Edoardo Ascari

Serum N-Terminal Pro–Brain Natriuretic Peptide Is a Sensitive Marker of Myocardial Dysfunction in AL Amyloidosis

Background—Brain natriuretic peptide (BNP) is a marker of ventricular dysfunction and can be used to assess prognosis in heart failure and after myocardial infarction. Heart involvement is the most important prognostic factor and causes death in almost all patients with light-chain amyloidosis (AL). We investigated the prognostic value of NT-proBNP and its utility in monitoring amyloid heart dysfunction. Methods and Results—NT-proBNP was quantified at diagnosis in 152 consecutive patients seen at the coordinating center of the Italian Amyloidosis Study Group (Pavia) from 1999 throughout 2001. Heart involvement was estimated on the basis of clinical signs, electrocardiography, and echocardiography. NT-proBNP concentrations differed in patients with (n=90, 59%) and without (n=62, 41%) heart involvement (median: 507.8 pmol/L versus 22.1 pmol/L, P =10−7). The best cutoff for heart involvement was at 152 pmol/L (sensitivity: 93.33%, specificity: 90.16%, accuracy: 92.05%) and distinguished two groups with different survival (P <0.001). The Cox multivariate model including NT-proBNP was better than models including echocardiographic and clinical signs of heart involvement. NT-proBNP appeared to be more sensitive than conventional echocardiographic parameters in detecting clinical improvement or worsening of amyloid cardiomyopathy during follow-up. Conclusions—NT-proBNP appeared to be the most sensitive index of myocardial dysfunction and the most powerful prognostic determinant in AL amyloidosis. It adds prognostic information for newly diagnosed patients and can be useful in designing therapeutic strategies and monitoring response. NT-proBNP is a sensitive marker of heart toxicity caused by amyloidogenic light chains.

A prognostic classification of myelofibrosis with myeloid metaplasia.

The dependence of survival time on a set of prognostic factors was explored by means of Coxs regression model in 137 cases of myelofibrosis with myeloid metaplasia (MMM). The following parameters recorded at diagnosis proved to be important independent indicators of a poor prognosis: a higher value for age, a lower value for Hb concentration, a higher value for immature myeloid cells in peripheral blood (IMC), a lower value for total erythroid iron turnover (TEIT), and a bone marrow red cell aplasia (RCA). A prognostic classification tree was constructed whose terminal nodes (risk groups), described by simple logical conditions upon important indicators, were characterized by significantly different expected survival. The two extreme risk groups lend themselves to a simple, but complete description. The low‐risk group (19.7% of the sample) comprises cases who had the diagnosis of MMM before age 45 and a number of IMC constantly lower than 24%. The actuarial proportion of patients surviving at 15 years was 100%. The high‐risk group (29.9% of cases) comprises patients with age greater than 45 and Hb lower than 13 g/dl, associated with RCA, or with a relatively decreased erythropoiesis (TEIT lower than 2 times the normal) or with IMC greater than 24%. Seven out of the 11 who died within this group developed blastic crisis. Median survival time of the group was 69 months.

The role of surgery in the multimodal treatment of primary gastric non‐Hodgkin's lymphomas a report of 76 cases and review of the literature

