Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay.

While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme-linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15-56 mg/m(2) ), dose-dependent inhibition of c20S and i20S chymotrypsin-like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%].

Intracranial multifocal dural involvement in multiple myeloma: case report and review of the literature.

Multiple myeloma is an incurable clonal B-cell malignancy with terminally differentiated plasma cells that accounts for 1% of all malignancies in the United States. It may present with tumors consisting of discrete masses of neoplastic monoclonal plasma cells in either bone or soft tissues. Central nervous system (CNS) involvement of myeloma is uncommon and is observed in approximately 1% of cases.

Pharmacotherapy of myelodysplastic syndromes.

Importance Of The Field: Despite the remarkable progress in the treatment of patients with myelodysplastic syndromes (MDS) in the past decade, response to the hypomethylating agents azacitidine and decitabine in non-del(5q) MDS patients remains at approximately 50%, leaving half of patients needing treatment with essentially no options. As biologic insight into the molecular pathways that account for disease evolution and clinical heterogeneity is expanded, the arsenal of potential drugs that may elicit significant response is also increasing. One of the greatest challenges for the treating physician is to decide when to initiate therapy and which therapy (approved drug or newer agents still in clinical trial) is likely to be the most beneficial.

Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: a case series illustrating utility in clinical practice.

Introduction: Increasing numbers of patients are presenting with relapsed/refractory multiple myeloma (MM) following treatment with bortezomib. Therefore, there is a need for effective and well-tolerated treatment strategies after failure of bortezomib-based regimens. Vorinostat, a histone deacetylase inhibitor, has demonstrated antiproliferative and proapoptotic activity alone and in combination with bortezomib in preclinical models of MM.

The current status and future of multiple myeloma in the clinic.

It is now recognized that all cases of multiple myeloma (MM) are preceded by the premalignant condition of monoclonal gammopathy of undetermined significance (MGUS). Although patients with MGUS are generally asymptomatic and currently managed by "watch and wait," the identification of high-risk patients whose disease will progress more rapidly to smoldering MM (SMM) and MM aids in timely intervention. The immunomodulatory agents thalidomide and lenalidomide and the proteasome inhibitor bortezomib are now routine components of MM therapy in both first-line and relapsed/ refractory settings.

Clinical implications of gene expression profiling in myelodysplastic syndromes: recognition of ribosomal and translational gene dysregulation and development of predictive assays.

Myelodysplastic syndromes (MDS) are a group of haematopoietic stem cell disorders that pose a unique challenge for gene expression profiling by virtue of their inherent heterogeneity. Despite monoclonality of MDS, the marrow picture is complicated by the presence of not only stromal cells but also by varying stages of differentiating diseased cells belonging to all three lineages. Now that reproducible results can be obtained from nanograms of RNA, it is possible to derive useful information from even a limited number of cells; for example, dysregulation of ribosomal and translational genes was detected in MDS patients compared to controls using a small number of CD34+ cells.

Extended follow-up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma.

High-quality response to multiple myeloma (MM) therapy can be predictive for improved outcomes. Novel agents may improve the depth of responses and therefore prolong survival. We report on the extended follow-up of a phase II study in frontline MM of bortezomib alone and in combination with dexamethasone.

Complete remissions observed in acute myeloid leukemia following prolonged exposure to lintuzumab: a phase 1 trial.

A multi-institutional, phase 1 dose-escalation trial of lintuzumab (humanized anti-CD33 antibody; SGN-33, HuM195) was performed in patients with CD33-positive myeloid malignancies. In this study, higher doses than previously tested and prolonged duration of treatment for responding patients were evaluated. Over the dose range of 1.

Variability of gross tumor volume delineation in head-and-neck cancer using PET/CT fusion, Part II: the impact of a contouring protocol.

The purpose of this study was to assess the efficacy of a gross tumor volume (GTV) contouring protocol on interobserver variability between 4 physicians in positron emission therapy/computed tomography (PET/CT) treatment planning of head-and-neck cancer. A GTV contouring protocol for PET/CT treatment planning was developed utilizing 4 stages: Preliminary contouring on CT alone, determination of appropriate PET windowing, accurate image registration, and modification of CT contouring with correctly formatted PET/CT display and rules for modality disagreement. Two neuroradiologists and 2 radiation oncologists (designated as A, B, C, and D, respectively) were given a tutorial of PET/CT coregistered imaging individualized to their skill level, which included a step-by-step explanation of the protocol with clinical examples.

A Phase II trial of autologous stem cell transplantation followed by mini-allogeneic stem cell transplantation for the treatment of multiple myeloma: an analysis of Eastern Cooperative Oncology Group ECOG E4A98 and E1A97.

Conventional allogeneic hematopoietic stem cell transplantation (HSCT) for multiple myeloma is associated with high transplantation-related mortality (TRM). Nonmyeloablative allogeneic transplantation (NST) uses the well-known graft-versus-myeloma (GVM) effect to eradicate minimal residual disease. The Eastern Cooperative Oncology Group conducted a Phase II trial of autologous HSCT followed by NST to provide maximal tumor cytoreduction to allow for a subsequent GVM effect.

Treatment of patients with myeloma with comorbid conditions: considerations for the clinician.

