,突变型平均年龄高于野生型。     

Myeloproliferative disorders

In 1951 William Dameshek classified polycythemia vera (PV), essential thombocytosis (ET), and primary myelofibrosis (PMF) as pathogenetically related myeloproliferative disorders (MPD). Subsequent studies demonstrated that PV, ET, and PMF are clonal disorders of multipotent hematopoietic progenitors. In 2005, a somatic activating mutation in the JAK2 nonreceptor tyrosine kinase (JAK2V617F) was identified in most patients with PV and in a significant proportion of patients with ET and PMF. Subsequent studies identified additional mutations in the JAK-STAT pathway in some patients with JAK2V617F(-) MPD, suggesting that constitutive activation of this signaling pathway is a unifying feature of these disorders. Although the discovery of mutations in the JAK-STAT pathway is important from a pathogenetic and diagnostic perspective, important questions remain regarding the role of this single disease allele in 3 related but clinically distinct disorders, and the role of additional genetic events in MPD disease pathogenesis. In addition, these observations provide a foundation for development of small molecule inhibitors of JAK2 that are currently being tested in clinical trials. This review will discuss our understanding of the pathogenesis of PV, ET, and PMF, the potential role of JAK2-targeted therapy, and the important unanswered questions that need to be addressed to improve clinical outcome.     

Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia

The annual incidence of polycythemia vera (PV) and essential thrombocythemia (ET) is approximately 2 and 1.5 per 100,000 inhabitants, respectively, if based on large population surveys and adjusted to a standard population. Survival for ET patients does not differ from that of the general population. However, it appears that PV patients have a significantly higher mortality, at least for patients diagnosed before 1990.     

Incidence and clinical risk factors for bleeding and thrombotic complications in myeloproliferative disorders

Summary Bleeding and thrombosis are frequent complications in myeloproliferative disorders (MPD) and are associated with severe organ damage and a high mortality. Elevated platelet count, elevated hematocrit, and patient age are regarded as risk factors for bleeding and thromboembolic events in MPD, although the significance of these parameters was not confirmed by clinical studies. We retrospectively analyzed vascular complications in 260 patients with MPD and tried to identify parameters predictive for bleeding and thromboembolic events. Our cohort consisted of 115 patients with chronic myeloid leukemia (CML), 84 patients with polycythemia vera (PV), 26 with essential thrombocythemia (ET), 25 with osteomyelofibrosis (OMF), and 10 patients with unclassifiable MPD. During a median follow-up period of 31 months, 126 patients with chronic MPD suffered bleeding or thrombotic events. Bleeding was observed in 57% of patients with OMF, 23% with PV, 20% with chronic phase CML, and 16% with ET. Thrombotic events were most common in patients with PV (36% of patients), followed by ET, OMF, and chronic phase CML (20%, 17%, and 6% of patients, respectively). Recurrent thrombotic episodes frequently occurred in patients with PV and ET, whereas patients with OMF often had more than one bleeding event. Thirty patients died of thrombohemorrhagic complications during follow-up. Multivariate analysis, including all patients with chronic MPD, revealed that elevated red blood cell count, higher hemoglobin level, and increased percentage of segmented neutrophils at the time of diagnosis were associated with thrombosis, whereas patients with bleeding complications were characterized by low red cell count, lower hemoglobin, and a lower percentage of segmented neutrophils. However, when analyzed by MPD subgroup, none of these parameters retained a predictive value for bleeding or thrombotic events. Moreover, elevated platelet count and patient age were not risk factors for bleeding complications. Thrombotic events were less frequent in patients below the age of 40, and were increased in patients aged 70 and above. However, this was primarily due to the high percentage of elderly patients in subgroups mainly affected by thrombosis (PV and ET). In most MPD subgroups, the rate of bleeding and thrombosis was highest just before and during the first months after diagnosis, and declined thereafter. Thrombohemorrhagic complications were less frequent after phlebotomy in PV and after therapy with alkylating agents in CML. The institution of cytoreductive therapy soon after the diagnosis was made may explain the reduced incidence of complications later in the disease. We conclude that morbidity and mortality from thrombohemorrhagic complications are high in myeloproliferative disorders. Subgroup and stage of the disease and previous complications are helpful in estimating the risk of a bleeding or thrombotic event. Conventional cytoreductive therapy may result in a reduction of these complications.     

