Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML).

Chronic myelomonocytic leukemia (CMML) characterized by cytopenias, bone marrow and peripheral blood cell dysplasia is notoriously hard to treat. Recent reclassification of CMML as a myelodysplastic/myeloproliferative (MDS/MPS) disease rather than a myelodysplastic syndrome (MDS) by the World Health Organisation (WHO) has led to a review of CMML patients treated with decitabine. Overall response rates (ORR) (complete response [CR]+partial response [PR]) in the subset of patients with CMML in one pivotal phase 3 trial (D-0007) and two phase 2 trials (PCH 95-11, PCH 97-19) decitabine were reviewed. For consistency across trials, all decitabine-treated patients were evaluated using the phase 2 response criteria (CR was defined by normocellular bone marrow with <5% blasts and normal Hgb, WBC, and platelet counts, and PR required 50% decrease in blast count, increases in Hgb by >1.5 mmol/L, WBC count by >1000, and platelet count by >50,000). A total of 31 patients diagnosed with CMML are included in this review. Similar demographics and disease characteristics were observed in all three studies, with an average age of 70.2 years and 71% of patients male. Baseline WBC of >20,000 were observed in 8/28 (29%) patients and baseline bone marrow blasts >5% in 11/28 (39%) patients. All clinical responses were centrally reviewed. The ORR was 25% (14% CR+11% PR). Hematologic improvement was observed in 11% of patients and stable disease in 39% of patients. The decitabine adverse event profile seen in CMML patients was similar to observations in other hematologic patient populations, with myelosuppression and related infectious complications. These data demonstrate encouraging activity for decitabine in CMML, and suggest that studies in other myeloproliferative diseases may be warranted.

Efficacy of NovoSeven during surgery on a haemophiliac with previous history of inhibitors.

Management of bleeding in haemophiliacs with a history of inhibitor remains problematic. With infusion of factor VIII (FVIII), development of an anamnestic response and possible appearance of high-titre inhibitor remains a valid concern. We report a case of a haemophiliac with a history of moderately high-titre FVIII inhibitor that had become undetectable. He had not received FVIII since 1997, when he became inhibitor negative. He had been managed during his bleeding episodes with prothrombin complex factor concentrates, which became less effective in controlling his bleeding. The patient had a history of recurrent, spontaneous shoulder joint dislocations with bleeding, pain and significant disability. Shoulder joint replacement surgery was suggested. Replacement therapy was discussed with the patient, who refused treatment with human FVIII because of his concern for possible anamnestic response and inhibitor rebound. Porcine FVIII was not acceptable due to his poor response when used once in the past, and his history of moderate allergic reaction. Therefore, recombinant factor VIIa (NovoSeven, Novo Nordisk, Princeton, NJ) was considered to be an acceptable option for the contemplated shoulder surgery. The patient underwent 2.5 h of surgery with NovoSeven infusion. The surgeons were impressed with the lack of bleeding in this traumatic surgery. Despite the continuously prolonged activated partial thromboplastin time and low FVIII levels, the patient maintained a remarkably dry surgical field. Effective haemostasis was achieved during and after this procedure. This case illustrates the usage of NovoSeven as an effective treatment modality in a haemophilia A patient with past history of inhibitor undergoing joint surgery.

IgM Myeloma: An IgM Gammopathy Distinct from Waldenstrom's Macroglobulinemia.

A 65-year-old patient with an IgM gammopathy, plasma cell infiltration of the bone marrow, lytic lesions of the skeleton, and symptoms of hyperviscosity was evaluated. A diagnosis of IgM myeloma was made. Treatment for multiple myeloma was initiated and resulted in a significant clinical response. There is ongoing debate whether IgM myeloma exists as a unique entity, oras a variant of Waldenstrom's macroglobulinemia. We reviewed the English literature and discovered only six cases documented as IgM multiple myeloma. Further investigation revealed 30 reported cases, which had characteristics typical of an IgM myeloma, but were documented as variations of B-cell neoplastic disease. We acknowledge IgM myeloma to be an entity distinct from Waldenstrom's macroglobulinemia. It is characterized by an IgM monoclonal gammopathy, a predominance of plasma cells infiltrating the bone marrow, and typically associated with osteolytic lesions and/or osteoporosis. Recognizing IgM myeloma is necessary for appropriate disease management.

A neurophysiological method of rapid detection and analysis of marine algal toxins.

