Age-related EBV-associated lymphoproliferative disorders in the Western population: a spectrum of reactive lymphoid hyperplasia and lymphoma

We investigated age-related EBV(+) B-cell lymphoproliferations in the Western population. The clinical features, histology, immunophenotype, EBV-encoded RNA in situ hybridization, and clonality by PCR of T-cell receptor gamma and immunoglobulin genes were categorized in 122 EBV(+) lesions as follows: (1) reactive lymphoid hyperplasia; (2) polymorphic extranodal or (3) polymorphic nodal lymphoproliferative disease (LPD); and (4) diffuse large B-cell lymphoma (DLBCL). Interphase FISH for IG and PAX5 gene rearrangements was performed on 17 cases of DLBCL. The overall median age was 75 years (range, 45-101 years; 67 men, 55 women), and 67, 79, 73, and 77 years, respectively, for groups 1 through 4. Sixteen of 21 cases of polymorphic extranodal LPD were classified as EBV(+) mucocutaneous ulcer. PCR for immunoglobulin genes was polyclonal in reactive lymphoid hyperplasia (84%) and monoclonal in 33%, 63%, and 56% of polymorphic extranodal and nodal LPD cases and DLBCL, respectively. All groups showed restricted/clonal T-cell receptor responses (27%-70%). By FISH, 19% of DLBCLs showed IGH@ rearrangements, but PAX5 was unaffected. Disease-specific 5-year survival was 100%, 93%, 57%, and 25% for groups 1-4, respectively, and 100% for patients with EBV(+) mucocutaneous ulcer. Disease volume was predictive of therapy response (P = .0002), and pathologic subtype was predictive of overall outcome (P = .001). Age-related EBV(+) B-cell LPD encompasses a wider disease spectrum than previously recognized and includes both reactive and neoplastic conditions. Reduction in the T-cell repertoire may contribute to decreased immune surveillance.     

A novel role for IL-22R1 as a driver of inflammation

The interleukin (IL)-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but this receptor is expressed on T cells from anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large cell lymphoma (ALCL) patients. To investigate the consequences of aberrant expression of this receptor on lymphocytes, we generated transgenic mice that express IL-22R1 on lymphocytes. The health of these animals progressively deteriorated at 8 to 12 weeks of age, as they displayed respiratory distress, rough coat and sluggish movement, and subsequent lethality due to multiorgan inflammation. The IL-22R1 transgenic animals developed neutrophilia that correlated with increased levels of circulating IL-17 and granulocyte colony-stimulating factor. In addition, these mice had increased serum IL-22 levels, suggesting that T cells expressing IL-22R1 generate IL-22 in a positive autoregulatory loop. As a result of the mouse model findings, we analyzed circulating cytokine levels in ALK(+)ALCL patients and detected elevated levels of IL-22, IL-17, and IL-8 in untreated patient samples. Importantly, IL-22 and IL-17 were undetectable in all patients who were in complete remission after chemotherapy. This study documents a previously unknown role of IL-22R1 in inflammation and identifies the involvement of IL-22R1/IL-22 in ALK(+)ALCL.     

High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder most commonly observed in HIV-infected patients. It is characterized by KSHV-infected plasmablasts that frequently express lytic genes. Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6. There is no standard therapy and no established response criteria. We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties. In a pilot study, 14 HIV-infected patients with symptomatic KSHV-MCD received high-dose zidovudine (600 mg orally every 6 hours) and the oral prodrug, valganciclovir (900 mg orally every 12 hours). Responses were evaluated using new response criteria. A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses. Median progression-free survival was 6 months. With 43 months of median follow-up, overall survival was 86% at 12 months and beyond. At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load. The most common toxicities were hematologic. These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD. This trial was registered at www.clinicaltrials.gov as #NCT00099073.     

Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome

The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.     