Seventy‐six patients with primary gastric non‐Hodgkins lymphomas (PGL) were diagnosed, and 75 were treated between 1975 and 1985. According to the Working Formulation 22 patients had low‐grade malignant histologic subtypes, 27 intermediate‐grade, and 27 high‐grade. Twenty‐four cases were diagnosed by endoscopic biopsies, 52 through laparotomy biopsies. Forty‐five underwent subtotal or total gastric resection; seven were considered unresectable at laparotomy; 23 did not undergo surgery because of the high operative risk, mainly due to advanced age and coexisting diseases; and one died of myocardial infarction a few days after admission, before starting therapy. All patients who did not undergo laparotomy were staged with bipedal lymphangiography or abdominal ultrasonography and/or computed tomography. Stage, evaluated according to the criteria of Musshoff, was I or II1 in 16 cases, II2 in five, and IV in the remaining 55. Treatment modalities included surgery (S), chemotherapy (CT), radiotherapy (RT), and combinations thereof in the following proportions: only S in ten cases, S + CT in 32 cases, S + RT in one case, S + CT + RT in two cases, CT only in 25 cases, CT + RT in five cases. No substantial differences in response to therapy and in survival were found in relation to the different treatments. Ten‐year survival was 43% in Stage I or II and 20% in Stage IV. Of the 45 resected patients, five postoperative deaths were recorded (11%). No bleeding or perforations were observed in the 30 unresected patients, and survival of such cases compared with that of the resected ones. These findings, together with data from the literature, suggest that some of the advantages claimed for surgery in PGL (debulking and abatement of the risk of perforation or hemorrhage during CT or RT) have been overestimated in relation to the intrinsic surgical risk and to the possibility of anticancer therapy. Gastric resection may still be unavoidable as a diagnostic procedure in a minority of cases and may represent the primary therapeutic procedure in clinically assessed early‐stage and low‐risk patients, but it cannot be considered mandatory whenever possible merely for debulking purposes or to obviate possible perforation or hemorrhage. The CT and/or RT can be effective in unresected and even bulky cases, providing minimal risk of severe hemorrhage or perforation.

Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study

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.

Changing clinical presentation of multiple myeloma

We compared the presentation features of three series of patients with multiple myeloma diagnosed between 1960 and 1971 (Kyle R, Mayo Clin Proc, 1975, 50, 29, n = 869), 1972 and 1986 (Clinica Medica, University of Pavia, n = 345) and 1987 and 1990 (Cooperative Group for Study and Treatment of Multiple Myeloma, n = 341). In the most recently diagnosed patients, the percentage of those who had symptoms related to multiple myeloma (i.e. any of bone pain, systemic symptoms, disturbances related to hypercalcemia, neurological involvement and hyperviscosity) was reduced (90 vs. 86 vs. 66%) (P less than 0.001), while the percentage of asymptomatic patients diagnosed by chance was increased (not reported, and 14 vs. 34%). In the most recent series, a lower percentage of spontaneous bone pain (68 vs. 60 vs. 37%, P less than 0.001) paralleled a lower incidence of advanced bone disease (osteolyses and pathological fractures, 60 vs. 64 vs. 34%), and renal failure (serum creatinine greater than 1.2 mg/dl) was also less common (56 vs. 44 vs. 33%, P less than 0.01), at least partially due to a decreased incidence of both hypercalcemia (30 vs. 20 vs. 18%, P less than 0.001) and of hyperuricemia (serum uric acid greater than 7 mg/dl, 47 vs. 32 vs. 26%, P less than 0.01). Systemic symptoms (weakness, infections, fever or weight loss) were reported more seldom by recently diagnosed patients, due to a decreased frequency of anaemia (haemoglobin less than 12 g/dl), leukopenia and thrombocytopenia, as well as of the systemic effects of bone pain and of renal insufficiency. These data indicate that multiple myeloma is diagnosed earlier now than in the past, and this must be taken into account when comparing survival data in treated series.

A modified high‐dose dexamethasone regimen for primary systemic (AL) amyloidosis

High‐dose dexamethasone (HD‐Dex) has been reported to benefit AL amyloidosis patients with varying response rates. Our preliminary experience with the usual HD‐Dex schedule indicated that the induction phase was rather toxic in AL patients. We therefore adopted a milder schedule consisting of dexamethasone 40 mg on d 1–4 q21 d for up to eight cycles. Overall 8 out of 23 (35%) treated patients responded to treatment in a median time of 4 months (range 2–6 months) without significant toxicity. This regimen may be considered front‐line therapy when autologous stem cell transplantation is not feasible and when a rapid response is particularly important.

