COVID-19 Stroke Apical Lung Examination Study 2: a national prospective CTA biomarker study of the lung apices, in patients presenting with suspected acute stroke (COVID SALES 2).

BACKGROUND: Apical ground-glass opacification (GGO) identified on CT angiography (CTA) performed for suspected acute stroke was developed in 2020 as a coronavirus-disease-2019 (COVID-19) diagnostic and prognostic biomarker in a retrospective study during the first wave of COVID-19. OBJECTIVE: To prospectively validate whether GGO on CTA performed for suspected acute stroke is a reliable COVID-19 diagnostic and prognostic biomarker and whether it is reliable for COVID-19 vaccinated patients. METHODS: In this prospective, pragmatic, national, multi-center validation study performed at 13 sites, we captured study data consecutively in patients undergoing CTA for suspected acute stroke from January-March 2021. Demographic and clinical features associated with stroke and COVID-19 were incorporated. The primary outcome was the likelihood of reverse-transcriptase-polymerase-chain-reaction swab-test-confirmed COVID-19 using the GGO biomarker. Secondary outcomes investigated were functional status at discharge and survival analyses at 30 and 90 days. Univariate and multivariable statistical analyses were employed. RESULTS: CTAs from 1,111 patients were analyzed, with apical GGO identified in 8.5 % during a period of high COVID-19 prevalence. GGO showed good inter-rater reliability (Fleiss κ = 0.77); and high COVID-19 specificity (93.7 %, 91.8-95.2) and negative predictive value (NPV; 97.8 %, 96.5-98.6). In subgroup analysis of vaccinated patients, GGO remained a good diagnostic biomarker (specificity 93.1 %, 89.8-95.5; NPV 99.7 %, 98.3-100.0). Patients with COVID-19 were more likely to have higher stroke score (NIHSS (mean +/- SD) 6.9 +/- 6.9, COVID-19 negative, 9.7 +/- 9.0, COVID-19 positive; p = 0.01), carotid occlusions (6.2 % negative, 14.9 % positive; p = 0.02), and larger infarcts on presentation CT (ASPECTS 9.4 +/- 1.5, COVID-19 negative, 8.6 +/- 2.4, COVID-19 positive; p = 0.00). After multivariable logistic regression, GGO (odds ratio 15.7, 6.2-40.1), myalgia (8.9, 2.1-38.2) and higher core body temperature (1.9, 1.1-3.2) were independent COVID-19 predictors. GGO was associated with worse functional outcome on discharge and worse survival after univariate analysis. However, after adjustment for factors including stroke severity, GGO was not independently predictive of functional outcome or mortality. CONCLUSION: Apical GGO on CTA performed for patients with suspected acute stroke is a reliable diagnostic biomarker for COVID-19, which in combination with clinical features may be useful in COVID-19 triage.

Transarterial chemoembolisation for very early and early stage hepatocellular carcinoma: single-centre experience.

AIM: To evaluate the safety and efficacy of transarterial chemoembolisation (TACE) in patients with very early and early stage hepatocellular carcinoma (VES-HCC). MATERIALS AND METHODS: A retrospective analysis was performed for all TACE procedures done at King's College Hospital, a tertiary liver centre, for VES-HCC during a 5-year period (January 2014-December 2018). Patients with solitary tumours ≤5 cm and patients with 2-3 tumours (each ≤3 cm) were included. RESULTS: Two hundred and thirty-seven eligible patients were included. Technical success was achieved in 233 (98.3%) procedures. TACE using drug-eluting beads (DEB-TACE) was performed in 192 (82.4%) procedures. A complete response was achieved in 109 (45.9%) patients. The recurrence rate was 44% (48 cases), during a median imaging follow-up of 31.9 months (IQR 15.9-44.7). Median overall survival was 71.1 months (95% confidence interval [CI]: 62.9-79.3). Median recurrence-free survival was 58.9 months (95% CI: 47.1-70.7). Sixty-six (27.8%) patients eventually underwent transplantation, and six (2.5%) patients underwent surgical resection. Mild, moderate, and severe adverse events were encountered in 2.9%, 5.4%, and 0.8% of cases, respectively. No 30-day mortality was encountered. CONCLUSION: DEB-TACE is safe and effective for treating VES-HCC patients, who are unsuitable for thermal ablation or surgery, and may offer comparable survival benefit. It can also be used as a bridge to transplantation for these patients.

Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers.

The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.

Renal allograft-related inflammation complicated by acute coronary syndromes: A case report.

INTRODUCTION: Persistent systemic inflammation is considered to be predictive for future cardiovascular events. Here, in a patient with pyelonephritis of his failed renal allograft, consecutive coronary angiograms proved that coronary artery disease progressed within 3 weeks, when infection was uncontrolled. PATIENT CONCERNS: A 52-year-old male type 2 diabetic with a failed renal allograft suffering from hematuria, leukocyturia, and chest pain at rest was hospitalized. DIAGNOSES: An acute coronary syndrome in presence of pyelonephritis was diagnosed. Besides pyelonephritis, the histological examination of the kidney transplant revealed signs of chronic rejection and the presence of a renal cell carcinoma in situ. INTERVENTIONS: A percutaneous coronary intervention was performed, and an elective surgery for allograft removal was scheduled. However, within 5 weeks after discharge, two more surges of infection coincided with episodes of unstable angina. OUTCOMES: Once the renal allograft has been removed, systemic inflammation was contained. The patient was not re-hospitalized for acute-coronary syndrome within the next 12 months. CONCLUSION: Surges of systemic inflammation due to infection were paralleled by instability of coronary plaques as documented by repeat coronary angiograms.

Role of inducibility and its dynamic change in the outcome of catheter ablation of atrial fibrillation: a single center prospective study.

BACKGROUND: The role of atrial arrhythmia inducibility as an endpoint of catheter ablation of atrial fibrillation (AF) has been a controversial subject in many studies. Our goal is to evaluate the significance of inducibility, the impact of multiple sites or protocols of stimulation or the change in inducibility status in a prospective study including patients with AF undergoing first catheter ablation. METHODS: We studied 170 consecutive patients with AF (62.9% paroxysmal) undergoing catheter ablation. All patients underwent two separate stimulation protocols before and after the ablation from the coronary sinus ostium and the left atrial appendage: burst pacing at 300, 250, 200 milliseconds (or until refractoriness) for 10 seconds and ramp decrementing from 300 to 200 milliseconds in increments of 10 milliseconds every three beats for 10 seconds. Inducibility was defined as any sustained AF or organized atrial tachycardia (AT) lasting >30 seconds. RESULTS: We had AF/AT inducibility in 55 patients at baseline compared to 36 following ablation. After a mean of 41, 3 months follow-up, 115 patients were free of AF. Inducibility before or after the ablation or change in inducibility status did not influence AF recurrence. There were no significant differences regarding paroxysmal or persistent patients with AF. CONCLUSIONS: Non-inducibility of atrial arrhythmia or change in inducibility status following pulmonary vein (PV) isolation and substrate modification are not associated with long-term freedom from recurrent arrhythmia. Therefore, the use of induction of an endpoint in AF ablation is limited.

Tibiocalcaneal arthrodesis using a simple external fixator.

Tibiocalcaneal arthrodesis has been a salvage option for conditions with extensive loss of the talar body. In conditions that preclude the use of internal fixation, external compression arthrodesis has been the preferred technique to achieve fusion about the hindfoot. Since Sir John Charnley elucidated the technique of compression arthrodesis using compression clamps, various modifications and techniques of external compression arthrodesis have been described. Various clinical and biomechanical studies have established the superiority of triangular transfixation in external compression arthrodesis. We have described a simple technique of compression arthrodesis after the principle of triangular transfixation using easily available hardware from Ilizarov instrumentation. This technique is relatively inexpensive in terms of the cost of the materials, uses a modular construct, and allows multiplanar correction of the hindfoot. It can be used intraoperatively to distract the hindfoot joints, especially in the presence of fibrosis and poor skin conditions. We believe this device can be a reasonable alternative to the conventional external fixation techniques for tibiocalcaneal arthrodesis.

Wolbachia infection lowers fertile sperm transfer in a moth.

The endosymbiotic bacterium Wolbachia pipientis manipulates host reproduction by rendering infected males reproductively incompatible with uninfected females (cytoplasmic incompatibility; CI). CI is believed to occur as a result of Wolbachia-induced modifications to sperm during maturation, which prevent infected sperm from initiating successful zygote development when fertilizing uninfected females' eggs. However, the mechanism by which CI occurs has been little studied outside the genus Drosophila. Here, we show that in the sperm heteromorphic Mediterranean flour moth, Ephestia kuehniella, infected males transfer fewer fertile sperm at mating than uninfected males. In contrast, non-fertile apyrene sperm are not affected. This indicates that Wolbachia may only affect fertile sperm production and highlights the potential of the Lepidoptera as a model for examining the mechanism by which Wolbachia induces CI in insects.

Intraspecific competition: the role of lags between attack and death in host-parasitoid interactions.

Many natural enemies do not immediately kill their host, and the lag this creates between attack and host death results in mixed populations of uninfected and infected hosts. Both competition and parasitism are known to be major structuring forces in ecological communities; however, surprisingly little is known about how the competitive nature of infected hosts could affect the survival and dynamics of remaining uninfected host populations. Using a laboratory system comprising the Indian meal moth, Plodia interpunctella, and a solitary koinobiont parasitoid, Venturia canescens, we address this question by conducting replicated competition experiments between the unparasitized and parasitized classes of host larvae. For varying proportions of parasitized host larvae and competitor densities, we consider the effects of competition within (intraclass) and between (interclass) unparasitized and parasitized larvae on the survival, development time, and size of adult moths and parasitoid wasps. The greatest effects were on survival: increased competitor densities reduced survival of both parasitized and unparasitized larvae. However, unparasitized larvae survival, but not parasitized larvae survival, was reduced by increasing interclass competition. To our knowledge, this is the first experimental demonstration of the competitive superiority of parasitized over unparasitized hosts for limiting resources. We discuss possible mechanisms for this phenomenon, why it may have evolved, and its possible influence on the stability of host-parasite dynamics.

Diagnostic utility of FLI-1 monoclonal antibody and dual-colour, break-apart probe fluorescence in situ (FISH) analysis in Ewing's sarcoma/primitive neuroectodermal tumour (EWS/PNET). A comparative study with CD99 and FLI-1 polyclonal antibodies.

AIMS: To compare the sensitivity and specificity of the recently commercially available FLI-1 monoclonal (FLI-1m) antibody with the currently used antibodies [CD99 and FLI-1 polyclonal (FLI-1p)] in the diagnosis of Ewing's sarcoma/primitive neuroectodermal tumour (EWS/PNET) and to determine the diagnostic value of the EWSR1 (22q12) dual-colour, break-apart rearrangement probe fluorescence in situ hybridization (FISH) technique. MATERIALS AND METHODS: Forty-three cases of well-documented EWS/PNET and 15 non-EWS/PNET cases were retrieved from the archival files. Immunohistochemistry (IHC) for FLI-1p, FLI-1m and FISH analysis was performed. RESULTS: The most sensitive and specific test panel for the diagnosis of EWS/PNET is the combination of CD99 and FLI-1p. FISH had a very high specificity (100%) but only a moderate sensitivity (50%). CONCLUSION: The combination of CD99 and FLI-1p is the method of choice for the diagnosis of EWS/PNET. EWRS1 (22q12) dual-colour, break-apart rearrangement probe FISH should be used as a confirmatory test in addition to CD99 and FLI1-p due to its high specificity.

Phenotypic and genotypic characterisation of persistent baculovirus infections in populations of the cabbage moth (Mamestra brassicae) within the British Isles.

The genotypic relatedness of persistent baculovirus infections within UK populations of Mamestra brassicae was assessed by sequencing amplified regions from polyhedrin and ie1. Most populations harboured Mamestra brassicae (Mb) nucleopolyhedrosis virus (NPV) which showed very little genotypic variation between populations. However, one population harboured a virus that closely resembled a baculovirus found previously only in Pine Beauty Moth (Panolis flammea) populations in Scotland. Persistent baculoviruses that had emerged spontaneously as lethal, overt infections from two of the insect populations were compared with the type strain of MbNPV and a mixture of P. flammea (Pafl) NPV strains, isolated from a single host, by bioassay in virus-free Spodoptera exigua larvae. Reactivated baculoviruses were as pathogenic as the stock virus and showed phenotypic characteristics closest to the type strain they most resembled genetically. Sequence data from the insect host cytochrome oxidase genes were compared and showed a high degree of sequence conservation between populations and it was not possible to determine whether the persistent baculovirus infections had arisen on many occasions or whether they represented a single initial infection that had spread with the host. However, the presence of two distinct virus genotypes in separate M. brassicae populations suggests multiple colonisations of the host are a possibility.