Patients with multiple myeloma (MM) frequently present with serious comorbidities such as renal impairment and/or diabetes. Treatment of these patient subsets poses a greater challenge: renal dysfunction can alter drug clearance leading to increased toxicity, and commonly used regimens can induce or exacerbate hyperglycemia. In recent years, novel targeted therapies have broadened and improved treatment options for all patients with MM.

Comparable outcomes in nonsecretory and secretory multiple myeloma after autologous stem cell transplantation.

Nonsecretory myeloma (NSM) accounts for <5% of cases of multiple myeloma (MM). The outcome of these patients following autologous stem cell transplantation (ASCT) has not been evaluated in clinical trials. We compared the outcomes after ASCT for patients with NSM reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1989 and 2003, to a matched group of 438 patients (4 controls for each patient) with secretory myeloma (SM).

Comparison of twin and autologous transplants for multiple myeloma.

Relapse is the overwhelming cause of treatment failure after autologous transplantation for multiple myeloma (MM). For patients with a syngeneic donor, twin transplants provide a healthy graft that is free of myeloma. The relative impact of the graft on posttransplant relapse can be estimated by comparing risk of relapse after hematopoietic cell transplantation from genetically identical twins versus autotransplants because confounding differences in minor or major histocompatibility antigens are absent in the syngeneic transplant setting.

Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma.

The Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST) demonstrated substantial activity with two dose levels of bortezomib (1.0 and 1.3 mg/m(2)), alone or with dexamethasone, in relapsed or refractory multiple myeloma.

Papillary lesions of the breast diagnosed by core needle biopsy: 71 cases with surgical follow-up.

Background: Papillary breast lesions comprise a spectrum of histopathologic diagnoses ranging from benign papillomas to papillary carcinomas. There is ongoing controversy regarding the management of papillary lesions diagnosed by core needle biopsy (CNB). Some authors advocate observation of papillary lesions when the CNB is benign, while others recommend surgical excision of all papillary lesions.

Combination of 5-azacytidine and thalidomide for the treatment of myelodysplastic syndromes and acute myeloid leukemia.

Background: The treatment of myelodysplastic syndromes (MDS) remains a challenge to the clinician despite recent advances. Many patients will either not respond or will have only limited and/or brief responses to single-agent therapy. Eventually, 30% of patients with MDS will progress and develop acute myeloid leukemia (AML).

Association between renal cell carcinoma and plasma cell dyscrasias: a case series of six patients.

Multiple malignancies in the same patient are unusual. This is particularly true for patients with hematologic malignancies who have a concomitant solid tumor. We report the unexpectedly higher frequency of renal cell carcinoma (RCC) associated with plasma cell dyscrasias.

A pilot study to evaluate the safety and clinical outcomes of once-weekly epoetin alfa 80,000 u in anemic patients with cancer receiving chemotherapy.

Background: Epoetin alfa is indicated for the treatment of chemotherapy-induced anemia at doses of 150 U/kg 3 times weekly or 40,000 U once weekly. Higher starting doses may lead to higher hematologic response rates (RRs), earlier hematologic responses, and earlier identification of nonresponders. The hematologic response and safety of epoetin alfa at a starting dose of 80,000 U once weekly in anemic patients (hemoglobin [Hb] View Article and Find Full Text PDF

Preliminary results of radiation therapy for prostate cancer in human immunodeficiency virus-positive patients.

Objectives: The purpose of this study was to report on the clinical outcomes of patients treated at our institution for prostate cancer (PCa) who had been previously diagnosed as Human immunodeficiency virus (HIV) positive.

Methods: The authors conducted a retrospective study of 14 PCa/HIV patients who were being treated for PCa with external beam radiotherapy, brachytherapy, or a combination of the two. Each patient's prostate-specific antigen (PSA) level, CD4 count, and viral load were obtained before the initial radiation treatment and at the time of their most recent follow-up.

Prognosis in myelodysplastic syndromes: are the new classifications useful?

Increased understanding of the biologic and clinical parameters that define subgroups of myelodysplastic syndromes has led to continuing refinement of classification strategies for diagnostic and prognostic use. The French-American-British classification, based primarily on morphology, was modified by the World Health Organization system to include the negative impact of multilineage dysplasias and higher blast counts. In addition, this system identifies a distinct clinical subgroup characterized by an isolated chromosome 5 deletion.

Liver involvement in multiple myeloma.

Clinical manifestations of liver involvement in multiple myeloma (MM) are uncommon. Rare cases of MM present as acute liver disease. We report a case of a 55-year-old woman with MM who presented with painless jaundice, mild pruritus, and abnormal liver function tests resembling acute cholestatic hepatitis without the stigmata of chronic liver disease.

Value of serum free light chain testing for the diagnosis and monitoring of monoclonal gammopathies in hematology.

The automated quantification of serum free kappa and lambda light chain concentrations provides a highly sensitive tool for the diagnosis and monitoring of monoclonal gammopathies. An abnormal kappa:lambda ratio supports the presence of clonal plasma cell expansion and requires further investigation. More than 94% of myeloma, light chain myeloma, and AL amyloidosis and, likewise, a majority of patients with light chain deposition disease are detectable with this technology.