Unsuccessful treatment of resistant thrombotic thrombocytopenic purpura with prostacyclin.

Prostacyclin has been suggested as a useful agent for patients with thromobotic thrombocytopenic pupura (TTP) refractory to plasma-exchange. We report our unsuccessful experience with iloprost in a patient with TTP resistant to plasma-exghange, vincristine and high dose immunoglobulins.

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.

Idiopathic chronic pigmentary purpura. Findings in 22 cases and proposal of a new classification.

22 cases of Idiopathic Chronic Pigmentary Purpura are described in 9 males and 13 females with an age range from 14 to 66. Clinical picture, morphology and distribution of the lesions varied. Laboratory and instrumental investigations excluded the presence of systemic diseases or toxic/pharmacological factors responsible for the purpuric eruption. On the basis of the clinical aspects and the histopathological results, an exclusively morphological classification of idiopathic purpuras in macular, papular and eczematic forms is proposed, maintaining that the old nosography is not justified and also taking into account the pathogenetic overlapping confirmed by recent immuno-histochemical and ultramicroscopical studies.

[Instrumental research of the functional character of the skin adnexa and microcirculation during chronic venous insufficiency]. / Recherche instrumentale du caractére fonctionnel des annexes cutanées et de la microcirculation au cours de l'insuffisance veineuse chronique (IVC).

We have led a microcirculatory and functional research of skin adnexa over 3 groups of 20 people each, who were affected with IVC at different grades and we have compared them to another group of 20 normal people. The microcirculatory researches (laser-Doppler, skin oximetry and thermometry) and functional ones of skin adnexa (sebometry and skin hydration) allowed us to get a nonunivocal behaviour between normal subjects and phlebopathies of I degree. For this reason, it is possible to consider these exams as screenings tests to determine the starting phases of phlebopathy, failing any skin marks. The reduced fluximetrical response taken by laser Doppler after postural variation and the reduction of hydration degree have been considered particularly significant.

Risk assessment in myelodysplastic syndromes: value of clinical, hematologic and bone marrow histologic findings at presentation.

We analyzed the prognostic value of clinical, hematologic and bone marrow (BM) histologic findings at presentation in 94 patients with myelodysplastic syndromes (MDS) (28 RA; 2 RARS; 34 RAEB; 6 CMML; 24 RAEB-t). With survival as the dependent variable, stepwise multivariate analysis indicated as the prognostically most important factors among the MDS taken as a whole: latency from the first symptoms to diagnosis, age, and percentage of BM blasts. In each main MDS group the most unfavorable initial characteristics were: 1) low Hb, no macro-megaloblastosis, male sex for RA/RARS; 2) low Hb and low platelet levels for RAEB/CMML; 3) granuloblastic hyperplasia and high BM blastosis for RAEB-t. Of the BM histologic parameters, only the percentage of blasts had significant prognostic value. Histologic assessment of BM blastosis, however, did not differ statistically from that based on cytologic examination of BM smears, so that marrow histology seemed not essential for initial prognostic assessment in MDS patients. The finding of abnormal localization of immature precursors (ALIP) in BM biopsies was associated with a negative trend without reaching statistical significance. Using four objective parameters of proven significance (age, Hb, platelets, and BM blasts) we devised a staging system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices.

[A retrospective study of 200 cases of lichen]. / Indagine retrospettiva su 200 casi di lichen.

In this study the data on 200 patients affected by various features of lichen planus (LP) are reported. All subjects were in-patients of the Department of Dermatology, Bari, from 1973 to 1988. In 87% of cases the disease appeared as lichen tuber planus, and in 9% there was involvement of mucous membranes. Equal involvement of sex incidence has been found, and the patients were middle-aged (mean, 47 years). The lesion were not subsided in about 10% of cases. Associated fortuitous skin conditions were mainly alopecia areata and vitiligo. In addition, LP has been observed in association with diabetes (8%) and hepatic diseases (10%). These last values could appear relevant, but in our region, Apulia, both diabetes and hepatitis, and especially B-hepatitis, are very frequent diseases. Our clinical follow-up did not allow to consider LP as a symptom of other subsequent organic diseases.

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.

Spontaneous splenic rupture during induction chemotherapy for acute promyelocytic leukemia successfully treated with splenectomy.

We report a case of acute promyelocytic leukemia who suffered spontaneous splenic rupture with massive hemoperitoneum while receiving intensive induction chemotherapy. Emergency computed tomography of the abdomen helped in the diagnosis of intra-abdominal bleeding. The patient was successfully treated with immediate splenectomy and made an uneventful postoperative recovery. Ten days after surgery chemotherapy could be resumed and complete remission was achieved. Although spontaneous splenic rupture is a rare complication of hematologic malignancies, this diagnosis should be considered in all patients with leukemia who develop acute abdominal pain with hypotension, even in the absence of splenomegaly.

