Calvarial bone development and suture closure in Dicer-deficient mice.

OBJECTIVE: To evaluate whether lack of Dicer during calvaria development would lead to dysmorphology of calvaria and suture closure in mice. MATERIALS AND METHODS: A conditional Dicer deficient under Osx promoter mouse was employed in this study. The 4- and 10-week-old conditional Dicer-deficient mice control littermates and Osx-cre transgenic mice were studied for calvarial bone morphology and suture closure. Dry skull, microcomputed tomography (µCT), histological and gene expression studies were investigated to evaluate the effect of Dicer deficiency on calvarial bone morphology and their related genes during calvaria development. RESULTS: The results elucidated that complete suture closure was observed in 10-week-old conditional Dicer-deficient mice while incomplete closure suture was observed in age-matched Osx-cre control mice. The µCT and histological sections demonstrated complete fusion of posterior frontal suture and dysmorphic calvarial bones in Dicer deficient mice compared to the ones in their littermates and age-matched Osx-cre control mice. Gene expression study demonstrated significantly increased expression of suture and calvarial bone-related genes, that is Tgf-beta family, Bmp3, Msx2, Alx4, Runx2 and Osx in Dicer-deficient mice during suture closure time. CONCLUSIONS: The results suggest mature miRNAs are important for suture closure and calvarial morphology during calvaria development.

Clinical Presentation of Pediatric Celiac Disease Patients in the Qassim Region Over Recent Years.

Introduction Celiac disease is an immune-mediated systemic disease. It is prevalent and has diverse clinical manifestations; gastrointestinal symptoms are more common in children, including failure to thrive, chronic diarrhea, vomiting, and abdominal distention. The diagnosis should be made at a precise time to evade severe irreversible complications, especially for pediatric patients. This study aimed to determine the clinical presentation and diagnosis, including laboratory, serological tests, and histopathological findings, in pediatric celiac disease patients. Patients and methods  From January 2019 to August 2021, all children with a confirmed celiac disease diagnosis at Maternity and Children's Hospital in Buraydah, Qassim region, Saudi Arabia, were studied retrospectively. Information was collected, including demographics, clinical presentation, and diagnostic modalities with serology and small intestinal histology reported by Marsh grading.  Results Fourteen patients were reviewed, with a mean age of 8.64 years. Marsh grading of those who underwent biopsy revealed that half of the patients had type 3a, and the rest had either type 1 or 3b celiac disease. Clinical manifestations included abdominal distention and chronic diarrhea, and some patients were asymptomatic. Conclusion Abdominal distention, chronic diarrhea, constipation, and nausea were the most common clinical features. Patients with a family history of celiac disease, longer symptom duration, and higher tissue transglutaminase immunoglobulin A (tTG-IgA) levels are more symptomatic.

Analysis of serum Haptoglobin using glycoproteomics and lectin immunoassay in liver diseases in Hepatitis B virus infection.

BACKGROUND: Hepatocellular carcinoma (HCC) due to Hepatitis B viral (HBV) infection is a major cause in Asia-Pacific countries. Its early detection is of paramount importance using a marker having both sensitivity and specificity. The present study promises diagnostic and prognostic markers by the identification of site-specific glycoforms on Haptoglobin (Hp) using LC-MS/MS and lectin ELISA in liver diseased conditions in HBV infection. METHODS: Three groups of patients: chronic, liver cirrhosis and HCC with HBV infection along with controls were enrolled. Hp was purified using affinity column chromatography and, peptide sequence, N-glycosylation site, glycan composition and glycoforms were identified using mass spectrometry. Quantitative lectin ELISA was used to measure levels of fucosylation on Hp in liver diseases due to HBV. RESULTS: Hp levels were significantly lower in HCC when compared with Non-HCC cases (p < .05). Fucosylated glycoforms were significantly increased at site Asn184, Asn207 and Asn211 in liver diseased stages versus controls. A significant association was observed between the Fuc-Hp/Hp Elisa index and, advanced liver disease stages and controls using lectin Elisa (p < .001). CONCLUSION: Quantitation of fucosylation levels on Hp protein using Lectin ELISA may be useful glycobiomarker either alone or in combination (AFP + DCP + FucHp; AUC = 0.94) in HBV HCC diagnosis in clinical practice.

Paroxysmal nocturnal hemoglobinuria testing in patients with myelodysplastic syndrome in clinical practice-frequency and indications.

