P104 White coat hypertension is associated with increased small vessel disease in the brain

Objective: Small vessel disease, measured by brain white matter hyperintensity (WMH), is associated with increased stroke risk and cognitive impairment. This study aimed to explore the relationship between WMH on computerised tomography (CT) and white coat hypertension (WCH) in patients with recent transient ischaemic attack (TIA) or lacunar stroke (LS). Methods: Ninety-six patients recruited for the ASIST trial (Arterial Stiffness in Lacunar Stroke and TIA) underwent measurement of clinic blood pressure (BP) and ambulatory BP monitoring (APBM) within two weeks of TIA or LS. Patients were grouped by BP phenotypes. Twenty-three patients had normotension (clinic BP 140/90 mmHg and day-time ABPM <135/85 mmHg). CT brain images were scored for WMH using the four-point Fazekas visual rating scale. Patients were grouped into no-mild WMH (scores 0–1) or moderate-severe (scores 2–3) groups. The relationship between BP and WMH was explored with chi-square and logistic regression accounting for known cardiovascular risk factors (age, gender, smoking, diabetes and hyperlipidaemia). Results: 44% of WCH patients had moderate-severe WMH compared to 17% of normotensives (p = 0.047). Logistical regression incorporating WCH as the independent factor and cardiovascular risk factors as independent variables showed WCH to be the only independent significant factor contributing to WMH (p = 0.024). Conclusion: Patients with WCH were more likely to have moderate-severe WMH on CT brain than normotensives. WCH was associated with increased WMH, independent of other cardiovascular risk factors. This study suggests that WCH is associated with increased small vessel disease in the brain and may benefit from treatment

Double-minute chromosomes in the leukocytes of a patient with a previous history of cervical carcinoma

Double-minute chromosomes (DMs) were observed in repeated samples in the leukocytes of a patient with a previous history of cervical carcinoma. The most interesting cytogenetic finding was the coexistence of DMs and a dicentric chromosome along with chromosome- and chromatid-type breaks and gaps. This observation suggests that DMs might originate through the breakage of existing chromosomes. The presence of DMs in leukocytes may also indicate the possibility that certain common agents cause DMs in tumor cells as well as in normal cells

Friend murine leukemia virus-immortalized myeloid cells are converted into tumorigenic cell lines by Abelson leukemia virus

Friend murine leukemia virus (Fr-MuLV) is a replication-competent murine retrovirus that induces acute nonlymphocytic leukemias in NFS/n mice. Fr-MuLV disease is divided into two stages based on the ability of the leukemia cells to grow in culture and transplant into syngeneic mice. Hematopoietic cells taken from the early stage of disease after Fr-MuLV infection grow as immortal myeloid cell lines in the presence of WEHI-3 cell-conditioned medium (CM) or interleukin 3. These growth factor-dependent cell lines do not grow in culture in the absence of CM and do not form tumors in syngeneic animals. If these Fr-MuLV-infected cells are superinfected with Abelson murine leukemia virus (Ab-MuLV), they lose their dependence on WEHI-3 CM and proliferate in culture in the absence of exogenous growth factors. Concomitant with the loss of growth factor dependence in culture, the Ab-MuLV-infected cell lines become tumorigenic in syngeneic mice. This secondary level of transformation is Ab-MuLV specific. Fr-MuLV-immortalized myeloid cell lines superinfected with Harvey murine sarcoma virus (Ha-MuSV) or amphotropic virus remain dependent on WEHI-3 CM for growth in vitro and are not tumorigenic in vivo. Neither Ab-MuLV- nor Ha-MuSV-infected normal mouse myeloid cell cultures produce growth factor-independent or tumorigenic cell lines. We conclude that at least two genetic events are needed to convert a murine myeloid precursor into a tumorigenic cell line. The first event occurs in Fr-MuLV-infected mice, generating cells that are growth factor dependent but immortal in vitro. The second event, which can be accomplished by Ab-MuLV infection, converts these immortal myeloid precursors into growth factor-independent and tumorigenic cells

Nucleolar organizer regions in patients with precancerous and cancerous lesions of the uterine cervix

Nucleolar organizer regions (Ag-NORs) were studied in patients with cervical precancerous and cancerous lesions along with controls. The data revealed a statistically significant decrease of Ag-NORs in cancer patients, as well as in women with severe precancerous lesions as compared with controls. A similar decrease in the amount of Ag-staining was also observed in both cancer and severe dysplasia cases. The study suggests a possible relationship of Ag-NOR activity to malignancy

