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Granulocytic sarcoma (GS) is a rare extramedullary tumor composed of immature myeloid cells. It is usually associated with leukemia or other myeloproliferative disorders, but can also occur without overt hematologic disease, i.e. in patients with a normal bone marrow and no history of acute myelogenous leukemia. This primary extramedullary lesion may indeed represent a diagnostic and therapeutic dilemma for both the hematopathologist and oncologist. We describe a case of GS diagnosed in a nonleukemic patient and review the literature regarding the pathologic features and treatment of this condition., (Copyright 2000 S. Karger AG, Basel)

The 'gold standard' for the treatment of polycythemia vera (PV) is to date undefined. We performed a retrospective analysis to evaluate the outcome of a cohort of PV patients treated with pipobroman (PB) at a single institution during a period of 20 years (November 1971-October 1991). During this period, a total of 366 adult PV patients were diagnosed according to Polycythemia Vera Study Group (PVSG) criteria. Of these, only 199 (54%) were treated with PB: 92 were males and 107 females, median age was 63.0 years (range 25.2-87.3 years). Major clinical characteristics at onset were as follows: 34 (17%) patients had splenomegaly >3 cm below costal margin, 70 (35%) had platelets >600,000/mm3, 79 (40%) had white blood cells >12,000 mm3; 97 (49%) had hypertension, 83 (42%) had minor neurological symptoms (as vertigo, headache, paresthesias), 33 (17%) had pruritus and 27 (13%) had thrombotic features. All patients received PB at the dosage of 1 mg/kg/day until response was achieved (hematocrit value <50% in males and <45% in females). Thereafter treatment was given according to toxicity and maintenance of response. All patients were phlebotomized before starting treatment (mean number of phlebotomies performed: three, range 2-4) and 47 of them received PB when hematocrit value was already reduced at response levels: therefore, while all patients are evaluable for acute and long-term toxicity, only 152/199 (76.4%) patients are evaluable for response to PB. During a median time of 2 months, all these 152 patients achieved the response; as maintenance, 128/199 (64.3%) patients were managed with PB alone and 71/199 (35.7%) patients received phlebotomies occasionally. Sixty-one out of 199 (30.6%) patients developed disease-related complications (25 neurological symptoms, 21 thrombotic complications, 12 cardiovascular problems, three hepatic failures). Eleven (5.5%) patients developed acute myelogenous leukemia (AML) after a median time of treatment of 89 months (range 33-188 months), 11 (5.5%) patients developed myelofibrosis (median time from treatment 71 months, range 31-182 months) and in six (3%) patients cancer occurred (median time from treatment 85 months, range 13-118 months). The cumulative risk of leukemia in PV was 2% (95% CI: 0-4%) and 6% (95% CI: 1-11%) at 5 and 10 years respectively; the cumulative risk of myelofibrosis was 2% (95% CI: 1-5%) and 9% (95% CI: 3-15%) at 5 and 10 years, respectively. As of May 1996, 33 (16.6%) patients are lost to follow-up, 40 (20.1%) are dead and 126 (63.3%) are alive with a median overall survival of 191 months. In conclusion, this retrospective analysis confirms the efficacy and safety of PB in PV patients and its low leukemogenic role; prospective studies are needed to evaluate the real impact of PB in the treatment of PV.

The chromosome 11q23 band is a genetic region frequently involved in nonrandom karyotypic abnormalities of acute leukemia. A genomic locus named ALL-1 or MLL, where 11q23 breakpoints are clustered, has been recently cloned and characterized. We have made use of an ALL-1-specific probe in Southern blot experiments to analyze the configuration of this gene in a large series of acute leukemia patients, representative of all different myeloid and lymphoid subtypes. Nine of 145 cases (6.2%) showed abnormal ALL-1 restriction fragments in leukemic DNAs. Of these nine cases, five patients in whom karyotypic data were available displayed chromosome 11q23 aberrations, including t(4;11) (three cases) and t(9;11) (two cases). Immunophenotypic and morphocytochemical characterization of ALL-1-rearranged acute leukemia revealed prevalence of poorly differentiated B lymphoid and/or monoblastic features. Considering the whole series, ALL-1 rearrangements were significantly associated with female sex, higher white blood cell counts at presentation, and very poor clinical outcome. The presence of residual disease was molecularly documented in one case at the time of clinical remission after induction treatment and was followed by early relapse. We conclude that ALL-1 rearrangements are new molecular markers of human leukemia with considerable diagnostic and prognostic relevance.