Simultaneous presentation of acute monoblastic leukemia and mantle cell lymphoma: case report and review of the literature.

This paper reports a 73-year old woman with simultaneous presentation of acute monoblastic leukemia (acute myeloid leukemia (AML), French-American-British (FAB) type M5a) and mantle cell lymphoma. The patient presented with wasting, generalized lymphadenopathy, an extensive infiltrative rash and pancytopenia. Bone marrow and lymph node histopatholology showed extensive infiltration by leukemic monoblasts. Marrow cytogenetics revealed a complex karyotype, including t(8;16)(p11;p13). Flow cytometric immunophenotyping of peripheral blood, lymph node and bone marrow demonstrated two populations, expressing CD5, CD19, CD20 and CD22 and CD45, HLA-DR, CD13, CD33, CD14 and CD38, respectively. A focus of abnormal lymphocytes in the lymph node biopsy demonstrated BCL1 expression and t(11;14)(p11;p13) by fluorescence in situ hybridization and immunoglobulin heavy chain gene rearrangement by the polymerase chain reaction. The patient received infusional cytarabine, daunorubicin and etoposide chemotherapy, with complete remission of both the AML and the mantle cell leukemia. To the authors' knowledge, this is the first report of simultaneous presentations of AML, FAB M5a and mantle cell lymphoma. The case is discussed and the literature is reviewed.

Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome.

BACKGROUND: Mutations in the imprinted gene CDKN1C account for approximately 10% of Beckwith-Wiedemann syndrome (BWS) cases. Fibroblasts from BWS patients with loss of methylation (LOM) at the imprinting control region (ICR) KvDMR1 have reduced CDKN1C expression. Another group of BWS patients with downregulated CDKN1C expression but with normal methylation at KvDMR1 has been identified. OBJECTIVE: To investigate the mechanism of CDKN1C silencing in BWS in these two classes of patients. METHODS: The CDKN1C promoter region was analysed for changes in DNA methylation using bisulphite sequencing, and for alterations in chromatin structure using the chromatin immunoprecipitation (ChIP) assay. RESULTS: There was only spurious CpG methylation of the CDKN1C promoter in fibroblast DNA from both normal individuals and patients with BWS, irrespective of the methylation status of KvDMR1. There was no detectable change in chromatin structure at the CDKN1C promoter in patients with LOM at KvDMR1. BWS patients with downregulated CDKN1C and normal methylation at KvDMR1 had depletion of dimethylated H3-K4 and enrichment of dimethylated H3-K9 and HP1gamma at the CDKN1C promoter, suggesting that in these cases gene silencing is associated with repressive chromatin changes. CONCLUSIONS: CDKN1C may be downregulated by multiple mechanisms including some that do not involve promoter methylation. In BWS patients with normal methylation at KvDMR1 and reduced expression of CDKN1C, repressive chromatin may play a role, but the absence of methylation and repressive chromatin structure at the CDKN1C promoter in BWS patients with LOM at KvDMR1 argues for a direct role of this epimutation in silencing CDKN1C.

Vertical transmission of sublethal granulovirus infection in the Indian meal moth, Plodia interpunctella.

Knowledge of the mechanisms of pathogen persistence in relation to fluctuations in host density is crucial to our understanding of disease dynamics. In the case of insect baculoviruses, which are typically transmitted horizontally via a lifestage that can persist outside the host, a key issue that remains to be elucidated is whether the virus can also be transmitted vertically as a sublethal infection. We show that RNA transcripts for the Plodia interpunctella GV granulin gene are present in a high proportion of P. interpunctella insects that survive virus challenge. Granulin is a late-expressed gene that is only transcribed after viral genome replication, its presence thus strongly indicates that viral genome replication has occurred. Almost all insects surviving the virus challenge tested positive for viral RNA in the larval and pupal stage. However, this proportion declined in the emerging adults. Granulin mRNA was also detected in both the ovaries and testes, which may represent a putative mechanism by which reduced fecundity in sublethally affected hosts might be manifested. RNA transcripts were also detected in 60-80% of second-generation larvae that were derived from mating surviving adults, but there was no difference between the sexes, with both males and females capable of transmitting a sublethal infection to their offspring. The data indicate that low-level persistent infection, with at least limited gene expression, can occur in P. interpunctella following survival of a granulovirus challenge. We believe that this is the first demonstration of a persistent, sublethal infection by a baculovirus to be initiated by a sublethal virus dose. We hypothesize that the 'latent' baculovirus infections frequently referred to in the literature may also be low level persistent, sublethal infections resulting from survival from initial baculovirus exposure.