Unexpectedly high prevalence of sarcoidosis in a representative U.S. Metropolitan population

The prevalence of sarcoidosis in the United States is unknown, with estimates ranging widely from 1 to 40 per 100,000. We sought to determine the prevalence of sarcoidosis in our health system compared to other rare lung diseases and to further establish if the prevalence was changing over time. We interrogated the electronic medical records of all patients treated in our health system from 1995 to 2010 (1.48 million patients) using the common ICD9 codes for sarcoidosis (135), lung cancer (162), and several other lung diseases characterized, like sarcoidosis, as "rare lung diseases". The patient demographic information (race, gender, age) was further analyzed to identify signature data patterns. The prevalence of sarcoidosis in our health system increased steadily from 164/100,000 in 1995 to 330/100,000 in 2010, and this trend could not be ascribed simply to changes in patient demographics or patient referral patterns. We further estimate that the prevalence of sarcoidosis exceeds 48 per 100,000 in Franklin County, Ohio, the demographic profile of which is nearly identical to that of the U.S. Sarcoidosis prevalence increased over time relative to lung cancer, a benchmark disease with stable disease prevalence, and exceeded that of other rare lung diseases. We postulate that the observed 2-fold increase in sarcoidosis disease prevalence in our health system is primarily related to improved detection and diagnostic approaches, and we conclude that the actual prevalence of sarcoidosis in central Ohio greatly exceeds current U.S. estimates.     

Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community

BACKGROUND & AIMS: The epidemiology of primary sclerosing cholangitis (PSC) in the United States is unknown. We report the incidence, clinical spectrum, and outcomes of PSC in Olmsted County, Minnesota. METHODS: Using the Rochester Epidemiology Project, a medical records linkage system in Olmsted County, Minnesota, we identified county residents with PSC, and the diagnosis was confirmed according to clinical, biochemical, radiographic, and histologic criteria. RESULTS: Twenty-two patients met diagnostic criteria for PSC in 1976-2000. The age-adjusted (to 2000 U.S. whites) incidence of PSC in men was 1.25 per 100,000 person-years (95% CI, 0.70 to 2.06) compared with 0.54 per 100,000 person-years (95% CI, 0.22 to 1.12) in women. The prevalence of PSC in 2000 was 20.9 per 100,000 men (95% CI, 9.5 to 32.4) and only 6.3 per 100,000 women (95% CI, 0.1 to 12.5). Seventy-three percent of cases had inflammatory bowel disease, the majority with ulcerative colitis. Survival among PSC patients was significantly less than expected for the Minnesota white population of similar age and gender (P < 0.001). CONCLUSIONS: These data represent the first population-based estimates of the incidence and prevalence of PSC in the United States. The incidence and prevalence of PSC were approximately one third of those previously described for primary biliary cirrhosis in the same population. Our data suggest that the prevalence of PSC in the United States, with its attendant medical burdens, is significantly greater than previously estimated.     

Incidence and prevalence of recurrent respiratory papillomatosis among children in Atlanta and Seattle.

The incidence and prevalence of recurrent respiratory papillomatosis (RRP) for children aged <18 years were estimated in 2 US cities, Atlanta and Seattle, in 1996. All otolaryngologists in a 24-county area in metropolitan Atlanta (101 physicians) and an 8-county area in metropolitan Seattle (139 physicians) agreed to participate in the study. Medical record chart abstraction was performed only for children with documented current residence in the study area (21 patients in Atlanta and 14 patients in Seattle). The incidence rate for juvenile RRP was 1.11/100,000 population in Atlanta and 0.36/100, 000 in Seattle. The prevalence rate was 2.59/100,000 population in Atlanta and 1.69/100,000 in Seattle. In neither city did prevalences differ significantly when stratified by sex or race. Extrapolation of these estimates to the US population suggests that 80-1500 incident cases and 700-3000 prevalent cases of juvenile RRP will occur in the United States during 1999.     

Generation of arachidonic acid metabolites from stimulated whole blood in patients with chronic myeloproliferative disorders

We have evaluated the arachidonic acid (AA) metabolism in patients with myeloproliferative disorders (MPD). In essential thrombocythemia (ET), the generation of thromboxane B2 was found significantly reduced and inversely correlated with platelet count. Polycythemia vera (PV) patients showed an increased formation of this metabolite of AA. Prostaglandin E2 and 6-keto-PGF1 alpha generation were markedly reduced in patients with chronic myelogenous leukemia. Our study confirms that the arachidonate metabolism is frequently deranged in patients with MPD. The opposite changes in thromboxane formation in ET and PV could be one of the factors responsible for the different incidences of thrombotic and hemorrhagic complications in these diseases.     