Background: Myelodysplastic syndrome (mds) is characterized by peripheral blood cytopenias, with most patients developing significant anemia and dependence on red blood cell (rbc) transfusion. In paroxysmal nocturnal hemoglobinuria (pnh), mutations in the PIGA gene lead to lack of cell-surface glycosylphosphatidylinositol, allowing complement-mediated lysis to occur. Paroxysmal nocturnal hemoglobinuria results in direct antiglobulin test-negative hemolysis and cytopenias, and up to 50% of patients with mds test positive for pnh cells. We wanted to determine whether pnh is considered to be a contributor to anemia in mds. Methods: Patients with a diagnosis of mds confirmed by bone-marrow biopsy since 2009 were reviewed. High-resolution pnh testing by flow cytometry examined flaer (fluorescein-labeled proaerolysin) binding and expression of CD14, CD15, CD24, CD45, CD59, CD64, and CD235 on neutrophils, monocytes, and rbcs. Results: In 152 patients with mds diagnosed in 2009 or later, the mds diagnosis included subtypes associated with pnh positivity (refractory anemia, n = 7, and hypoplastic mds, n = 4). Of 11 patients who underwent pnh testing, 1 was positive (9.0%). Reasons for pnh testing were anemia (n = 3), new mds diagnosis (n = 2), hypoplastic mds (n = 2), decreased haptoglobin (n= 1), increased rbc transfusion requirement (n= 1), and unexplained iron deficiency (n= 1). Conclusions: Testing for pnh was infrequent in mds patients, and the criteria for testing were heterogeneous. Clinical indicators prompted pnh testing in 6 of 11 patients. Given that effective treatment is now available for pnh and that patients with pnh-positive mds can respond to immunosuppressive therapy, pnh testing in mds should be considered. Prospective analyses to clarify the clinical significance of pnh positivity in mds are warranted.

Internal medicine fellowship directors' perspectives on the quality and utility of letters conforming to residency program director letter of recommendation guidelines.

Background: In May 2017, the Alliance for Academic Internal Medicine (AAIM) published guidelines intending to standardize and improve internal medicine residency program director (PD) letters of recommendation (LORs) for fellowship applicants. Objectives: This study aimed to examine fellowship PDs impressions of the new guidelines, letter writers' adherence to the guidelines, and the impact of LORs that conformed to guidelines compared to non-standardized letters. Methods: The authors anonymously surveyed fellowship PDs from January to March 2018 to gather input about LORs submitted to their programs during the 2017 fellowship application cycle. Results: A total of 78% of survey respondents were satisfied with letters that followed the AAIM guidelines, whereas 48% of respondents were satisfied with letters that did not. Fellowship PDs felt that letters that followed the AAIM guidelines were more helpful than letters that did not, especially for differentiating between applicants from the same institution and for understanding residents' performance across the six core competency domains. Fellowship PDs provided several suggestions for residency PDs to make the LORs even more helpful. Conclusion: Fellowship PD respondents indicated that LORs that followed the new AAIM guidelines were more helpful than letters that did not.

Suppression of natural killing in vitro by monocytes and polymorphonuclear leukocytes: requirement for reactive metabolites of oxygen.

Natural killer cells spontaneously lyse certain tumor cells and may defend against malignancy. We have previously shown that natural killing (NK) by human peripheral blood mononuclear cells (PBMC) is suppressed in vitro by phorbol diester tumor promoters, including 12-O-tetradecanoylphorbol-13-acetate (TPA). We here demonstrate that suppression of NK is mediated by monocytes or polymorphonuclear leukocytes (PMN) and that suppression is dependent on the generation of reactive forms of molecular oxygen (RO), particularly hydrogen peroxide (H2O2). NK was suppressed not only by TPA but also by opsonized zymosan (yeast cell walls), which, like TPA, was not toxic to PBMC. Both TPA and zymosan stimulated the production of superoxide anion (O2-) and H2O2 by PBMC. Production of RO correlated with suppression of NK. When PBMC were depleted of monocytes, the production of RO and the suppression of NK were both markedly reduced. Suppression could be restored by monocytes or PMN, both of which produced RO in response to TPA or zymosan. Suppression of NK was dependent on RO. Monocytes or PMN from a patient with chronic granulomatous disease, whose cells cannot generate RO, did not mediate suppression of NK. Suppression was also reduced in glucose-free medium, which did not support the generation of RO. Suppression of NK by TPA was inhibited by catalase. Bovine superoxide dismutase had a limited effect on suppression, even in high concentration, and tyrosine-copper (II) complex, which also enhances dismutation of O2- to H2O2, had almost no effect on suppression. When H2O2 was directly generated enzymatically from glucose oxidase and glucose, NK was suppressed and suppression was reversed by catalase. NK was also suppressed by the enzymatic generation of O2- from xanthine oxidase and xanthine, but suppression under these conditions was again inhibited by catalase and not by superoxide dismutase, indicating that suppression was due to the secondary formation of H2O2 from O2-. These results indicate that H2O2 is important in suppression of NK. Myeloperoxidase did not appear to play a role in suppression because inhibition of this enzyme by sodium azide, cyanide, or aminotriazole did not prevent suppression of NK. Suppression of NK was reversible; after exposure to zymosan, NK could be partially restored by the addition of catalase and superoxide dismutase or by the removal of zymosan. These studies demonstrate cellular regulation of NK by monocytes or polymorphonuclear leukocytes and indicate a role for RO in immunoregulation.