Targeting SLMAP-ALK—a novel gene fusion in lung adenocarcinoma

Assessment of ALK gene rearrangements is strongly recommended by the Molecular Testing Guideline for Selection of Lung Cancer Patients proposed by IASLC, AMP, and CAP at the time of diagnosis for patients with advanced stage disease. Non- small-cell lung cancer (NSCLC) with ALK gene rearrangements or the resulting fusion pro- teins have been, for the most part, successfully targeted with ALK tyrosine kinase inhibitors (TKIs). The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in EML4. Recent studies have suggested that EML4-ALK variants may have differential responses to TKIs. Additionally, non-EML4- ALK fusions that result from ALK rearrangements with diverse 5′ partners could possibly have varied biologic and clinical implications in their therapeutic responses and outcomes of patients with NSCLC. Existing literature documents at least 20 non-EML4 fusion partners for ALK, and the clinical responsiveness to crizotinib ranges from increased sensitivity to re- sistance. This underscores the importance of identifying the precise 5′ fusion partner to ALK before initiation of therapy. Herein we report the identification of a novel SLMAP-ALK fusion in a patient with NSCLC

Do RARA/PML fusion gene deletions confer resistance to ATRA-based therapy in patients with acute promyelocytic leukemia?

Acute promyelocytic leukemia (APL) is characterized by the translocation t(15;17)(q22;q21), resulting in the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion protein in 95% cases whereas variant translocations involving PLZF (11q23), NPM (5q35), NUMA (11q13) and STAT5b (17q23) account for the rest. Leukemias with PML-RARA translocations respond well to all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) therapy whereas those with PLZF-RARA fusions respond poorly. Although primary resistance to ATRA is rare, secondary or acquired resistance is frequently observed in patients treated with ATRA alone or in combination with other chemotherapy regimens. However, molecular abnormalities mediating resistance to ATRA therapy are underexplored. Here, we report two cases of APL with RARA-PML deletions on der(17) or der(15), which displayed clinical evidence of primary and secondary resistance to therapy, respectively

Identification of a 6-cM Minimal Deletion at 11q23.1–23.2 and Exclusion of PPP2R1B Gene as a Deletion Target in Cervical Cancer

Previous functional and deletion mapping studies on cervical cancer (CC) have implicated one or more tumor suppressor genes (TSGs) on chromosome 11 at q13 and q22–24 regions. Of these, the 11q22–24 region exhibits frequent allelic deletions in a variety of solid tumor types, sug- gesting the presence of critical genes for tumor suppression in this region. However, the precise region of deletion on 11q is not clearly defined in CC. In an attempt to accurately map the deleted region, we performed an extensive loss of heterozygosity (LOH) mapping in 58 tumors using 25 polymorphic loci on both the short and long arms. The pattern of LOH identified three sites of deletions, two on 11p (p15.11–p15.3 and p12–13), and one on 11q (q23.1–q23.2). The 11q23.1–q23.2 exhibited highest fre- quency (60.6%) of deletions, suggesting that this could be the site of a candidate TSG in CC. The minimal deletion at 11q23.1–23.2 was re- stricted to a 6-cM region between 123.5 and 129.5 cM genetic distance on chromosome 11, identifying the site of a potential TSG important in the pathogenesis of CC. At least five known genes and 28 UniGene clusters were mapped to the present commonly deleted region. In addition, we have excluded a previously known TSG PPP2R1B at 11q23 as a deletion target in CC. The definition of the minimal deletion and the availability of expressed sequence resources should facilitate the identification of the candidate TSG

Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML

A unique mRNA produced in leukemic cells from a t(15;17) acute promyelocytic leukemia (APL) patient encodes a fusion protein between the retinoic acid receptor a (RARa) and a myeloid gene product called PML. PML contains a cysteine-rich region present in a new family of apparent DNA-binding proteins that includes a regulator of the interleukin-2 receptor gene (Rpt-1) and the recombination-activating gene product (RAG-l). Accordingly, PML may represent a novel transcription factor or recombinase. The aberrant PML-RAR fusion product, while typically retinoic acid responsive, displays both cell type- and promoter-specific differences from the wild-type RARa. Because patients with APL can be Induced into remission with high dose RA therapy, we propose that the nonliganded PML-RAR protein is a new class of dominant negative oncogene product. Treatment with RA would not only relieve this inhibition, but the activated PML-RAR protein may actually promote myelocyte differentiation

CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to c-secretase inhibitors

Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with c-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to c-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs. Leukemia (2006) 20, 1279–1287. doi:10.1038/sj.leu.2404258; published online 11 May 200

The spectrum of myelodysplastic syndromes post-solid organ transplantation: A single institutional experience

An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48–64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis