Targeting the terminase: An important step forward in the treatment and prophylaxis of human cytomegalovirus infections.

A key step in the replication of human cytomegalovirus (HCMV) in the host cell is the generation and packaging of unit-length genomes into preformed capsids. Enzymes required for this process are so-called terminases, first described for double-stranded DNA bacteriophages. The HCMV terminase consists of the two subunits, the ATPase pUL56 and the nuclease pUL89, and a potential third component pUL51.

Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.

Background: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met.

Methods: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America.

Serum and urinary levels of CD222 in cancer: origin and diagnostic value.

The mannose 6-phosphate/insulin-like growth factor 2 receptor (CD222, M6P/IGF2R) is a multifunctional transmembrane type I receptor, mostly localized intracellularly, less on the surface of all types of mammalian cells. It is known both to transport lysosomal enzymes through their mannose 6-phosphate moieties and to internalize extracellular ligands like insulin-like growth factor 2 or plasminogen. CD222 is involved in regulation of cell proliferation, migration, T cell activation, and apoptosis.

Efficacy and safety of frontline rituximab, cyclophosphamide, doxorubicin and prednisone plus bortezomib (VR-CAP) or vincristine (R-CHOP) in a subset of newly diagnosed mantle cell lymphoma patients medically eligible for transplantation in the randomized, phase 3 LYM-3002 study.

This post-hoc subanalysis of the LYM-3002 phase 3 study assessed the efficacy and safety of substituting vincristine in rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHOP; n = 42) for bortezomib (VR-CAP; n = 38) in a subgroup of 80 mantle cell lymphoma (MCL) patients aged <60 years who did not receive stem cell transplantation (SCT) despite medical eligibility. Complete response (CR)/unconfirmed CR (CRu) rates were 67 vs. 39% (odds ratio 3.

Gender-Specific Aspects in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation: A Single-Center Experience.

Objective: Limited data exist on gender-specific aspects in hematologic malignancies and have been obtained mostly in non-Hodgkin lymphomas. The objective of this study was to investigate gender-specific aspects in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT).

Methods: A retrospective data analysis of 191 patients with MM who underwent ASCT was performed.

Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) with aggressive disease characteristics resulting in multiple relapses after initial treatment. Lenalidomide is an immunomodulatory agent approved in the US for patients with relapsed/refractory MCL following bortezomib based on results from 3 multicenter phase II studies (2 including relapsed/refractory aggressive NHL and 1 focusing on MCL post-bortezomib). The purpose of this report is to provide longer follow-up on the MCL-001 study (follow-ups were 6.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation).

Association between quality of response and outcomes in patients with newly diagnosed mantle cell lymphoma receiving VR-CAP R-CHOP in the phase 3 LYM-3002 study.

In the phase 3 LYM-3002 study comparing intravenous VR-CAP with R-CHOP in patients with newly-diagnosed, measurable stage II-IV mantle cell lymphoma, not considered or ineligible for transplant, the median progression-free survival was significantly improved with VR-CAP (24.7 14.4 months with R-CHOP; <0.

Tetrahalogenated benzimidazole D-ribonucleosides are active against rat cytomegalovirus.

Background: Benzimidazole D-ribonucleosides are potent and selective inhibitors of CMV infection that have been shown to target the viral terminase, the enzyme complex responsible for viral DNA cleavage into single unit-length genomes and subsequent DNA packaging into procapsids. Here, we evaluated the viral inhibition by benzimidazole D-ribonucleosides against rat cytomegalovirus (RCMV).

Methods: Antiviral activity of compounds ClRB and BTCRB against RCMV was quantified by measurement of plaque formation.

A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS).

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m on days 1 and 2 of cycle 1; 27 mg/m thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS).

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

Objective: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer.

Methods: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy.

Outcome in Multiple Myeloma Patients Eligible for Stem Cell Transplantation: A Single-Center Experience.

Autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for selected patients with multiple myeloma (MM). Many data exist on ASCT in the era of novel agents. We retrospectively analyzed 189 patients (108 males and 81 females) with biopsy-proven MM, who had received ASCT after induction therapy with either conventional chemotherapy alone or in combination with novel agents at our department.

Longer-term follow-up and outcome by tumour cell proliferation rate (Ki-67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL-001(EMERGE) pivotal trial.

Patients with mantle cell lymphoma (MCL) generally respond to first-line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL-001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long-term efficacy follow-up of the prospective phase II MCL-001 study (N = 134), including new exploratory analyses with baseline Ki-67 (MIB1), a biological marker of tumour proliferation.

Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma.

Background: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma.

Methods: In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.

Novel agents have a significant impact on survival of patients with multiple myeloma.