Natural killing of tumor cells by human peripheral blood cells. Suppression of killing in vitro by tumor-promoting phorbol diesters.

Tumor-promoting phorbol diesters were shown to suppress natural killing in vitro by human peripheral blood mononuclear cells. The inhibitory effect of different phorbol diesters and their analogues correlated with their potency as tumor promoters, the most effective agent being 12-O-tetradecanoylphorbol-13-acetate (TPA). Both peripheral blood cells and targets specifically bound TPA, and natural killing could be inhibited by pretreatment of either cell population with TPA, though this was less effective than direct addition of TPA to the assay. Cells that had been pretreated with TPA released TPA and metabolites of tPA during subsequent incubation in fresh medium. This release of tPA was evidently responsible for the inhibition of natural killing by pretreated target cells; in experiments where labeled and unlabeled target cells were mixed, pretreatment of unlabeled targets with TPA inhibited killing of labeled targets. Suppression of natural killing by TPA was greatly reduced when adherent cells were removed from the peripheral blood cells, suggesting that monocytes mediate suppression. Inhibition of natural killing by TPA provides a model for examining the regulation of natural killing. Suppression of natural killing by phorbol diesters may contribute to their activity as tumor promoters.

Effect of Gd and Cr substitution on the structural, electronic and magnetic phases of SrRuO3: a case study of doping and chemical phase separation.

We explore the crystal structure, electrical resistivity and magnetic behavior of the compositional series (SrRuO3)[Formula: see text] (GdCrO3) x (where [Formula: see text]), which resides between orthorhombic ferromagnetic (FM) metal SrRuO3 ([Formula: see text] K) and orthorhombic antiferromagnetic (AFM) insulator GdCrO3 ([Formula: see text] K). Crystal structure analysis reveals that complete solid solution exists only up to [Formula: see text], above which chemical phase separation of two/three phases occurs, and persists up to [Formula: see text]. X-ray photoelectron spectroscopy measurement also corroborates the existence of [Formula: see text] for the intermediate composition [Formula: see text], which reinforces the astonishing scheelite-type GdCrO4 formation (at ambient pressure) for [Formula: see text] compositions. Electrical resistivity measurements affirm the temperature driven metal to insulator (M-I) transition for [Formula: see text] and [Formula: see text] samples. Low temperature insulating state in these samples is interpreted by electron-electron interaction of weak disordered systems. Precise analysis of temperature dependent resistivity for [Formula: see text] samples (which have insulating ground state) dictate that the transport phenomenon is mainly associated with Arrhenius-type charge conduction, Mott's variable range hopping, short-range and long-range Coulomb interaction mediated hopping processes, due to the high degree of randomness. Interruption of magnetic Ru-O-Ru interaction by Ru-O-Cr and Cr-O-Cr interactions lowers the FM transition temperature (T C), and thereby introduces Griffiths phase in phase separated samples. Furthermore, we believe that a sharp rise in magnetization at low temperature for [Formula: see text] samples is due to the formation of AFM GdCrO4 phase. Prominent thermal hysteresis in temperature dependent magnetization curves for [Formula: see text], and appearance of spin-reorientation transition for [Formula: see text] are the distinct indications for transformation into canted AFM GdCrO3 oxide at higher x. The effective magnetic moment ([Formula: see text]) continuously increases with the incorporation of higher moment elements (Gd and Cr); while coercive field (H C) exhibits an abrupt variation as a function of x at the onset of phase separation.