Potentially Inappropriate Medications and Functional Decline in Elderly Hospitalized Patients

OBJECTIVES: To verify whether the use of potentially inappropriate medications (PIMs) is associated with loss of independence in elderly in-patients by promoting adverse drug reactions (ADRs).
DESIGN: Prospective observational study.
PARTICIPANTS: Five hundred six patients aged 65 and older admitted to 11 acute care medical wards.
MEASUREMENTS: In-hospital loss of one or more activities of daily living (ADLs) and three or more ADLs. PIMs were identified according to diagnosis-independent Beers criteria and ascertained by study physicians based on daily review of medical and nurse records. The relationship between risk factors and outcomes was assessed using logistic regression.
RESULTS: Overall, 104 patients (20.6%) were taking at least one PIM at the time of admission (baseline users), and 49 (9.7%) were newly prescribed at least one PIM during their hospital stay. The loss of one or more ADLs occurred in 9.6% of baseline users, 16.3% of new users, and 8.5% of nonusers ( P =.21) and that of three or more ADLs in 7.7% of baseline users, 12.2% of new users, and 4.8% of nonusers ( P =.10). The lack of association was confirmed after correction for potential confounders, including ADRs. The occurrence of ADRs was strongly associated with both outcomes (odds ratio (OR)=7.80, 95% confidence interval (CI)=3.53–17.3 for the loss of ≥1 ADLs; OR=3.98, 95% CI=1.50–10.5 for the loss of ≥3 ADLs), but PIMs caused only six of 106 ADRs.
CONCLUSIONS: ADRs to any drugs more than the use of PIMs might be associated with functional decline in elderly hospitalized patients, but because the power of this study was too limited to definitively exclude a direct relationship between PIMs and functional decline, this merits further investigation.     

Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma

To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12 of 12 aggressive blastoid MCL variants and in 4 of 4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5 of 16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27^kip1, FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27^kip1, FRKHL-1, MDM2, Bad, mTOR, GSK-3, IB, and led to cell-cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and 1 with inactive Akt) and 3 of 4 cell lines showed loss of PTEN expression. PIK3CA mutations were not detected. We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. These data suggest that PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL.      

Unexpected results in the constitution of small supernumerary marker chromosomes

Traditional approaches for the classification of Small Supernumerary Marker Chromosomes (sSMC), mostly based on FISH techniques, are time-consuming and not always sufficient to fully understand the true complexity of this class of rearrangements. We describe four supernumerary marker chromosomes that, after array-CGH, were interpreted rather differently in respect to the early classification made by conventional cytogenetics and FISH investigations, reporting two types of complex markers which DNA content was overlooked by conventional approaches: 1. the sSMC contains non-contiguous regions of the same chromosome and, 2. the sSMC, initially interpreted as a supernumerary del(15), turns out to be a derivative 15 to which the portion of another chromosome was attached. All are likely derived from partial trisomy rescue events, bringing further demonstration that germline chromosomal imbalances are submitted to intense reshuffling during the embryogenesis, leading to unexpected complexity and changing the present ideas on the composition of supernumerary marker chromosomes.     

Comparison of Microlife BP A200 Plus and Omron M6 Blood Pressure Monitors to Detect Atrial Fibrillation in Hypertensive Patients

Introduction

Self-monitoring home blood pressure (BP) devices are currently recommended for long-term follow-up of hypertension and its management. Some of these devices are integrated with algorithms aimed at detecting atrial fibrillation (AF), which is common essential hypertension. This study was designed to compare the diagnostic accuracy of two widely diffused home BP monitoring devices in detecting AF in an unselected population of outpatients referred to a hypertension clinic because of high BP.

Methods

In 503 consecutive patients the authors simultaneously compared the accuracy of the Microlife? BP A200 Plus (Microlife) and the OMRON? M6 (OMRON) home BP devices, in detecting AF.

Results

Systolic and diastolic BP as well as heart rate (HR) values detected by the two devices were not significantly different. Pulse irregularity was detected in 124 and 112 patients with the OMRON M6 and Microlife BP A200 Plus devices, respectively. Simultaneous electrocardiogram (ECG) recording revealed that pulse irregularity was due to AF in 101 patients. Pulse irregularity detected by the OMRON M6 device corresponded to AF in 101, to supraventricular premature beats in 18, and to frequent premature ventricular beat in five patients, respectively. Pulse irregularity detected by the Microlife BP A200 Plus device corresponded to AF in 93, to supraventricular premature beats in 14, and to ventricular premature beats in five patients. The sensitivity for detecting AF was 100%, the specificity was 92%, and diagnostic accuracy 95% for the OMRON M6 and 100%, 92%, and 95 for the Microlife BP A200 Plus, respectively. AF was newly diagnosed by ECG recordings in 47 patients, and was detected in all patients by the OMRON device, and in 42 patients by the Microlife device.

Conclusion

These results indicate that OMRON M6 is more accurate than Microlife BP A200 Plus in detecting AF in patients with essential hypertension. Widespread use of these devices in hypertensive patients could be of clinical benefit for the early diagnosis and treatment of this arrhythmia and related consequences.