We have examined the effectiveness of the in vitro rat hippocampal slice preparation as a means of rapidly and specifically detecting the marine algal toxins saxitoxin, brevetoxin, and domoic acid and have identified toxin-specific electrophysiological signatures for each. Brevetoxin (PbTX3, 50-200 nM) produced a significant reduction in orthodromic population spike amplitude which was quick to reverse during a 50 min wash-out, while antidromic population spikes and field EPSPs exhibited only slight reductions, and fibre spiof orthodrokes showed no change at all. Domoic acid (100 nM) produced a robust, reversible increase in amplitude mic spikes, and the appearance of multiple spikes (i.e., epileptiform activity) within minutes of toxin wash-in. Other notable features of the domoic acid signature included a significant decrease in amplitude of the field EPSPs, and a complete absence of effect on either antidromic or fibre spikes. Fifty nanomolar saxitoxin (PSP) abolished all responses in all slices. Only antidromic spikes showed any recovery during wash-out. Field EPSP and fiber spike analysis further demonstrated that the preparation is capable of reliably detecting saxitoxin in a linearly responsive fashion at toxin concentrations of 25-200 nM, and tests of naturally contaminated shellfish confirmed the utility of this assay as a screening method for PSP. Our findings suggest that the in vitro hippocampal slice preparation has potential in the detection and analysis of three marine algal toxins important to the shellfish industry.

Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar).

A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P =.001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P <.05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P =.04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P =.004). PSC-MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.

Estimated Blood Loss in Group O as Compared to Non-group O Radical Prostatectomy Patients.

BACKGROUND AND OBJECTIVES: Blood group O individuals have been shown to have lower levels of von Willebrand factor (vWF). It is not known if these differences are associated with an increased bleeding risk. We retrospectively assessed estimated blood loss (EBL) in group O and non-group O men undergoing radical prostatectomy. MATERIALS AND METHODS: All patients undergoing radical retropubic prostatectomy from October 1986 through January 1997 were evaluated for ABO type, EBL in the operating room and red blood cell (RBC) transfusion requirements. RESULTS: Complete data were available for 138 group O and 168 non-group O men. Average intraoperative blood loss was 1996 mLs for all men and there was no significant difference in the EBL or transfusion requirements for group O patients. Substantial blood loss (EBL of at least 3 liters) did occur in 20.3% of group O and 13.1% of non-group O patients (P = 0.12). There were no significant differences between the two groups in the number of autologous, allogeneic or total RBCs transfused either intraoperatively or within 48 hours of surgery. CONCLUSION: There was no difference in blood loss or RBC transfusion requirements between group O and non-group O patients undergoing radical prostatectomy. The lower levels of vWF that have been found in group O individuals do not appear to put group O men at significant risk for greater operative blood loss or transfusion requirements during radical prostatectomy. SUMMARY: Group O men undergoing radical prostatectomy do not have greater estimated blood loss or transfusion requirements as compared to non-group O men.

Dexamethasone, cyclophosphamide, idarubicin and etoposide (DC-IE): a novel, intensive induction chemotherapy regimen for patients with high-risk multiple myeloma.

We evaluated toxicities and responses to a novel, dose intensive and time sequenced, chemotherapy programme (DC-IE) in 45 patients with high-risk myeloma. DC-IE consisted of: dexamethasone (days 1-4); cyclophosphamide (day 5); idarubicin and etoposide (days 8-10). Complete response (CR) was achieved in four patients, six patients achieved near complete responses (nCR) and 21 patients achieved a partial remission (PR). Overall response rate was 76% (CI 56-94%) for newly diagnosed patients (n = 21) and 62% (CI 36-81%) for relapsed/refractory patients (n = 24). Toxicities were limited to myelosuppression; two patients died of sepsis during neutropenia (4%). DC-IE is active and tolerable for high-risk multiple myeloma, including patients with relapsed or refractory disease to anthracycline containing regimens.

Metastatic seminoma simulating malignant lymphoma in an HIV infected hemophiliac.

