Lymph node reticulum cell neoplasm with progression into cytokeratin-positive interstitial reticulum cell (CIRC) sarcoma: a case study.

AIMS: To detail on sequential biopsies the morphological and immunohistochemical features of a case of primary lymph nodal fibroblastic reticulum cell (FBRC) tumour which progressed into a clinically aggressive cytokeratin-positive interstitial reticulum cell (CIRC) sarcoma. METHODS AND RESULTS: A 70-year-old female underwent surgical excision of an enlarged submandibular lymph node. The nodal architecture was effaced by a neoplastic proliferation of medium to large cells, round to oval to spindle in shape, growing in a storiform pattern. The tumour stained for vimentin, CD68, factor XIIIa, alpha1-antitrypsin, fascin and actin. Dendritic and endothelial cell markers were negative. A diagnosis of FBRC tumour was made by combining pathological and clinical data. The patient received no therapy but 5 months later the tumour relapsed, exhibiting a deceptively pleomorphic cytology, phenotypic changes (strong cytokeratin positivity), intense p53 expression and aggressive clinical course with fatal outcome. In-situ hybridization for Epstein-Barr virus was negative. CONCLUSIONS: We speculate that the morphological changes and p53 expression of the relapsing neoplasm might reflect tumour cell dedifferentiation, in keeping with the aggressive clinical course. The intense p53 expression suggests that this oncoprotein might also play a role in reticulum cell tumorigenesis.

Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients.

BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) is a myeloproliferative disorder, characterized by the expansion of the red cell mass. Our purpose was to evaluate the efficacy of pipobroman (PB) in the long-term control of PV and to assess early and late events. DESIGN AND METHODS: From June 1975 to December 1997, 163 untreated patients with PV (median age 57 years, range 30-82) were treated with PB in a single Institute for a median follow-up of 120 months. The diagnosis was made according to the Polycythemia Vera Study Group criteria. PB was given at the dose of 1 mg/kg/day until hematologic response (hematocrit < 45% and platelets < 400x109/L) and of 0.3-0.6 mg/kg/day as maintenance therapy. RESULTS: Hematologic remission was achieved in 94% of patients in a median time of 13 weeks (range 6-48). Median overall survival was 215 months, with a standardized mortality ratio of 1.7. The cumulative risk of death was 11%, 22%, and 26% at 7, 10, and 12 years, respectively. The incidence of thrombotic events was 18.4x105 person-year and the cumulative risk was 6%, 11%, 16%, and 20% at 3, 7, 10, and 12 years respectively. Acute leukemia occurred in 11 patients, myelofibrosis in 7, and solid tumors in 11. The 10-year cumulative risk of leukemia, myelofibrosis, and solid tumors was 5%, 4%, and 8%, respectively. In the logistic analysis age over 65 (p = 0.0001) and thrombotic events at diagnosis (p = 0.001) were significantly correlated with a higher risk of death. Female gender (p = 0.02) and age over 65 (p = 0.01) significantly influenced the occurrence of thrombotic complications. Age was the only significant risk factor for leukemia (p = 0.04) and for solid tumors (p = 0.03), while the duration of PB treatment did not influence these risks. No significant risk factor was demonstrated for myelofibrosis. INTERPRETATION AND CONCLUSIONS: This study demonstrates in a large series of patients, observed for a long period, that pipobroman is effective in the long-term control of PV. The risk of early thrombotic complications at 3 years is 6% and the 10-year risk of acute leukemia, late myelofibrosis, and solid tumors is 5%, 4%, and 8%, respectively. The duration of pipobroman treatment did not correlate with these events.

Unilateral retinal vasculitis associated with hairy cell leukaemia: immunogenetic study.

This report describes a case of retinal vasculitis which occurred in hairy cell leukaemia and was localized only in the right eye. An immunogenetic study investigates the possible genetic association between vascular uveitis and hairy cell leukaemia.

Randomized clinical study comparing aggressive chemotherapy with or without G-CSF support for high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia evolving from MDS.