The Ultrastructural Localization of Factor VIII-Antigen in Human Platelets, Megakaryocytes and Endothelial Cells Utilizing a Ferritin-labelled Antibody

By means of electron microscopy combined with the use of monospecific anti‐factor VIII‐antigen (VIIIR:AG) antibodies conjugated to ferritin, the subcellular localization of VIIIR:AG in platelets, megakaryocytes and in endothelial cells has been established. The reported results suggest the possibility that the megakaryocyte is able to synthesize VIIIR:AG and also to secrete it by means of a microcanalicular system similar to that present in the endothelial cell. Platelets may derive their VIIIR:AG content partly from the megakaryocyte and partly from the plasma.

Vincristine sulfate for the treatment of thrombotic thrombocytopenic purpura refractory to plasma-exchange

Abstract: Among all the patients treated by the Italian Cooperative Group for TTP, we retrospectively reviewed the results obtained using vincristine (VCR) in 8 TTP patients (4 men and 4 women, average age: 39.25 years, range: 23–48) who did not respond to combined apheretic and pharmacologic treatment. All patients, after failing to respond to treatment, were started on VCR at the dose of 2 mg, i.v., once a week. Despite this treatment, 4 patients (50%) died 1, 7, 12 and 25 days after the first VCR dose, respectively. The other 4 patients who received VCR achieved complete remission 24, 30, 40 and 50 days from the beginning of the treatment. Total doses of VCR ranged from 2 to 6 mg in the deceased group, and from 6 to 14 mg in the cured patients. In our experience, VCR is a promising agent to treat TTP patients resistant to conventional plasma‐exchange and pharmacologic therapy.

HODGKIN'S DISEASE PROGNOSIS: A DIRECTLY PREDICTIVE EQUATION

586 patients with Hodgkins disease diagnosed between 1970 and 1979 were staged and treated in the same way. Multivariate analysis was used to delineate the prognostic roles of several clinical features at diagnosis. A multiple regression analysis was applied to an exponential model for survival-time distribution, which proved to fit the data accurately. Several clinical characteristics were studied and those that could singly discriminate survival significantly were chosen as predictive variables for the multiple regression. These were: sex, age, stage, histological subtype, presence of constitutional symptoms, mediastinal mass, and erythrocyte sedimentation rate (ESR), and haemoglobin and serum albumin concentrations. ESR, stage, histological subtype, and age proved to be the best prognostic factors, while sex and albumin had minor value. The presence of symptoms, mediastinal bulk, and haemoglobin were not so important. A linear equation for the six variables was derived to calculate the estimated median survival time for any given patient. This equation was validated on an external group of 179 similar patients.

Quantitative evaluation of erythropoietic activity in dysmyelopoietic syndromes

Summary. Based on the morphological appearances of the bone marrow and peripheral blood, 43 patients with dysmyelopoietic syndromes were categorized into four types: refractory anaemia with excess of blasts, chronic myelomonocytic leukaemia, primary acquired sideroblastic anaemia and refractory anaemia with cellular marrow, without excess of blasts and/or ring sideroblasts. Ferrokinetics allowed three distinct groups of patients to be defined. All cases of refractory anaemia with excess of blasts and chronic myelomonocytic leukaemia were classified in the same group. They were characterized by relative marrow failure and had a high likelihood of developing acute leukaemia. At the other end of the spectrum, individuals with primary acquired sideroblastic anaemia had high erythropoietic activity which was largely ineffective. They had a benign clinical course without evidence of leukaemic transformation. In the middle group, in terms of erythropoietic activity, lay patients with refractory anaemia with cellular marrow and a few individuals with primary acquired sideroblastic anaemia. Their clinical course and risk of developing acute leukaemia were intermediate between the other two groups. These findings indicate that separate entities may exist within the spectrum of dysmyelopoietic syndromes. In clinical practice, they may be recognized by morphological studies and other simple laboratory means.