Mechanisms of MLL gene rearrangement: site-specific DNA cleavage within the breakpoint cluster region is independent of chromosomal context.

The MLL gene at chromosome band 11q23 is specifically cleaved at a unique site within its breakpoint cluster region (bcr) during the higher order chromatin fragmentation associated with apoptosis. We now show that the same specific DNA cleavage event can be detected in an exogenous MLL bcr fragment that is integrated into the genome outside of its normal chromosomal context, as well as in an extrachromosomal episome containing an MLL bcr fragment. We also show that episomal or randomly integrated copies of the MLL bcr behave similar to the endogenous MLL bcr when tested in a scaffold-associated region (SAR) assay. Furthermore, an episomal murine MLL bcr introduced into human cells is cleaved at the same site as the endogenous murine MLL bcr; this episomal murine MLL bcr also functions as a SAR in human cells. We conclude that both nuclear DNA scaffold attachment as well as site-specific DNA cleavage can be directed by sequences contained within the MLL bcr, and that it is feasible to study these events using episomal shuttle vectors.

Acute myeloid leukemia in the setting of low dose weekly methotrexate therapy for rheumatoid arthritis.

Methotrexate is in widespread use as second-line therapy for rheumatoid arthritis. Treatment with methotrexate in this and other settings has not been associated with the development of therapy-related leukemias. Four patients with rheumatoid arthritis are reported who developed acute myeloid leukemia (AML) while receiving low dose weekly methotrexate therapy in the absence of previous or concomitant treatment with known leukemogenic agents. AML in these four patients was of different morphologic subtypes and was associated with heterogeneous cytogenetic abnormalities, cell surface marker expression and multidrug resistance protein expression. None of the recognized features of therapy-related leukemia were present in these four nor in five previously-reported patients. It is likely that the occurrence of AML in patients with rheumatoid arthritis in the setting of methotrexate therapy represents the coincidence of these two diseases, and does not reflect a causal relationship.

Erythropoietin-dependent transformation of myelodysplastic syndrome to acute monoblastic leukemia.

Acute monoblastic leukemia (acute myeloid leukemia [AML], French-American-British type M5a) with leukemia cutis developed in a patient 6 weeks after the initiation of erythropoietin (EPO) therapy for refractory anemia with ringed sideroblasts. AML disappeared from both marrow and skin after the discontinuation of EPO. Multiparameter flow cytometric analysis of bone marrow cells demonstrated coexpression of the EPO receptor with CD45 and CD13 on the surface of blasts. The incubation of marrow cells with EPO, compared to without, resulted in 1.3- and 1.6-fold increases, respectively, in tritiated thymidine incorporation and bromodeoxyuridine incorporation into CD13(+) cells. Clinical and laboratory findings were consistent with the EPO-dependent transformation of myelodysplastic syndrome (MDS) to AML. It is concluded that leukemic transformation in patients with MDS treated with EPO may be EPO-dependent and that management should consist of the discontinuation of EPO followed by observation, if clinically feasible.

Intrachromosomal genomic instability in human sporadic colorectal cancer measured by genome-wide allelotyping and inter-(simple sequence repeat) PCR.

We have used genome-wide allelotyping with 348 polymorphic autosomal markers spaced, on average, 10 cM apart to quantitate the extent of intrachromosomal instability in 59 human sporadic colorectal carcinomas. We have compared instability measured by this method with that measured by inter-(simple sequence repeat) PCR and microsatellite instability assays. Instability quantitated by fractional allelic loss rates was found to be independent of that detected by microsatellite instability analyses but was weakly associated with that measured by inter-(simple sequence repeat) PCR. A set of seven loci were identified that were most strongly associated with elevated rates of fractional allelic loss and/or inter-(simple sequence repeat) PCR instability; these seven loci were on chromosomes 3, 8, 11, 13, 14, 18, and 20. A lesser association was seen with two loci flanking p53 on chromosome 17. Coordinate loss patterns for these loci suggest that at least two separate sets of cooperating loci exist for intrachromosomal genomic instability in human colorectal cancer.

High-dose cytosine arabinoside and idarubicin treatment of chronic myeloid leukemia in myeloid blast crisis.