One hundred and five consecutive primary high-risk myelodysplastic syndromes (MDS) or secondary acute myeloid leukaemia (sAML) evolving from MDS (performance status 0-3, ECOG) entered this study. Induction chemotherapy (CT) consisted of idarubicine 12 mg/m2 i.v. on days 1 and 2, etoposide 60 mg/m2/12h i.v. for 5d, Ara-C 120 mg/ m2/12h i.v. for 5d (one or two courses). Patients were randomized to receive or not G-CSF (5 microg/kg/d subcutaneously 48 h after the end of CT). 52 cases underwent CT alone and 53 CT+G-CSF. The CT+ G-CSF patients had a significantly shorter duration of neutropenia (8 nu 16d) with a lower incidence of infections and significantly better responses (CR+PR: 74% v 52%, P<0.05). 40 patients entered CR: 17 with CT and 2 3 with CT+G-CSF. Responders underwent two consolidation courses with the same CT, followed by high-dose Ara-C (2 g/m2 every 12h for 3 d). Most CRs were clonal. At present 21 responders have relapsed (median relapse-free survival 4 5 months). Eight responders received an allo-BMT, six are alive in CR 7-57 months post-transplant. Therefore allo-BMT only increases the chance of a long survival and possible cure. In conclusion, CT+G-CSF did not prolong either CR duration or survival; the growth factor support, however, increased the number of allo-transplantable cases by inducing higher remission rates and improving clinical conditions.

Growth factors in the therapy of myelodysplasia: biological aspects.

Growth factors (GF) are reported to play an important role in the therapy of myelodisplastic syndromes (MDS). After in vitro administration a consistent group of MDS may respond to GF but the possibility of differentiation, regulation or expansion of myelodisplastic clones following GF therapy is still a question to be answered as their optimum dose and combinations. To validate if in vivo treatment with GF, may promote the regulation or the recovery of myelopoiesis and/or modify the clonality of the responses, we gave G-CSF after intensive chemotherapy in high risk MDS and acute leukemia evolving from MDS patients. According to our data the use of G-CSF after intensive chemotherapy may improve the CR rate without increase of leukemic transformation. However the answer were clonal and the remission duration remained very short so we suggest to utilize this time to perform other therapeutic strategies such as, when possible, the BMT.

Results of CAV regimen (CCNU, melphalan, and VP-16) as third-line salvage therapy for Hodgkin's disease.

BACKGROUND: A prospective study was conducted to assess the efficacy and toxicity of a salvage regimen consisting of CCNU, Melphalan, and VP-16 (CAV) given at 28-day intervals in patients with Hodgkin's disease (HD) relapsing after primary therapy or refractory to the alternating MOPP/ABVD regimen. PATIENTS AND METHODS: This study included 58 patients (median age: 34 years), with resistant or relapsing HD. Primary therapy had consisted of alternating MOPP/ABVD (81%) or MOPP alone (19%); 38% of patients were relapsing from prior complete remission (CR) while 62% had resistant disease. Extranodal disease was present in 55% and B-symptoms in 72% of patients; one-fifth had bulky disease and/or bone marrow involvement. The CAV was used as first salvage in half of the patients. RESULTS: Complete remission was obtained in 17 patients (29%); unfavorable factors for CR in univariate analysis were the presence of bulky disease and the failure to achieve CR with prior therapy. Nine patients (53% of remitters) have subsequently relapsed with a 10-month median duration of CR. The 3-year overall survival after CAV was 25% with an 18-month median survival; significant differences in survival were found according to the extent of disease, the presence of B-symptoms and the HD status (prior sensitive or resistant disease, first or subsequent relapse). Seven patients are long-term remitters (12%), and one of them has been given high-dose chemotherapy and autologous bone marrow transplantation at relapse after CAV. The CAV toxicity was mostly hematological; severe pancytopenia occurred in six cases with two cases of fatal infections and one of fatal hemorrhage. CONCLUSION: CAV therapy was moderately effective as third-line salvage in patients with HD resistant to alternating MOPP/ABVD or previously given two different regimens for relapse; the toxicity was mostly hematological and supportive therapy was needed in one-third of the patients.