The Gain-of-Function JAK2 V617F Mutation Shifts the Phenotype of Essential Thrombocythemia and Chronic Idiopathic Myelofibrosis to More “Erythremic” and Less “Thrombocythemic”: A Molecular,Histologic, and Clinical Study

We investigated the prevalence of the JAK2 V617F gain-of-function mutation in patients with Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph- MPD) and explored the links between JAK2 mutational status and the clinicopathologic picture of essential thrombocythemia (ET), chronic idiopathic myelofibrosis (CIMF), and polycythemia vera (PV). Allele-specific polymerase chain reaction results for 59 ET, 18 CIMF, and 9 PV cases were compared with values for clinical variables at presentation and last follow-up and with the diagnostic trephine bone marrow biopsy pictures. JAK2 V617F was found in 38 (64%) of ET cases, 7 (39%) of CIMF cases, and 9 (100%) of PV cases. The ET patients with the mutant JAK2 showed significantly higher (although not overtly polycythemic) red blood cell parameter values, lower platelet counts, and higher white blood cell counts. Similar trends were found in CIMF. Megakaryocyte clustering was much less pronounced in the CIMF cases with mutant JAK2, with an analogous trend occurring in the ET cases. Bone marrow cellularity values and the numbers of CD34+ and CD117+ blasts in the ET and CIMF groups did not differ. Fibrosis was slightly less marked in the ET cases with mutant JAK2. The mutation did not significantly influence the clinical course during the follow-up in either disease in the short term (median follow-up, 22 months). The JAK2 V617F mutation is prevalent in all Ph- MPD and may skew their presenting phenotype, including bone marrow histology, toward a more "erythremic" and less "thrombocythemic" phenotype.     

AML transformation in 56 patients with Ph− MPD in two well defined populations

The Philadelphia chromosome‐negative (Ph?) chronic myeloproliferative disorders (MPD) have an inherent tendency for transformation into acute myelogenous leukaemia (AML). The long‐term rate of leukaemic transformation in unselected MPD patients was studied in well‐defined MPD populations in Gothenburg, Sweden and the Côte d′Or area, Burgundy, France, respectively. Over a median observation time of 15 yr, 56 subjects (7%) out of a total of 795 patients with Ph? MPD transformed to AML. The yearly incidence of AML transformation was 0.38% in polycythaemia vera (PV), 0.37% in essential thrombocythaemia (ET) and 1.09% in idiopathic myelofibrosis (IMF). The incidence of AML development was significantly higher in IMF as compared with both PV and ET (P = 0.002 and P = 0.02, respectively). Six of the patients who developed AML had never been treated with cytoreductive agents and two had only been exposed to interferon. In IMF, the average time from diagnosis to AML transformation was 42 ± 33 months, which was significantly shorter than for both PV and ET (88 ± 56 and 76 ± 57 months; P = 0.0075 and P = 0.027, respectively). The time from diagnosis to AML transformation appears to be a continuous event as regards all three MPD entities. It was shown that 17 out of the 18 patients with PV who developed AML were females; this was true despite the fact that the male/female ratio for the whole PV group was 146/171 (0.85). As regards ET and IMF patients who transformed to AML, the gender ratio showed slight male predominance (1.33 and 1.13, respectively). The average survival time for the 56 MPD patients who developed AML was 4.6 ± 5.5 (range 0–28) months and did not differ with respect to the three subtypes of pre‐AML MPD.     

Birthplace and esophageal cancer incidence patterns among Asian‐Americans

The incidence of esophageal adenocarcinoma in the United States has risen rapidly over the last 30 years, whereas the incidence of esophageal squamous cell carcinoma has fallen dramatically. In contrast, parts of Asia have extremely high rates of squamous cell carcinoma, but virtually no adenocarcinoma. Within the United States, Asian‐Americans as a whole, have low rates of esophageal adenocarcinoma and higher rates of squamous cell carcinoma. It is unclear what the patterns are for those Asians born in the United States. The relative influence of ethnicity and environment on the incidence of esophageal cancer in this population is unknown. We identified all cases of esophageal adenocarcinoma and squamous cell carcinoma from the California Cancer Registry 1988–2004, including 955 cases among 6 different Asian ethnicities. Time trends were examined using Joinpoint software to calculate the annual percentage changes in regression models. Rates of esophageal squamous cell carcinoma varied substantially among different Asian ethnic groups, but squamous cell carcinoma was much more common than adenocarcinoma in both foreign‐born and US‐born Asian‐Americans. Rates of squamous cell carcinoma were slightly higher among US‐born Asian men (4.0 per 100,000) compared with foreign‐born Asian men (3.2 per 100,000) and White men (2.2 per 100,000), P = 0.03. Rates of adenocarcinoma were also slighter higher among US‐born Asian men (1.2 per 100,000) compared with foreign‐born Asian men (0.7 per 100,000), P = 0.01. Rates of squamous cell carcinoma decreased for both US‐born and foreign‐born Asians during this period, whereas adenocarcinoma remained low and stable. These results provide better insight into the genetic and environmental factors affecting the changing incidence of esophageal cancer histologies in the United States and Asia.     