Although most common, malignant lymphoma and Kaposi's sarcoma are not the only malignancies encountered in lymph nodes from HIV-infected patients. An increased frequency of testicular germ cell tumors in HIV-infected individuals has been reported. We report here the first case, to our knowledge, of a metastatic seminoma in an HIV-infected hemophiliac. The atypical clinical presentation, cervical and axillary adenopathy, simulated malignant lymphoma. The diagnosis was first suspected when a fine needle aspiration biopsy from an enlarged cervical node revealed a mixture of benign appearing lymphocytes and loosely cohesive large tumor cells in a "tigroid" background. Immunocytochemistry and a subsequent excisional biopsy confirmed the cytologic diagnosis. Metastatic germ cell tumors should be considered in the differential diagnosis of HIV-related lymphadenopathy.

Myelodysplastic syndromes in the elderly: the role of growth factors in management.

Myelodysplastic syndrome (MDS) comprises a group of heterogeneous clonal bone marrow disorders leading to peripheral cytopenia(s) and hypercellular marrow in the majority of the patients. The morphology of the cell lines is characterized by dysplastic features in some or all cell lines. The FAB classification has divided MDS in five subgroups, namely (1) RA (refractory anemia); (2) RARS (refractory anemia with ring sideroblasts); (3) CMML (chronic myelomonocytic leukemia); (4) RAEB (refractory anemia with excess blasts); and (5) RAEB-T (refractory anemia with excess blasts in transformation). Myelodysplastic syndrome remains primarily a disease of the elderly. With a reported median age of 74.4 years, patients have a chronic relentless course with complication of cytopenias, and a significant number of MDS patients, especially from the RAEB and RAEB-T categories, end up in acute myeloid leukemic transformation. Cytogenetic abnormalities are present in 40-58% of the cases and can provide not only help in diagnosis, but also understanding regarding the clinical course and prognostic aspect. Management of MDS is quite pragmatic and at this stage far from satisfactory. Various modalities have included use of differentiating agents, aggressive chemotherapy, bone marrow transplant and, more recently, significant interest has been generated in the use of hematopoietic growth factors. Differentiating agent trials have been unrewarding so far; chemotherapy trials have resulted in less benefit and more early toxic deaths, especially in the elderly MDS patients where the disease predominates. Bone marrow transplant appears suitable for some patients who are at a younger age. Salvation from this disease is being searched in the proper usage of hematopoietic growth factors and cytokines. There has been concern, however, that usage of growth factors has led to early and enhanced transformation of these patients to frank acute leukemic states. This concept appears to be somewhat refuted by newer controlled trials with GM-CSF and G-CSF, emphasizing that the acute leukemic transformation is the natural course of the disease and is not hastened by growth factor use. Preliminary studies are also suggesting that a combination of growth factors, especially G-CSF and erythropoietin as compared to chemotherapies, could be more beneficial in prolonging the survival of MDS patients who have progressed to the acute leukemic phase. More studies are needed for the understanding of the pathogenetic mechanism(s) in order to facilitate a more suitable and appropriate management strategy for MDS.

High levels of interleukin-6 are associated with low tumor burden and low growth fraction in multiple myeloma.

Interleukin-6 (IL-6) is a multifunctional cytokine postulated to play a central role as a growth factor for multiple myeloma (MM). We evaluated the spontaneous secretion of IL-6 in supernatants of Ficoll-Hypaque--enriched bone marrow (BM) cultures from 35 patients with MM. The levels of IL-6 were correlated with biological and clinical characteristics of the disease. High levels of IL-6 production defined a subgroup of patients with low tumor burden as determined by lower serum beta 2-microglobulin (B2M) (P = .02) and lower percentage of myeloma cells infiltrating the bone marrow (P = .003), higher synthetic rates of monoclonal protein (P = .006), and low proliferative compartments as measured by the percentage of Ki-67--positive myeloma cells. Patients with high proliferative fractions (Ki-67--positive myeloma cells > 20%) had significantly lower levels of IL-6 when compared with patients with low proliferative fractions (P = .005). Our findings do not support IL-6 as a major growth factor for MM, but demonstrate an association of high levels of IL-6 secretion with low tumor cell burden and low proliferative fraction.

Polycythemia as a complication of human immunodeficiency virus infection.

HIV infection is commonly associated with cytopenias. The occurrence of erythrocytosis is rare, with only one report in the medical literature. We have described the case of an asymptomatic patient found to be seropositive for HIV. The blood counts were initially normal except for mild eosinophilia and thrombocytopenia. Over the next 18 months erythrocytosis developed and thrombocytopenia worsened. Workup at that time revealed elevated red cell mass, suppressed erythropoietin, normal arterial oxygen saturation, and splenomegaly documented by abdominal computed tomography. Zidovudine therapy was started in April 1990, when the CD4 cell count dropped below 500/mm3. Over the next 4 months the hematologic indexes returned to normal levels. The patient remains asymptomatic.