Is the HELLP syndrome due to inherited factors? Report of two cases.

The etiology and pathogenesis of the HELLP syndrome, a multisystem disease occurring only in pregnancy, are still unclear. Curiously, very few authors have investigated whether inherited factors may be involved. We report two cases of HELLP syndrome in two unrelated women whose fetuses were relatives (first cousins). The first case concerned a woman aged 32 with a normal course pregnancy who was admitted to the hospital for fever, nausea and vomiting, low platelets, hemolysis and increased liver enzymes. Abruptio placentae with fetal death and severe disseminated intravascular coagulation with hemorrhages ensued within a few hours. Hysterectomy was then performed. After treatment with transfusions and drugs the patient slowly improved; 28 days later she left the hospital in good condition. The second case involved a woman aged 31 with a normal course pregnancy who was admitted to the hospital for epigastric pain, nausea, low platelets, hemolysis and increased liver enzymes. The patient underwent an immediate cesarean section and delivered a live infant; no bleeding occurred during or after delivery. The patient's condition rapidly improved and she left the hospital after 13 days. Until now, no author has proved that inherited fetal factors are at work in the HELLP syndrome. Our observations suggest a role for genetic factors, and this needs to be investigated in prospective studies.

Early-stage Hodgkin's disease: long-term results with radiotherapy alone or combined radiotherapy and chemotherapy.

BACKGROUND: Controversy still exists over the optimal management of early-stage Hodgkin's disease (HD); presentation features may have a different prognostic impact according to initial therapy, and long-term toxicity must be fully evaluated. PATIENTS AND METHODS: This study included 164 patients with stage IA-IIA HD treated with radiotherapy (RT) alone or combined radio- and chemotherapy (CT) according to presenting features and their attendant prognostic significance. The RT group included 88 patients with favorable prognostic features; the combined modality group included 76 patients with one or more unfavorable features. In the RT group, 85% of patients received extended-mantle or STNI; in the combined modality group, RT consisted of mantle- (49%), extended mantle- (37%), and involved-field irradiation (14%); CT consisted of 6 cycles of MOPP before 1984; 3 cycles of ABVD were substituted for MOPP thereafter. RESULTS: Complete remission was obtained in 94% and 99% of patients of the RT and combined modality groups, respectively. The 10-year actuarial relapse-free survival (RFS) in the RT group was 62% and was influenced by stage (p = 0.04) and histology (p = 0.01); in the combined modality group, RFS was 88% and was influenced by the presence of bulky disease. Overall survival and tumor mortality between the therapy groups were comparable. RT-related toxicity consisted of mediastinal fibrosis (8 cases), myelitis (3), hypothyroidism (2); other long-term events included 2 cases of acute leukemia in the combined MOPP and RT group. Altogether, 8 of 20 patients who died were in their first complete remission. CONCLUSIONS: In stage IA-IIA HD, the combined modality therapy reduced the risk of relapse compared to radiation alone; long-term toxicity of RT was not negligible and relapses could occur late.

Antithrombin III biological activity and emotional stress in patients with coronary artery disease.

We studied the effect of emotional stress (mental arithmetic for 10 minutes) in ten postinfarction patients and in ten age-matched, apparently healthy subjects as controls. Blood samples for the determination of epinephrine and AT III levels were taken in basal conditions, at the end of mental stress and after 30 minutes of recovery. Mental stress induced a significant increase in epinephrine levels and a significant decrease in AT III levels in control subjects. Both parameters returned to baseline values after 30 minutes of recovery. On the contrary, in postinfarction patients AT III levels of recovery were still significantly lower than those of baseline, suggesting a reduced ability to restore the original concentration of this physiologic inhibitor. Our data can contribute to a better understanding of the complex relationships among phychosocial factors, the haemostatic system and vascular disease.