Background: In addition to conventional chemotherapeutic regimens and autologous transplantation, novel agents are now part of the treatment armamentarium against multiple myeloma (MM). To evaluate the presumed benefit of novel agents, we performed an analysis of patients with MM at our institution before and after the availability of novel agents.

Design And Methods: In all, 200 consecutive patients with newly diagnosed MM (male = 119; female = 81; median age: 61.

Human cytomegalovirus resistance to deoxyribosylindole nucleosides maps to a transversion mutation in the terminase subunit-encoding gene UL89.

Human cytomegalovirus (HCMV) infection can cause severe illnesses, including encephalopathy and mental retardation, in immunocompromised and immunologically immature patients. Current pharmacotherapies for treating systemic HCMV infections include ganciclovir, cidofovir, and foscarnet. However, long-term administration of these agents can result in serious adverse effects (myelosuppression and/or nephrotoxicity) and the development of viral strains with reduced susceptibility to drugs.

Metabolism of cyclopropavir and ganciclovir in human cytomegalovirus-infected cells.

Human cytomegalovirus (HCMV) is a widespread pathogen that can cause severe disease in immunologically immature and immunocompromised patients. The current standard of therapy for the treatment of HCMV infections is ganciclovir (GCV). However, high incidence rates of adverse effects are prevalent and limit the use of this drug.

Extracellular matrix remodeling by bone marrow fibroblast-like cells correlates with disease progression in multiple myeloma.

The pathogenesis of multiple myeloma (MM) is regarded as a multistep process, in which an asymptomatic stage of monoclonal gammopathy of undetermined significance (MGUS) precedes virtually all cases of MM. Molecular events characteristic for the transition from MGUS to MM are still poorly defined. We hypothesized that fibroblast-like cells in the tumor microenvironment are critically involved in the pathogenesis of MM.

Screening for adenoviruses in haematological neoplasia: High prevalence in mantle cell lymphoma.

Human adenoviruses possess oncogenic capacity which is well documented in mammalian animal models, but their possible implication in human malignancy has remained enigmatic. Following primary infection, adenoviruses can persist in a latent state in lymphocytes where the virus is apparently able to evade immune surveillance. In the present study, we have employed a broad-spectrum adenovirus polymerase chain reaction (PCR) assay to systematically screen more than 200 diagnostic specimens of different lymphoid malignancies including acute lymphocytic leukaemia (n=50), chronic lymphocytic leukaemia (n=50), various types of malignant lymphoma (n=100) and multiple myeloma (n=11) for the presence of adenoviral sequences.

Bortezomib administered subcutaneously is well tolerated in bortezomib-based combination regimens used in patients with multiple myeloma.

Objective: Bortezomib (Btz) has emerged as a standard of care in the treatment of patients with multiple myeloma (MM), but Btz-induced peripheral neuropathy (PNP) has a particularly negative impact on patients' quality of life. According to a recent study, PNP was significantly less frequent with subcutaneous administration of Btz. Here, we report our experience regarding the efficacy and tolerability of standard combination regimens in MM with subcutaneous Btz.

Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study.

Purpose: Although dose-intensive strategies or high-dose therapy induction followed by autologous stem-cell transplantation have improved the outcome for patients with mantle-cell lymphoma (MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bortezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven tumoricidal and antiproliferative activity in MCL.

Rituximab, Ara-C, dexamethasone and oxaliplatin (R-ADOx) is effective for treatment of elderly patients with relapsed mantle cell lymphoma.

Purpose: The management of patients with mantle cell lymphoma (MCL) not eligible for stem cell transplantation in relapse after receiving standard approaches remains challenging, and the search for active and tolerable regimens is still warranted.

Patients And Methods: We have retrospectively analyzed activity of rituximab (375 mg/m(2) i.v.

Resistance of human cytomegalovirus to cyclopropavir maps to a base pair deletion in the open reading frame of UL97.

Human cytomegalovirus (HCMV) is a widespread pathogen in the human population, affecting many immunologically immature and immunocompromised patients, and can result in severe complications, such as interstitial pneumonia and mental retardation. Current chemotherapies for the treatment of HCMV infections include ganciclovir (GCV), foscarnet, and cidofovir. However, the high incidences of adverse effects (neutropenia and nephrotoxicity) limit the use of these drugs.

A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma.

Multiple myeloma (MM) typically follows a relapsing course with many patients requiring multiple therapies. This single-arm phase 2 study prospectively evaluated the efficacy and safety of bortezomib retreatment in MM patients who had relapsed after achieving at least a partial response (≥ PR) to prior bortezomib-based therapy. Patients aged ≥ 18 years, with measurable, secretory MM, who relapsed ≥ 6 months after prior bortezomib treatment were eligible.