Therapy of essential thrombocythemia with alpha-interferon: results and prospects.

Conventional treatment of symptomatic essential thrombocythemia (ET) consists of long-term administration of myelosuppressive cytotoxic agents which, although efficacious in most cases, are associated with leukemogenic potential. Alpha-interferon (IFN) exerts a dose-dependent inhibitory influence on thrombopoiesis through a direct antiproliferative effect on megakaryocytic precursors. Therefore, it may provide a biologic, potentially non-mutagenic alternative to conventional cytotoxic treatments. At daily doses ranging from 1 to 5 M.U., alpha-IFN is efficacious in inducing a hematologic response in most patients with ET. Response to IFN is a gradual process. The median time to hematologic response varies from 1 to 3 months and a significant proportion of patients reach and maintain normal platelet counts with low doses (1-3 M.U./d). Normalization of marrow megakaryocytosis requires longer treatment (9-12 months). Also patients resistant to cytotoxic drugs may respond to alpha-IFN, suggesting a lack of cross-resistance between the two treatment modalities. Side-effects, although not severe, represents a limit to the administration of adequate doses of IFN in about 25% of cases. Once hematologic response has been obtained, both low-dose IFN and cytotoxic drugs are effective as maintenance. The full potentialities of alpha-IFN in ET in combination with cytotoxic drugs or with other cytokines need to be further investigated.

Interferon alpha-2b as therapy for patients with Ph'-positive chronic myelogenous leukemia.

We treated 114 Ph'+ chronic myeloid leukemia (CML) patients, 105 of whom were in chronic phase (CP) and 9 in accelerated phase (AP), with interferon alpha-2b (IFN alpha-2b) at intermittent or daily doses of 2-5 MU/m2. Of 35 previously untreated CP patients, 22 (63%) showed complete hematological response (CHR). This was significantly influenced by initial risk status. In 19 of the 22 CHR patients the median of Ph'+ cells decreased from 100% to 58%. Of 36 patients pretreated for less than 12 months, 19 (53%) achieved CHR. CHR rate was significantly related to IFN dose. Cytogenetic improvement was observed in 15 of the 19 patients, the median of Ph'+ cells dropping from 100% to 76%, with complete suppression of the Ph' chromosome in 1 case. Of the 34 patients pretreated for greater than 12 months, 21 (62%) obtained CHR. Cytogenetic improvement was observed in 10 cases, the median of Ph'+ cells declining from 100% to 66%. 1 of 9 AP patients obtained CHR. After a median follow-up of 32 months for the 63 CHR patients, 49 (78%) are still in disease control: 34 on IFN therapy, 15 after bone marrow transplantation (BMT) (13 autologous and 2 allogeneic). Blastic transformation (BT) occurred in 9 of 63 (14%) CHR patients and in 24 of 51 (47%) patients with less than CHR. IFN alpha-2b has proved to be an effective treatment for CML. Its combination with other treatment modalities represents an interesting and promising approach for future studies.

Mitoxantrone and etoposide: an effective regimen for refractory or relapsed acute myelogenous leukemia.

23 adult patients with refractory or relapsed acute myelogenous leukemia (AML) received salvage chemotherapy with mitoxantrone and etoposide. The regimen consisted of mitoxantrone, 10 mg/m2/d by 30-min infusion, and etoposide 100 mg/m2/d by 30-min infusion, given 12 h apart for 5 consecutive d. Of 23 patients treated, 13 met the criteria for highly refractory disease (6 primary resistant; 4 with early relapse during maintenance; 3 relapsed and refractory to reinduction). 10 patients had relapsed off-therapy more than 6 months after achieving first CR. Overall, 14 patients (61%) achieved a complete remission (CR): 6/13 (46%) with refractory AML, and 8/10 (80%) with relapsed AML. 2 patients had a partial remission, 2 died in aplasia, and 5 were nonresponders. In responding patients, the median time for recovery of granulocyte count was 27 d. The most important nonhematologic side effect was oral mucositis, which was severe in 35% of cases. No signs of cardiac toxicity were observed. The median CR duration was 5 months (range, 2 to 12+ months). The combination of mitoxantrone and etoposide appears a highly effective and relatively well tolerated salvage regimen for refractory and relapsed AML. Its incorporation into first-line induction and consolidation programs for newly diagnosed AML patients should be considered.

Interferon alpha-2b as treatment for Philadelphia-negative chronic myeloproliferative disorders with excessive thrombocytosis.