N-ras and p53 gene mutations in Japanese patients with myeloproliferative disorders

Alterations of the N-ras oncogene and p53 tumor suppressor gene have been demonstrated to play an important role in pathogenesis of hematological malignancies. We simultaneously investigated genetic lesions of both genes in bone marrow cells from 64 Japanese patients with myeloproliferative disorders (MPD), including polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (MF), by direct sequencing analysis. No mutations of the N-ras gene were detected in any cases. Two patients, one with chronic neutrophilic leukemia derived from PV and one with acute mylogenous leukemia derived from ET, exhibited three mutations of the p53 gene. Among them, two were missense mutations in exon 5 or 7 and one was a deletion in exon 5. All samples in chronic phase or from MF were devoid of mutations in both genes. These data suggested that disruptions of both genes are extremely rare in MPD in chronic phase and that loss of functions in the p53 gene could be involved in progression of MPD such as PV and ET.     

Bone marrow stromal cells in myeloproliferative disorders

The number of bone marrow-derived fibroblastoid colony-forming cells (CFU-F) and the production of colony-stimulating activity (CSA) by bone marrow stromal cells were studied in 71 patients with myeloproliferative disorders (MPD). The numbers of CFU-F in chronic-phase chronic myelogenous leukemia (CML), polycythemia vera (PV) and essential thrombocythemia (ET) were not different from those in normal subjects. However, the number of CFU-F in acute-phase CML was markedly decreased. Bone marrow adipocyte colony-forming capacity (adipo-CFC), which was previously shown to reflect both the number of preadipocytes and the stromal cell function in vivo, was increased in patients with chronic-phase CML, PV and ET, but was absent in acute-phase CML patients. The production of CSA by marrow stromal cells of MPD patients, however, was not different from that of normal subjects. These results suggest that the characteristics of marrow stromal and its precursor cells of chronic-phase MPD patients were not different from those of normal subjects, however, they became changed in acute-phase CML patients.     

Association of monoclonal gammopathy and polycythemia vera or essential thrombocythemia: study of a large cohort of patients

Concomitant cases of monoclonal gammopathies with polycythemia vera (PV) and essential thrombocythemia (ET) have been described. We report our experience in a large cohort of patients with ET and PV and the occurrence of M protein in such a population. Retrospective evaluation of clinical and laboratory records of 164 patients with PV and 218 with ET was performed, and 500 subjects matched for sex and age were used as controls. The patients were divided into group A (younger than 55 years), group B (55-70 years), and group C (over 70 years), and the presence of M protein was sought at the time of diagnosis and later during follow-up. M protein was found in 14 patients with myeloproliferative disorders (MPDs), representing 3.6% of patients both with ET and PV, and in 10 subjects of the control group (2%). M protein was detected in 2.1% of MPD patients of group A, in 4.8% of group B, and in 5.7% of group C and in 1.6% of controls of group A, 2.7% of group B, and 2% of group C. No significant statistical difference was observed. The occurrence of M protein in PV and ET does not seem to differ from that observed in the control group. A more relevant increase in the incidence of M protein in MPDs than in the controls was observed by dividing patients and controls by age. However, no statistical significant difference was documented.     

Spontaneous megakaryocyte colony formation in myeloproliferative disorders is not neutralizable by antibodies against IL3, IL6 and GM-CSF

Summary. Megakaryocyte progenitor growth in 42 patients with myeloproliferative disorders (MPD), including 23 essential thrombocythaemia (ET), eight polycythaemia vera (PV). six chronic myelogenous leukaemia (CML) and five primary myelofibrosis (PMF), was studied in vitro using plasma clot assay and serum-free agar culture. Spontaneous megakaryocyte colonies (CFU-MK) were found in 34/40 (80%) blood and 14/18 (77.8%) bone marrow plasma clot cultures, and also observed in 27/35 (77.1%) blood and 10/18 (55.6%) bone marrow serum-free agar cultures. In the blood of 27 patients with MPD (15 ET, four PV, four CML and four PMF) and the bone marrow of 10 patients (five ET, four CML and one PV), spontaneous colony formation was observed in both plasma clot and serum-free agar cultures. However, spontaneous CFU-MK was only found in plasma clot culture, but not in agar culture in two blood (one ET and one CML) and four bone marrow cultures (one ET, two PV, one CML). The colony numbers were greatly increased in the presence of aplastic anaemia serum (AAS) under both conditions. In 17 patients (12 ET, two CML and three PV) with spontaneous megakaryocyte colonies, anti-cytokine antibody neutralizing experiments were carried out in blood cultures. Anti-IL3, anti-IL6 and anti-GM-CSF antibody, alone or in combination, at different concentrations (1, 5 and 10 μg/ml), were added into plasma clot or agar cultures without exogenous stimulating growth factors. The results showed that the numbers of spontaneous megakaryocyte colonies were not significantly decreased in the presence of these monoclonal antibodies in the cultures. The data indicated that the megakaryocyte progenitor growth in MPD under in vitro conditions was heterogenous, and independent of exogenous stimulatory factors in most patients and that optimal megakaryocyte colony development in MPD still requires exogenous growth factors.