Effect of mental stress on platelet function in normal subjects and in patients with coronary artery disease.

We studied the effect of emotional stress (mental arithmetic for 10 min) in 10 postinfarction patients and in 10 age-matched apparently healthy subjects as controls. Blood samples for platelet function studies and for the determination of epinephrine levels in serum were taken in basal conditions, at the end of mental stress and after 30 min of recovery. Patients were studied twice, in washout of medications and after oral administration of dipyridamole, 200 mg twice a day for 6 consecutive days. Mental stress induced in patients significant increments in different hemodynamic parameters (heart rate, systolic blood pressure and diastolic blood pressure) and in serum epinephrine levels. Concomitantly, the test produced a significant increase in platelet aggregation (induced by 3 microM ADP or 1 microgram/ml collagen), the formation of circulating platelet aggregates and an increase in plasma thromboxane B2 levels. Hemodynamic parameters and platelet function tests returned to baseline values after 30 min. Similar activation of hemodynamic parameters, similar increase in epinephrine levels and lower increase in platelet function by emotional stress were observed in control subjects. Treatment of patients with dipyridamole had no effect on stress-induced increase in hemodynamic parameters and epinephrine levels, but decreased stress-related platelet activation. These data can contribute to a better understanding of the complex relationships between psychosocial factors, the hemostatic system and vascular disease.

Thromboxane production by platelets during tumor cell-induced platelet activation.

We have evaluated in a homologous system the mechanisms of platelet activation by cells isolated from fresh human tumor tissues and the role of thromboxane B2 (TxB2) generation in this process. Thirty-eight of the 46 tumor tissues considered showed a high platelet-aggregating activity, with no particular distribution in any specific tumor type. Apyrase caused a nonsignificant reduction in the aggregation response, hirudin did not change it, while iodoacetic acid or p-hydroxymercuriphenylsulfonate, specific cysteine proteinase inhibitors, significantly reduced the platelet-aggregating capacity of these tumor cells. In 9 colon carcinomas and in 8 breast carcinomas the levels of TxB2 produced by platelets after addition of tumor cells were measured: tumor cell-induced platelet aggregation was accompanied by a significant production of the metabolite; indobufen, a cyclooxygenase inhibitor, significantly reduced aggregation and particularly TxB2 production, while the drug had no effect on both parameters if preincubated with tumor cells only. These data suggest that cells isolated from different human tumor tissues activate platelets through the activity of tumor-associated cysteine proteinase(s); platelet aggregation by tumor cells is largely dependent on arachidonic acid metabolism in platelets, while such metabolism in tumor cells does not play a significant role.

Extramedullary disease in Ph'-positive chronic myelogenous leukemia: frequency, clinical features and prognostic significance.

Of 349 consecutive patients with Philadelphia-positive chronic myelogenous leukemia (Ph' + CML), 14 (4%) developed extramedullary disease (EMD) during their illness. The sites of EMD were: bone (57%), lymph nodes (29%), skin and soft tissues (21%), central nervous system (14%). The median time from diagnosis of CML to the occurrence of EMD was 48 months. At the time of diagnosis of EMD, 7 patients were hematologically in chronic phase, while 7 showed features of accelerated or blastic CML. For patients lacking medullary blastic transformation criteria, the median time from diagnosis of EMD to blast crisis was 4 months. The overall median survival from development of EMD was 5 months. In conclusion, EMD may occur during the course of CML either in the context of a frank blastic transformation, or as an isolated tumoral infiltrate which heralds an impending blast crisis. Its recognition requires a prompt change to acute-phase chemotherapy.

Combination chemotherapy with alternating MOPP-ABVD in advanced Hodgkin's disease.

