Henri Guy

Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery.

PURPOSE The prognosis of invasive pulmonary aspergillosis (IPA) occurring in neutropenic patients remains poor. We studied whether new strategies for early diagnosis could improve outcome in these patients. PATIENTS AND METHODS Twenty-three histologically proven and 14 highly probable IPAs in 37 hematologic patients (neutropenic in 36) were analyzed retrospectively. RESULTS The most frequent clinical signs associated with IPA were cough (92%), chest pain (76%), and hemoptysis (54%). Bronchoalveolar lavage (BAL) was positive in 22 of 32 cases. Aspergillus antigen test was positive in 83% of cases when tested on BAL fluid. Since October 1991, early thoracic computed tomographic (CT) scans were systematically performed in febrile neutropenic patients with pulmonary x-ray infiltrates. This approach allowed us to recognize suggestive CT halo signs in 92% of patients, compared with 13% before this date, and the mean time to IPA diagnosis was reduced dramatically from 7 to 1.9 days. Among 36 assessable patients, 10 failed to respond (amphotericin B [AmB] plus fluorocytosyne, n = 2; itraconazole + AmB, n = 8) and died of aspergillosis. Twenty-six patients were cured or improved by antifungal treatment (itraconazole with or without AmB, n = 22; voriconazole, n = 4). In 15 of 16 cases, surgical resection was combined successfully with medical treatment. Achievement of hematologic response, early diagnosis, unilateral pulmonary involvement, and highest level of fibrinogen value < 9 g/L were associated with better outcome. CONCLUSION In febrile neutropenic patients, systematic CT scan allows earlier diagnosis of IPA. Early antifungal treatment, combined with surgical resection if necessary, improves IPA prognosis dramatically in these patients.

Increasing Volume and Changing Characteristics of Invasive Pulmonary Aspergillosis on Sequential Thoracic Computed Tomography Scans in Patients With Neutropenia

PURPOSE In patients with neutropenia, thoracic computed tomography (CT) halo and air-crescent signs are recognized as major indicators of invasive pulmonary aspergillosis (IPA). Nevertheless, the exact timing of CT images is not well known. PATIENTS AND METHODS Seventy-one thoracic CT scans were analyzed in 25 patients with neutropenia with surgically proven IPA. RESULTS On the first day of IPA diagnosis with early CT scan (d0), a typical CT halo sign was observed in 24 of 25 patients. At that time, the median number of thoracic lesions was two (range, one to six), and pulmonary involvement was bilateral in 12 cases. The halo sign was present in 68%, 22%, and 19% of cases on d3, d7, and d14, respectively. Similarly, the air-crescent sign was seen in 8%, 28%, and 63% of cases on the same days. Otherwise, a nonspecific air-space consolidation aspect was seen in 31%, 50%, and 18% of cases on the same days. The analysis of calculated aspergillary volumes on CT showed that, despite antifungal treatment, the median volume of lesions increased four-fold from d0 to d7, whereas it remained stable from d7 to d14. Overall, 21 patients (84%) were cured by the medical-surgical approach. CONCLUSION In patients with neutropenia, CT halo sign is a highly effective modality for IPA diagnosis. The duration of the halo sign is short, and it demonstrates the value of early CT. The increase of the aspergillosis size on CT in the first days after IPA diagnosis is not correlated with a pejorative immediate outcome when using a combined medical-surgical approach.

Feasibility of using quinine, a potential multidrug resistance-reversing agent, in combination with mitoxantrone and cytarabine for the treatment of acute leukemia.