Chronic myeloid leukemia in myeloid blast crisis (CML-MBC) is highly resistant to standard induction chemotherapy regimens. Anecdotal results from previous clinical trials support the concept of dose escalation in patients with CML-MBC. Eight patients with CML-MBC were treated with cytosine arabinoside (Ara-C) 1.5-3.0 g/m2 intravenously over 1 hr every 12 hr for 12 doses and idarubicin 12 mg/m2 intravenously daily for 3 days. Sixteen previous reports describing the use of Ara-C-based chemotherapy regimens in patients with CML-MBC were also reviewed. Our patients' median age was 62 years (range, 42-69 years). One patient achieved complete hematologic remission (95% confidence interval, 0.3%, 53%). The median survival for our patients was 7.3 months. These results were not different from previous published reports using Ara-C-based chemotherapy regimens to treat CML-MBC. In summary, the combination of high-dose Ara-C and idarubicin did not improve the overall prognosis of patients with CML-MBC. Innovative approaches need to be explored for this patient population.

Trisomy 6 in basal cell carcinomas correlates with metastatic potential: a dual color fluorescence in situ hybridization study on paraffin sections.

BACKGROUND: Most basal cell carcinomas (BCCs) are indolent lesions; a few become locally aggressive or even metastatic. Little is known about the molecular and genetic alterations in this malignant transformation. Conventional karyotyping in BCC has revealed a high frequency of nonclonal, structural rearrangements, with few cases that show multiple, unrelated, small clones suggestive of a multicellular origin. Trisomy 6 was described recently in a few BCCs, but the biologic significance of the appearance of trisomy 6 in BBCs was not clear. METHODS: Thirty cases including 4 metastatic, 4 locally aggressive, and 22 conventional nonaggressive BCCs were studied. Fluorescence in situ hybridization (FISH) was performed on 4 microm tissue sections, using alpha-centromeric enumeration probes for chromosome 6 (SpectrumGreen, Vysis Inc., Downers Grove, IL) and chromosome 4 (SpectrumOrange, Vysis Inc., Downers Grove, IL, used as disomic cell control). Trisomy 6 was semiquantitated within tumor cells and nonneoplastic cells in each case. RESULTS: Trisomy 6 was identified in all 4 metastatic BCCs within tumor cells and in corresponding BCCs at the primary cutaneous site in 2 of these 4 cases. Two locally aggressive BCCs, 1 of which had preceding radiation exposure, also showed trisomy 6. All nonaggressive BCCs and nonneoplastic cells were disomic for chromosome 6. CONCLUSIONS: Trisomy 6 has been identified as a cytogenetic aberration representative of tumor cells in aggressive and metastatic BCC. None of the nonaggressive BCCs in this study demonstrated trisomy 6. Acquisition of trisomy 6 by tumor cells in BCC may lead to the emergence of metastatic potential. Additional studies to define the underlying mechanisms may be valuable in preventing aggressive behavior in BCC.

Truncated STAT proteins are prevalent at relapse of acute myeloid leukemia.

Signal transducer and activator of transcription (STAT) proteins are implicated in the control of cell survival, proliferation and differentiation in response to hematopoietic cytokines. C-terminally truncated STAT isoforms (STATbeta), as opposed to the full length form (STATalpha), have a competitive or even transdominant negative effect on gene induction mediated by the STAT pathway. We have previously demonstrated that while constitutively active STAT proteins were detected in ten of 36 (28%) for STAT3 and eight of 36 (22%) for STAT5 in pretreatment samples from newly diagnosed acute myeloid leukemia (AML) patients, a significantly larger fraction of samples [21 of 27 (78%)] expressed STATbeta proteins. To determine whether STATbeta expression was maintained or increased after relapse in AML, we compared STAT activity and isoform expression at diagnosis and at relapse in 17 patients. In this selected group, constitutively active STAT3 was detected in 13 of 17 (76%) AML samples at diagnosis but was detected in only four of these patients at relapse. Constitutively active STAT5 was detected in three of 17 (18%) AML samples at diagnosis; but only two at relapse. In contrast, STATbeta protein expression was observed in 12 of the 17 pretreatment samples (71%) and in 16 of 17 samples at relapse. Only one patient did not express STATbeta at relapse. Our results suggest that STATbeta isoform expression, rather than level of constitutive activity, may be involved in disease progression in AML.