Fifty untreated adult patients with advanced Hodgkin's disease (HD) were given alternating MOPP-ABVD chemotherapy in a prospective eight-cycle program. This series included 33 patients with stage II-III disease and bulky lymphoma and/or B symptoms, and 17 patients with stage IV disease. Nodular sclerosis amounted to 52%, and systemic symptoms were present in 70% of patients. The median follow-up was 50 months from the initiation of therapy (range: 36-78 months). The complete remission rate was 80%, with no differences according to the main patient characteristics before therapy, except for bulky (65%) versus non bulky (88%) disease (p = 0.05). The actuarial 4-year overall (OS) and relapse-free survival were 78% and 71%, respectively. No clear-cut pretreatment characteristics showed an influence on survival, although there was a trend favoring non bulky versus bulky disease (p = 0.08). The actuarial 4-year OS of complete responders was 92%; all 13 patients who died had evidence of HD; the cause of death was disease progression and organ failure in 11 cases, acute myelomonocytic and opportunistic infections with AIDS in the other two cases, respectively. No severe pancytopenia episodes or life-threatening complications occurred during therapy; gastrointestinal and neurological toxicity were mild and no patient refused to complete the treatment. Menstruating women were given estrogen-progesterone combinations, and all continued to have regular menses throughout chemotherapy and afterwards; a young woman had a normal pregnancy resulting in a normal live birth. Only one case of stable amenorrhea was observed. Oligospermia after chemotherapy was seen in seven of 10 tested males, and azoospermia in one case.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemorrhagic and thrombotic complications in polycythemia vera. A clinical study.

This study reviewed the clinical and hematologic characteristics of 161 patients with polycythemia vera treated with myelosuppressive agents, with or without antiaggregating platelet therapy, in order to determine the features associated with a risk of hemorrhagic or thrombotic complications. At presentation, 7 patients (4.3%) showed hemorrhages and 36 (22%) complained of thrombotic events. None of the evaluated clinical and hematologic parameters was significantly related to hemorrhagic or thrombotic presentation. During the clinical course, four of 107 patients (3.7%) experienced hemorrhagic complications and 34/107 patients (28%) complained of occlusive events, which accounted for 30% of total deaths. Among the clinical and hematologic presenting features, only age over 60 yrs could be identified as an unfavorable prognostic factor for the occurrence of thromboembolic episodes. Marked thrombocytosis, a high packed cell volume (PCV) and the thrombotic onset were not significantly related to the thrombotic risk. Platelet count and PCV at the time of the occlusive episode did not correlate with the clinical event; however, inadequate control of the proliferative disease seemed to increase the thrombotic tendency. Antiaggregating drugs, although unable to avoid thrombosis in our experience, might be safely associated with the myelosuppressive therapy, particularly in selected patients.

Central nervous system (CNS) leukemia: the role of high dose cytarabine (HDAra-C).

Knowing the good penetration of systemic HDara-C into the CNS, we treated with this approach overt meningeal leukemia, either isolated or with bone marrow (BM) disease, in 31 adults: 18 ALL, 4 ANLL, 1 lymphoid blast crisis of CGL (LBC-CGL), and 8 non-Hodgkin's lymphoma (NHL). Treatment consisted of Ara-C, 3 g/m2 i.v. q 12 h, by 3 h infusion for 8 doses, followed by 4 doses at day 21. Complete remitters received consolidation with four monthly 4-dose courses of HDara-C. Additional multidrug consolidation and direct CNS therapy with intrathecal (i.t.) methotrexate (MTX) or Ara-C +/- cranial RT was administered to the 11 remitters last treated. Twenty of 31 patients (64%) achieved CR: 10/10 with isolated meningeal leukemia and 10/21 with concurrent CNS and BM disease. Of the remaining 11 patients, 8 had cerebrospinal fluid (CSF) clearing with persistent BM disease. In all cases but one CNS symptoms resolved promptly. CR median duration was 6 months (range 2 to 20). The main toxicity was myelosuppression requiring intensive support. There was no neurologic toxicity. These results show that systemic HDara-C is highly effective in acute leukemias and NHL with CNS involvement, and suggest the utility of this regimen for sanctuary chemoprophylaxis in patients at high risk for CNS disease.