PURPOSE We demonstrated previously that sera from quinine-treated patients reversed the multidrug resistance (MDR) of a human leukemic cell line. We now report a phase I and II clinical study that examined the toxicity of the combination of quinine with mitoxantrone and cytarabine (Ara-C). PATIENTS AND METHODS Fifteen adult patients with relapsed or refractory acute leukemia were treated with quinine formiate (30 mg/kg/d in continuous intravenous (IV) infusion from day 1 through day 5 or 6) associated with Ara-C (1 g/m2 in 3-hour IV infusion twice a day for 5 days) and five increasing doses of mitoxantrone (from 8 mg/m2/d for 4 days to 12 mg/m2/d for 5 days). RESULTS The main toxicity was severe myelosuppression: the mean times to leukocyte recovery (> 500/microL), granulocytes recovery (> 500/microL), and platelet count recovery (> 50,000/microL) were 23 days (range, 17 to 29 days), 30.6 days (range, 17 to 48 days), and 35.4 days (range, 14 to 75 days), respectively. The nonhematopoietic toxicity of this regimen was acceptable. Nausea and vomiting were common, but severe mucositis was observed in only two patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia and a clinically well-tolerated bradycardia. Tinnitus and vertigo were observed in 10 cases (67%), and mild hearing loss and transient increase of serum bilirubin were observed in six patients (40%). Total quinine serum levels reached a steady-state concentration between 6.4 and 18 mg/L in 24 hours. Complete remission (CR) was achieved in eight of 14 (57%) assessable patients, and partial response (PR) was achieved in two additional patients (14%). P-glycoprotein expression was detected on blast cells from five of 13 studied patients before treatment. A response was observed in all P-glycoprotein-positive cases. CONCLUSION Quinine can be used safely as a potential reversing agent of MDR for the treatment of clinically resistant acute leukemias.

Surgical Management of Invasive Pulmonary Aspergillosis in Neutropenic Patients

BACKGROUND The aim of our study was to clarify the indications for operation in invasive pulmonary aspergillosis. METHODS Nineteen patients with hematologic malignancy, in whom invasive pulmonary aspergillosis developed during the course of neutropenia, had operations. Neutropenia lasted 28 days (range, 15 to 45 days). The preoperative diagnosis of invasive pulmonary aspergillosis was based on computed tomographic scan findings (halo or air crescent signs). RESULTS Eight patients underwent emergency operations, before marrow recovery, for prevention of massive hemoptysis. The criterion for operation was an aspergillosis lesion that contacted the pulmonary artery on computed tomography. A lobectomy was performed in all cases. A sleeve resection of the pulmonary artery was necessary on two occasions. There was one postoperative death due to extensive aspergillosis. The length of hospitalization after operation was 13 days (range, 6 to 18 days). Seven patients were treated by elective resection of a residual mass (before hematologic therapy in 6 cases). The types of resection performed were lobectomy (n = 4), lingulectomy (n = 1), and wedge resection (n = 2). There were no postoperative deaths. The average length of stay before discharge from the hospital was 11 days (range, 7 to 20 days). The surgical resection was performed as a diagnostic procedure in the 4 remaining patients after an allotted time of 14 days (range, 4 to 24 days) from initiation of antifungal therapy. CONCLUSIONS The combination of antifungal agents and surgical resection is an efficient strategy for the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancy.

Sufficient levels of quinine in the serum circumvent the multidrug resistance of the human leukemic cell line K562/ADM

Reversal of multidrug drug resistance (MDR) has been achieved in vitro by a variety of agents including verapamil, quinidine, cyclosporine A, and amiodarone. The toxicity of these agents precludes the achievement of sufficient levels in the serum to circumvent efficiently the MDR in vivo. The authors previously demonstrated that quinine, the widely used antimalarial agent, is able to reverse primary resistance of rat colon cancer cells to anthracyclines. In this report, the efficiency of quinine formiate in reversing the doxorubicin (ADM) (Adriamycin, Adria Laboratories, Columbus, OH) resistance of the well‐defined MDR human leukemic cell line K562/ADM was demonstrated. In culture medium, quinine is slightly less effective than verapamil in increasing the cytotoxicity and uptake of ADM when both drugs are used at the same concentration. A nontoxic dose of 5 μg/ml is necessary to reverse the MDR in K562/ADM cells. In patients receiving quinine formiate in a continuous intravenous infusion, a significant correlation (r = 0.84) was found between the serum levels of quinine and the ability of sera to increase ADM uptake in K562/ADM cells. When quinine is administered at a conventional dose (25 to 30 mg/kg/d), serum levels consistently reach more than 8 μg/ml without severe side effects; ear noises and vertigo are the dose‐limiting side effects. At these concentrations, quinine induces a more than double increase in ADM uptake in K562/ADM cells. Pharmacokinetic data indicate that quinine should be administered 24 to 36 hours before anti‐cancer drugs in clinical trials that test its efficiency as a modifier of MDR in human hematologic malignant neoplasms.