Blastoschizomyces capitatus (formerly named Trichosporon capitatum or Geotrichum capitatum) is a rare cause of invasive fungal disease in immunocompromised hosts. We retrospectively studied epidemiologic, clinical, pathologic, and microbiologic features of this infection during a 68-month period at the Division of Hematology of the University La Sapienza in Rome. Twenty patients with evidence of B. capitatus were identified: 12 were infected, four were possibly infected, and four had evidence of B. capitatus colonization but were not infected by this fungus. Pulmonary infiltrates were seen in seven infected patients; four of these patients eventually developed mycetomalike cavitations. Eight infected patients presented clinical and radiologic features of focal hepatitis compatible with hepatosplenic candidiasis. Of the 12 infected patients, two did not receive any antifungal treatment and died, five did not show any response to systemic antifungal therapy, and five received prolonged amphotericin B plus 5-fluorocytosine therapy. Of the last group, three patients achieved stable remission of their acute leukemia and were cured, and two improved but had an apparent relapse of B. capitatus infection after their acute leukemia recurred.

An assessment of the lymphocyte sub-populations and cell mediated cytotoxicity was made in 12 adults with acute non-lymphoid leukemia after stopping chemotherapy. No significant differences were found between ANLL and controls, for absolute lymphocyte count, %SIg/+ cells, Fc gamma + cells and ERFC. The OKT4+/OKT8+ was reduced in ANLL. Leu-7+ cells were significantly higher in ANLL. Moreover it appears that in ANLL lymphocyte function is restored early after stopping chemotherapy.

Thirty patients with advanced acute leukemia and lymphoma were treated with the sequential combination of high dose ARA-C (HiDAC 3 gm/m2 infused i.v. over 3 h at 0, 12, 24, 36 h) and asparaginase (ASP 6.000 IU/m2 i.m. at hour 42). The sequence was given on day 1 and 8 irrespective of the degree of myelosuppression. Of 22 patients with leukemia there was only one who was absolutely refractory to therapy. Complete remission was induced in 3 patients with ANLL (30%) and in 3 with ALL (30%). Three patients became hypoplastic but recovered with blasts and 12 died from infection, complicated by intracranial hemorrhage in 3, during hypoplasia. Of 8 patients with lymphoma, 2 were clearly refractory to therapy, one died from sepsis and the remaining 5 all entered remission (2 CR + 3 PR, 62%). Activity of HiDAC/ASP against CNS disease is suggested by the clinical response seen in patients with overt meningeal or intracerebral involvement. Toxicity associated with HiDAC/ASP was mainly hematologic. All but one patient experienced hypoplasia and severe pancytopenia; documented infections and major hemorrhages occurred in 80 and 20% of patients respectively. We conclude that HiDAC/ASP is a regimen with definite activity against acute leukemia and lymphoma including CNS disease. Alternate treatment schedules should be explored in order to reduce marrow toxicity.

Between October 1980 and October 1981, cefotaxime plus amikacin were used in the treatment of 131 febrile episodes that occurred in 108 neutropenic patients with hematologic malignancies. The overall clinical response was 86.2%. Fevers of unknown origin and clinically or microbiologically documented infections responded in 88.8 and 84.4% of the cases, respectively. Renal toxicity occurred in 3.8% of the cases. In vitro studies showed that cefotaxime and amikacin were active against 78.7 and 94.7% of the pathogens, respectively, despite the high frequency (31%) of multiply resistant strains of Pseudomonas aeruginosa (defined as in vitro simultaneously resistant to carbenicillin, gentamicin, tobramycin and sisomicin) isolated from blood and infected sites. Synergy studies performed against 35 gram-negative bacilli isolated from blood revealed the presence of synergism between cefotaxime and amikacin in 54% of the cases. The peak levels of bactericidal activity in the serum of patients receiving cefotaxime plus amikacin showed median values of 1:128 and 1:8 against Escherichia coli and P. aeruginosa septicemias, respectively.