Isolated limb perfusion for recurrent melanoma of the extremity.

Recent reports in the literature suggest that hyperthermic isolated limb perfusion (HILP) may be effective in preventing local recurrence in patients with deeply invasive melanoma or in patients with recurrent disease confined to the extremity. It has been used in the past as an adjuvant treatment after resection of the primary melanoma or recurrence, or as a therapeutic measure if all the disease on the extremity cannot be resected. A prospective, nonrandomized trial of 16 patients with melanoma with recurrent disease confined to the extremity underwent HILP. The protocol involved the wide local excision of all recurrent disease when possible, elective or therapeutic node dissection when indicated, and HILP using cisplatin. In 11 patients in whom all recurrent disease could be resected and the HILP was considered prophylactic, only 1 patient's disease has recurred in the perfusion circuit. Before the perfusion, the 11 patients had a total of 19 local or intransit recurrences. Of the 5 patients in whom all recurrent disease could not be resected, disease persisted in 4 patients. When compared with a concurrent control population of patients with extremity melanoma who had a local recurrence and were not perfused, the patients with melanoma who underwent HILP had a significant prolongation of disease-free survival (p less than 0.05), but a similar actuarial survival. In this study, we demonstrate that HILP can prevent local regional recurrences in patients with metastatic melanoma who are at high risk for further recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

The evaluation of putative tumor markers for malignant melanoma.

Biomarkers have long held out the promise that malignancies might be diagnosed early and that patients could be monitored more confidently during their clinical course to more reliably predict recurrence and the effect of therapy. Reliable tumor markers have been described for colon carcinoma, hepatomas, and other tumors, but no reliable marker has been identified to monitor the course of malignant melanoma. Recently, the plasma level of lipid-bound sialic acid (LASA-P) has been described as reflecting an alteration in the surface membrane of cancer cells. An attempt was made to correlate the LASA-P level, along with the serum level of neuron-specific enolase, a glycolytic enzyme specific to cells of neuroectoderm origin including melanocytes, with clinical disease activity with a follow-up to at least 2 years. Two hundred seventy patients had blood samples drawn at various times during their clinical course for assay of LASA-P and neuron-specific enolase. Eighty of the patients (30%) sampled developed a recurrence sometime during their clinical course, whereas another 10 patients had active disease noted at diagnosis with evaluative tumor markers. The sensitivity and specificity of neuron-specific enolase was 27% and 77%, respectively, and cannot be recommended as a marker for melanoma. LASA-P showed a sensitivity of 65%, with 55 patients recurring and having active disease with abnormally high markers and 35 patients recurring or having active disease with normal markers. Specificity of the LASA-P test was 76%. When recurrence was associated with elevated LASA-P levels, the elevated level preceded recurrence by a median of 9.3 months. LASA-P may be a useful marker to follow patients with malignant melanoma.

Adjuvant chemotherapy in malignant melanoma using dacarbazine, carmustine, cisplatin, and tamoxifen: a University of South Florida and H. Lee Moffitt Melanoma Center Study.

A prospective, nonrandomized trial was performed of the four-drug chemotherapy protocol consisting of dacarbazine, carmustine, cisplatin, and tamoxifen citrate given to high-risk patients for recurrence of melanoma after local regional treatment. The treated patients were consecutively registered and 6 patients who did not elect to be treated served as the control population. Criteria for inclusion in the trial were the presence of four or more lymph nodes positive for metastatic melanoma on regional modal dissection, the presence of metastatic disease in second station lymph node areas such as the iliac basin, greater than 5 cm in maximal diameter tumor burden in the nodal basin, and patients who had resected stage 4 (systemic metastases) disease with clear margins and were rendered free of disease. Actuarial survival curves for the treated group and the control subjects were similar (p = 0.91). There was a definite trend toward an increased disease-free survival for the group receiving adjuvant chemotherapy (p = 0.09). The mean disease-free survival for the control population was 200 days and for the treated group, 600 days. The study suggests a therapeutic benefit for adjuvant chemotherapy treatment of patients with metastatic melanoma who have been rendered free of disease but are at high risk for recurrence.