Bone Marrow Necrosis and Human Parvovirus Associated Infection Preceding an Phl + Acute Lymphoblastic Leukemia

A case of bone marrow necrosis associated with a serologically documented recent Parvovirus B 19 infection which preceded the development of PH1+ acute lymphoblastic leukemia is reported. No conclusions can be drawn on the basis of a single case but the question of the role of human Parvovirus B19 in the pathogenesis of bone marrow necrosis is discussed. It is suggested that the virus may act as a co-factor for the induction of bone marrow necrosis, in some cases.

Systemic Mast Cell Disease Associated with Hairy Cell Leukaemia

Systemic mast cell disease (SMCD) can be regarded as a tumorous proliferation of tissue mast cells involving various organs. The frequency with which SMCD is found in patients with haematological disorders suggests that the association is non-random. The association includes primarily, myeloid disorders such as myelodysplastic syndromes and acute or chronic myeloproliferative disorders. Lymphoproliferative disorders may also occur but more rarely, mostly non-Hodgkins low grade B cell lymphomas. In this report a case is described in which SMCD occurred in a patient with hairy cell leukaemia.

New case of t(3;17)(q26;q22) as an additional change in a Philadelphia-positive chronic myelogenous leukemia in acceleration.

A new case of t(3;17)(q26;q22) was observed in a Philadelphia-positive (Ph+) chronic myelogenous leukemia in acceleration 1 month before occurrence of the blastic phase. Abnormal megakaryocytopoiesis and thrombopenia were noted, but blast cells did not express platelet markers. The same translocation was previously reported in three myeloproliferative disorders in acceleration or in the process of becoming acute. Translocations or inversions of chromosome 3 with breakpoint involving the band 3q26 were specifically associated with megakaryoblastic acute phase or abnormal megakaryocytopoiesis. This report confirms that the t(3;17)(q26;q22) is a specific nonrandom chromosomal abnormality associated with the acute nonlymphoblastic phase of myeloproliferative disorders and megakaryocytopoiesis dysfunction.

ASSOCIATION OF A CHROMOSOMAL 9.12 TRANSLOCATION WITH B CELL PRECURSOR LYMPHOBLASTIC BLAST CRISIS OF A Ph+ CHRONIC MYELOGENOUS LEUKAEMIA

The Philadelphia or Ph chromosome. product of the reciprocal translocation t(9:22) lq34:q l l ) (or a variant of this translocation), is found in the leukaemia cells of virtually all patients with chronic myeloid leukaemia (CML). Additional chromosomal abnormalities are usually observed during the blast phase (Bernstein et d. 1980). The most common of them are + 8. + Ph and i( 1 7q) that account for 70% of cases with additional change (Alimena et nl. 1987). In rare cases, these additional chromosome changes are known to be specifically associated with cytologic subtypes of acute leukaemias (ALL i.e. t( 15: 17) in promyelocytic blastic transformation (Berger et 01, 1983) or changes involving 3q2 1 in blast crisis with abnormal megakaryocytopoiesis (Bernstein et al. 1986). But no obvious consistent cytogenic correlations have yet emerged in lymphoid blast crisis of CML. We have identified, in the leukaemia cells of a B cell precursor lymphocytic blast crisis of a CML. a nonrandom chromosome abnormality recently described in childhood B cell precursor acute lymphocytic leukaemia (ALL) as a tdic (9:12) (pl?l:p1?2) (Carroll et al, 1987). A 63-year-old man presented in September 1 9 8 6 with clinical and morphological features typical of CML in chronic phase. Diagnosis was confirmed by identification of the t (9:22)(q34;ql l ) in bone-marrow cells. Treatment with Busulfan. then Hydroxyurea was given. The blast phase occurred in September 198 7: clinical examination disclosed hepatosplenomegaly: the peripheral blood WBC count was 24 x l O Y / l with 20% blast cells. Haemoglobin concentration was 10.0 g/dl and platelet count was 28 x 10y/l. The bonemarrow aspirate was hypercellular, with 85% agranular, peroxidase negative blast cells, and no megakaryocytes. Immunologic characterization of leukaemic bone-marrow cells was performed by standard techniques (indirect immunofluorescence) for surface immunoglobulins (sIg), cytoplasmic immunoglobulins (cIg) surface antigens and detection of terminal deoxynucleotidyl transferase (TdT). Blast cells expressedTdT (88%). CD19 (82%). CD9 (74%). CDlO (70%). CD20 (79%). CD24 (98%) and HLA-DR (83%) but no sIg ( < I % ) or cIg (< 1%). Expression of the other surface antigens studied was below 20% (CD1 to CD8, CD21, CD22.