Polymorphonuclear leukocytes (PMN) from 11 patients with acute non-lymphoid leukemia (ANLL) in complete remission and off therapy for at least 22 months were studied for their oxidative metabolism and motility. In all patients, PMN motility tests revealed no consistent abnormality, whereas cells from 2 patients showed a selective impairment of oxidative metabolism, as assessed by the low capacity to reduce nitroblue tetrazolium and/or to generate chemiluminescence when stimulated with phorbol myristate acetate. No morphological change was detectable in PMN from these patients. However, the functional alterations appeared related to an early tendency to relapse, as both patients developed an acute phase after 5 and 9 months from testing, respectively. This suggests that abnormal PMN may circulate in ANLL patients in complete remission in spite of a normal differential count and that functional studies may be useful for detecting such a population.

Eight patients with overt central nervous system (CNS) leukemia and lymphoma were treated with sequential administration of systemic high-dose cytosine arabinoside (HiDAC) and asparaginase (ASP) with no direct CNS therapy. Complete clearing of the cerebrospinal fluid (CSF) was achieved in six (86%) of seven patients with meningeal disease, generally after the first course of therapy. Two patients presented with evidence of extensive intracerebral disease; both responded with a greater than 50% regression of the tumor infiltrates. Concomitant extraneurologic localizations responded equally well to HiDAC/ASP: responses were seen in four of five patients, including complete remission in three of four patients who presented with marrow involvement. Toxicity was generally moderate and limited to myelosuppression (eight of eight patients), tolerable nausea and vomiting (eight of eight patients), mild hepatotoxicity (two of eight patients), and oral mucositis (one of eight patients). These results indicate that HiDAC/ASP is a tolerable and highly effective treatment modality for CNS leukemia and lymphoma and suggest its potential role for sanctuary chemoprophylaxis.

The prognostic significance of the pretreatment growth characteristics of marrow blasts was examined in 37 patients with acute nonlymphocytic leukemia (ANLL) treated with a similar therapeutic regimen. Initial mitotic index (MI) and in vitro 3H-thymidine labeling index (LI) were broadly distributed showing no correlation to other initial variables, such as age or absolute blast count. No relationship whatsoever was observed between the pretreatment LI, MI and either the likelihood of achieving a complete remission or the remission and survival length. We conclude that the initial growth characteristics of marrow blasts do not play a significant role in predicting the therapeutic response in ANLL; age, modality of therapy and, possibly, the dynamic perturbations of the proliferative activity of the blast cells induced by treatment should be regarded as more reliable prognostic indicators in ANLL.

Sixty-three patients with acute nonlymphoid leukemia (ANLL) under cytostatic treatment were investigated in a randomized trial to determine whether oral administration of cotrimoxazole (TMP/STX) would reduce the rate of infection. Four significant differences were observed between the group given TMP/STX (30 patients) and the control group (33 patients): 1) the mean duration of severe granulocytopenia (less than or equal to 500 PMN/mm3) before the first febrile episode was longer in prophylaxis group, 14.26 days versus four in the control group (p less than 0.001); 2) the number of febrile episodes was 37 in TMP/STX group and 69 in control group (p less than 0.01); 3) 23 patients on prophylaxis presented at least one febrile episode versus 33 in the control group (p less than 0.01); 4) deaths due to infection were two in the TMP/STX group versus 11 in control group (p less than 0.05). Prophylaxis with TMP/STX appears to be useful since by reducing the number of febrile episodes and deaths due to infection, it increases the survival of leukemia patients under cytostatic drugs. Nevertheless, further studies on a larger number of patients are necessary in order to confirm the true efficacy of the drug in the reduction of sepsis and death due to infection.