We treated 32 patients with Ph1-negative chronic myeloproliferative disorders (CMD) with excessive thrombocytosis with Interferon alpha-2b (IFN alpha-2b): 26 had essential thrombocythaemia, ET (18 previously untreated, eight pretreated); one thrombocythaemia after treatment for Hodgkin's disease (HD); two thrombocythaemia associated with non-Hodgkin's lymphoma (NHL); three stage II idiopathic myelofibrosis (IM). IFN was given at daily doses of 1-4 x 10(6) IU. Twenty-seven patients (84%) responded, 17 (53%) achieved complete haematologic response after a median time of 12 weeks, and 10 (31%) partial haematologic response. Median platelet levels declined in complete haematologic response patients from 1,190 to 335 x 10(9)/l. Normalization of megakaryocyte (MK) levels was observed in 8/17 complete haematologic response patients treated for 9-12 months, with decreased bone marrow (BM) cellularity. Side effects requiring dose reduction or discontinuation of treatment occurred in 28% of cases with IFN doses of 2 or 4 x 10(6) IU. After 1 year of continuous IFN treatment, responses were maintained with conventional chemotherapy or low-dose IFN. This study demonstrates that IFN has definite therapeutic activity in CMD with excessive thrombocytosis. This biological agent, either alone or in combination with other antineoplastic treatment, may represent a new therapeutic approach for these disorders.

Bone marrow and blood involvement by non-Hodgkin's lymphoma: a study of clinicopathologic correlations and prognostic significance in relationship to the Working Formulation.

In a series of 172 patients with non-Hodgkin's lymphoma (NHL) classified according to the Working Formulation (WF) the overall incidence of bone marrow infiltration (BM+) at diagnosis was 39%: 59% for low-grade (LGML), 30% for intermediate-grade (IGML), and 25% for high-grade malignant lymphomas (HGML). The features most significantly correlated with the presence of BM+ were a low grade of histological malignancy, the degree of splenomegaly and high values of LDH, while those correlated with the extent of BM+ were a non-focal pattern of BM disease, the presence of blood involvement at diagnosis, and the degree of BM fibrosis. Blood involvement was detected at diagnosis in 13% of patients, and a further 16% developed a leukemic phase during the course of the disease. Blood involvement correlated significantly with splenomegaly, bulky disease, advanced clinical stage, and extent of BM+. The presence of BM infiltration 'per se' at diagnosis did not significantly affect prognosis. However, the extent of BM disease was correlated with a poorer outcome in IGML and HGML patients. Regarding peripheral blood involvement, in LGML patients only late leukemic conversions were significantly associated with a worse prognosis. In patients with IGML and HGML, either initial or subsequent blood involvement was correlated with significantly poorer outcome.

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)

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.

Interferon alpha-2b as therapy for Ph'-positive chronic myelogenous leukemia: a study of 82 patients treated with intermittent or daily administration.

The authors treated a total of 82 patients with Ph'-positive chronic myelogenous leukemia (CML) with recombinant interferon alpha-2b (IFN alpha-2b). Sixty-five patients in chronic phase (CP), 28 of whom were untreated and 37 pretreated, and nine patients in accelerated phase (AP), were started on IFN three times a week. Patients in CP were randomized to receive 2 or 5 X 10(6) IU/m2, while patients in AP were all given the dose of 5 X 10(6) IU/m2, in addition to concomitant chemotherapy. Patients in CP who were unresponsive to the lower dose were crossed to the higher dose. Of 63 evaluable patients in CP, 43 (68%) responded, 29 (46%) achieved complete hematologic response (CHR), and 14 (22%) achieved partial hematologic response (PHR). The response rate appeared to be significantly influenced by the IFN dose in pretreated patients. Of the nine patients in AP, two attained PHR and one CHR. More recently, eight previously untreated CP cases were submitted to daily IFN administration at doses from 2 to 5 X 10(6) IU/m2. This daily schedule was also applied to patients who had obtained, with the intermittent treatment, a PHR persisting unmodified for six months (nine patients) or an unstable CHR (five patients). Seven of the eight previously untreated patients, and five of the nine PHR patients crossed to daily IFN reached CHR. In the total series of previously untreated patients, the response rate proved to be significantly influenced by the initial risk status. Cytogenetic improvement was seen in 37 of 53 responders (70%) treated for more than 3 months, the median of Ph'-positive cells declining from 100% to 65% (range 0% to 95%). Complete suppression of Ph' chromosome was observed in one case. The cytogenetic response was persistent for over 6 months in 21 patients, but the lowest value of Ph' positivity was usually unstable. At a median follow-up of 56 weeks, 23 of 36 (64%) CHR patients remain in continued disease control with IFN. A blastic transformation (BT) occurred in seven of 21 unresponsive patients and in one of the 36 CHR patients. The authors' data confirm that IFN alpha-2b, especially at daily doses, is effective in inducing clinical and cytogenetic response in a good proportion of patients with CML in the benign phase. Longer follow-ups will define the exact influence of this agent on the natural course of the disease.