Gender differences in risk profile and outcome of Middle Eastern patients undergoing percutaneous coronary intervention.

OBJECTIVES: To determine the gender differences in cardiovascular risk profile and outcomes among patients undergoing percutaneous coronary intervention (PCI). Methods: In a prospective multicenter study of consecutive Middle Eastern patients managed with PCI from January 2013 to February 2014 in 12 tertiary care centers in Amman and Irbid, Jordan. Clinical and coronary angiographic features, and major cardiovascular events were assessed for both genders from hospital stay to 1 year. Results: Women comprised 20.6% of 2426 enrolled patients, were older (mean age 62.9 years versus 57.2 years), had higher prevalence of hypertension (81% versus 57%), diabetes (66% versus 44%), dyslipidemia (58% versus 46%), and obesity (44% versus 25%) compared with men, p less than 0.001. The PCI for ST-segment elevation myocardial infarction was indicated for fewer women than men (23% versus 33%; p=0.001). Prevalence of single or multi-vessel coronary artery disease was similar in women and men. More women than men had major bleeding during hospitalization (2.2% versus 0.6%; p=0.003) and at one year (2.5% versus 0.9%; p=0.007). There were no significant differences between women and men in mortality (3.1% versus 1.7%) or stent thrombosis (2.1% versus 1.8%) at 1 year. Conclusion: Middle Eastern women undergoing PCI had worse baseline risk profile compared with men.Except for major bleeding, no gender differences in the incidence of major adverse cardiovascular events were demonstrated.

Nondermatophytic onychomycosis by Fusarium oxysporum in an immunocompetent host.

Fusarium onychomycosis is not uncommon in tropical countries but is worth reporting. We report a case of nondermatophytic onychomycosis by Fusarium oxysporum in an immunocompetent woman from Buldhana district of Maharashtra (India). Bilateral involvement of great toe nail, chronic duration and acquisition of infection due to peculiar practice of daily pasting floors with mud and dung, is interesting. The case was successfully treated with topical and oral terbinafine with a dose of 250 mg daily for 3 weeks.

Myo-inositol trisphosphate-mediated calcium release from internal stores of Entamoeba histolytica.

Calcium mobilisation from internal stores of the parasitic protozoan Entamoeba histolytica was studied by fluorescence measurements of the calcium indicator quin 2 and 45Ca2+ incorporation studies in saponin-permeabilised amoebae. Prior energy-dependent calcium sequestration was found to be necessary for subsequent release of calcium by inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). Both Ins(1,4,5)P3 and inositol 2,4,5-trisphosphate (Ins(2,4,5)P3) could release calcium equally well from permeabilised E. histolytica with similar EC50 (concentration which produced half maximal release) values for calcium release. Ins(1,4,5)P3-mediated calcium release occurred from a vesicular store, was sensitive to prior treatment by heparin and was attenuated by prior addition of a lower concentration of Ins(1,4,5)P3. cAMP failed to influence inositol trisphosphate induced calcium release, indicating the absence of control mechanisms through cAMP-dependent phosphorylation. GTP neither induced calcium release nor could potentiate inositol trisphosphate mediated calcium mobilisation. A saturating concentration of Ins(1,4,5)P3 could release 50% of radiolabelled calcium sequestered by energy-dependent mechanisms in E. histolytica. The energy-dependent calcium sequestration was inhibited by vanadate and the calcium antagonist Diltiazem but not by dicyclohexylcarbodiimide (DCCD), suggesting the involvement of an endoplasmic reticulum-like structure in calcium storage. Binding studies showed specific association of [3H]Ins(1,4,5)P3 to crude membrane fractions of E. histolytica, which was significantly inhibited by heparin in a dose-dependent manner. IC50 (concentration which produced half-maximal inhibition) values for displacement of radiolabelled Ins(1,4,5)P3 binding by unlabelled Ins(1,4,5)P3 and Ins(2,4,5)P3 were estimated to be 0.99 microM for both isomers. Our results suggested that Ins(1,4,5)P3-mediated calcium release from internal stores of E. histolytica most probably occurred in an inositol trisphosphate receptor-dependent manner.

Criteria for marrow engraftment: comparison of reticulocyte maturity index with conventional parameters.

Reticulocyte maturity index (RMI) has recently been proposed as an early indicator of marrow engraftment. We compared the RMI with conventional bone marrow engraftment criteria including total leukocyte count (WBC), absolute neutrophil count (ANC), reticulocyte count (RC) and the day of last platelet transfusion required to maintain the platelet count (PC) > or = 20 x 10(9)/l in 37 patients undergoing allo- or autologous BMT. There was no discrepancy in predicting engraftment between RMI, ANC, WBC and RC. RMI indicated engraftment earlier (median day 17, range 10-63 days) than the ANC (median day 19, range 8-63 days), WBC (median day 19, 9-71), RC (median day 19, 11-125) or PC (median day 29, 11-237). RMI heralded engraftment preceded ANC, WBC, RC or PC in 22, 21, 34 and 32 patients, respectively. RMI signal occurred 6 days prior to the rise in ANC in patients who engrafted later than 25 days (n = 7). Trend analysis showed that ANC fluctuated more frequently (6/37 patients) than RMI (1/37). Combined use of ANC and RMI (whichever increased first) predicted engraftment earlier (median 15 days) and more confidently (no false starts) than either used alone.

Quantitation of primitive and lineage-committed progenitors in mobilized peripheral blood for prediction of platelet recovery post autologous transplant.

Leukapheresis collections obtained following one of four mobilization regimens from 90 cancer patients were analyzed for their content of various progenitor cell types including erythroid and granulopoietic colony-forming cells in methylcellulose (total CFC), CFC-megakaryocyte (CFC-Mk), CFC detected after 10, 35 and 56 days in long-term culture (LTC), and total CD34+ cells. The number of each of these progenitor cell types collected from individual patients varied over 1000-fold. Nevertheless, within an individual leukapheresis, there was a significant correlation between the number of CD34+ cells and each progenitor type (except day 56 LTC CFC) suggesting that all of them are mobilized by a common mechanism. Patients who had previously received extensive chemotherapy and/or radiotherapy mobilized fewer of all these cell types than those who had not. For the 65 patients who proceeded to autologous transplantation, the median times to an absolute neutrophil count (ANC) of > or =0.5 x 109/l and the last platelet transfusion post transplant were 13 and 11 days, respectively, with 14 (22%) of patients having platelet recovery delayed beyond day 21. There was no significant difference between patients who had or had not received extensive chemo/radiotherapy or among the different mobilization regimens for time to neutrophil or platelet recovery or the number of platelet or red blood cell transfusions received post transplant. Threshold doses of the different cell types transplanted (per kg of patient weight) which predicted rapid platelet recovery were 2 x 106 CD34+ cells, 5 x 105 total CFC and 2.5 x 104CFC-Mk. Corresponding thresholds for progenitor activity measured in LTC could not be established. These results further support the view that standard mobilization regimens yield progenitor numbers that are, in most cases, nonlimiting for generating neutrophil and platelet recoveries within 2 to 3 weeks after myeloablative therapy. Assessment of the CD34+ cell and/or CFC content of leukapheresis collections may identify patients in whom platelet recovery is likely to be significantly delayed although CFC-Mk enumeration does not appear to offer any unique predictive advantage.

Testicular relapse of acute promyelocytic leukemia after allogeneic BMT.

After treatment of acute leukemia (typically ALL and the monocytic variants of AML), relapse may occur at sites other than the marrow. Isolated extramedullary relapse of acute promyelocytic leukemia (APL) however, is rare. We describe such an event in a man who underwent allogeneic BMT for APL in second relapse and 4 years later presented with testicular relapse. The marrow was morphologically and cytogenetically normal, but RT-PCR analysis revealed the specific PML/RAR chimeric RNA transcript.

Positive direct antiglobulin tests in myeloma patients. Occurrence, characterization, and significance.

Review of direct antiglobulin testing (DAT) in 88 patients with multiple myeloma (MM) and five with Waldenstrom's macroglobulinemia revealed 26 cases with a positive DAT. Twenty-two of these had immunoglobulin G-M protein, three had light chain MM, and one had immunoglobulin A-MM protein. None of the immunoglobulin GD-MM (n = 2), nonsecretory MM (n = 5), or Waldenstrom's macroglobulinemia patients (n = 5) were positive. None of the patients had hemolysis attributable to the adsorption of the M protein. The serum concentration of M protein was higher in DAT-positive patients (57.6 +/- 3.8 g/L, mean +/- SEM) than in the negative ones (35.7 +/- 6.4 g/L; probability value of the difference was less than 0.01). The erythrocyte eluates from DAT-positive patients contained a single immunoglobulin, of the same class as the M protein, and did not react with a panel of ABO-compatible erythrocytes. Addition of melphalan during incubation did not affect the results. The M protein of DAT-positive patients was of immunoglobulin G-3 subclass in 7 of 10 patients. A positive direct antiglobulin test frequently is seen in patients with multiple myeloma, the reaction is due to passive adsorption of the M protein onto the erythrocytes, is most frequently observed with immunoglobulin G3-MM, and usually does not produce hemolysis.

Deposition of transforming growth factor-beta in the marrow in myelofibrosis, and the intracellular localization and secretion of TGF-beta by leukemic cells.

The marrows of 10 patients with hematologic malignancies were examined by immunohistochemistry using anti TGF-beta antibody, CC(1-30), which detects secreted TGF-beta, and compared with four normal marrows. TGF-beta was not demonstrated in marrows with a normal level of reticulin fibrosis; however, TGF-beta was observed within collagen in marrows having collagen fibrosis or increased reticulin fibrosis. The extent of TGF-beta deposition paralleled the severity of fibrosis (P < .0001), and occurred even with normal or reduced numbers of megakaryocytes. Using another TGF-beta antibody, LC(1-30), which detects intracellular TGF-beta, TGF-beta was detected by immunofluorescence in discrete sites in the cytoplasm of immature and mature myeloid and large granular lymphocytic leukemia cells. These sites colocalized with areas detected by an anti-granule antibody (D545) suggesting that TGF-beta was stored in granules. However, neither the TGF-beta mRNA content nor the degree of TGF-beta secretion by these leukemic cells correlated with the extent of TGF-beta deposition in the marrow. Thus, TGF-beta deposition in marrow may contribute to myelofibrosis, but the source of this cytokine in the absence of megakaryocytes requires further study.

Myelodysplastic syndrome with hypereosinophilia and a nonrandom chromosomal abnormality dic(1;7): confirmation of eosinophil clonal involvement by fluorescence in situ hybridization.

We report a case of de novo myelodysplastic syndrome (MDS) with hypereosinophilia and dic(1;7) in which eosinophil clonal involvement was confirmed by fluorescence in situ hybridization. There have been two previous reports in the literature of eosinophilic MDS with dic(1;7) or t(1;7) in which eosinophil clonality was demonstrated. The specific breakpoints on chromosomes 1 and 7 differ in the three cases, making it difficult to implicate disruption of a single gene as causative; nevertheless, the nonrandom occurrence of t(1;7) or dic(1;7) with malignant eosinophilic proliferations suggests that this chromosomal rearrangement is involved in the etiology of the disease.

Intra-cerebral relapse following prolonged remission after autologous stem cell transplantation for multiple myeloma.

Central nervous system (CNS) myeloma is a rare phenomenon, especially so after high-dose therapy (HDT) and stem cell transplantation. We describe a case of isolated CNS relapse of myeloma post autologous transplantation that followed a prolonged progression-free interval. Issues regarding the pathophysiology and management of this unusual complication are discussed.

Therapy-related acute myelogenous leukemia associated with 11q23 chromosomal abnormalities and topoisomerase II inhibitors: report of four additional cases and brief commentary.

We report 4 additional cases of therapy-related acute myelogenous leukemia (t-AML) with the translocation t(9;11)(p22q23). Chemotherapy for the primary malignancy (breast carcinoma in 2, non-Hodgkin's lymphoma in 2) included agents with topoisomerase II inhibitory activity (doxorubicin in 2; doxorubicin and etoposide in 1; doxorubicin, etoposide and mitoxantrone in 1) as well as alkylators. In agreement with previous reports, the leukemia was monoblastic (FAB M5 subtype) in all 4 patients, with only 1 having prior myelodysplasia, and the latency period from primary therapy was relatively short (24-48 months). All patients received potentially curative treatment for the leukemia which included allogeneic bone marrow transplantation in 3; however, all died (3 of t-AML and 1 of lymphoma). Therapy-related AML associated with exposure to agents with topoisomerase II inhibitory activity (epipodophyllotoxins and anthracyclines) is a distinct entity, the genetic basis and optimal treatment of which remain to be determined.