Role of combination bortezomib and pegylated liposomal doxorubicin in the management of relapsed and/or refractory multiple myeloma

The first in class proteasome inhibitor bortezomib (B) received its initial regulatory approval for therapy of patients with multiple myeloma (MM) in the relapsed/refractory setting. Modulation of proteasome function, however, is also a rational strategy for chemosensitization, and a variety of agents have shown synergistic activity with bortezomib pre-clinically, including anthracyclines. This formed the basis for evaluation of a regimen of bortezomib with pegylated liposomal doxorubicin (PLD). PLD+B, in a phase I study, induced a predictable and manageable toxicity profile, and showed encouraging anti-MM activity. In a recent international, randomized phase III trial, PLD+B demonstrated a superior overall response rate and response quality compared to bortezomib alone, as well as a longer time to progression, duration of response, progression-free survival, and overall survival. Sub-analyses revealed benefits in almost all clinically relevant subgroups, including several which would be considered to have high-risk disease. These findings have led to the establishment of the PLD+B regimen as one of the standards of care for patients with relapsed and/or refractory myeloma. Efforts are now underway to build on this combination further by adding other active anti-myeloma agents. In this review, we will discuss the role of PLD+B as an important addition to our therapeutic armamentarium for patients with MM

Metastatic Squamous Cell Carcinoma to the Cervical Lymph Nodes From an Unknown Primary Cancer : Management in the HPV Era

Background Patients with metastases in the lymph nodes of the neck and no obvious primary tumor, neck cancer with unknown primary (NCUP), represent a management challenge. A majority of patients have metastatic squamous cell carcinoma (SCC), although other histologies do occur. Methods We comprehensively reviewed the literature, compared available guidelines, and conferred with an international team of experts. Results Positron emission tomography-computed tomography (PET-CT) and fine needle aspiration (FNA) under ultrasound guidance increase accuracy of diagnosis. Immunohistochemistry (IHC), determination of human papilloma virus (HPV) status, by p16 staining or by in situ hybridization (ISH), and next-generation gene sequencing can guide us regarding probable primary sites and tumor biology. Narrow Band Imaging (NBI) has been introduced for the early detection of subtle mucosal lesions. Direct laryngoscopy (DL) and tonsillectomy have long been procedures used in the search for a primary site. More recently, TransOral Robotic Surgery (TORS) or Transoral LASER Microsurgery (TLM) have been introduced for lingual tonsillectomy. Conclusions New technologies have been developed which can better detect, diagnose, and treat occult primary tumors. Decisions regarding therapy are based on the primary tumor site (if discovered) and N stage. Options include neck dissection with or without postoperative adjuvant therapy, primary irradiation, or combined chemotherapy with irradiation. The preferred treatment of patients whose primary remains unidentified is controversial.Peer reviewe

Recognition of early mortality in multiple myeloma by a prediction matrix

Early mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%-14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r-ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma-specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow-up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ-5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient-specific treatment strategies to improve outcomes

Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma

[Objective] Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma.[Materials & methods] HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size).[Results] Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time.[Conclusion] Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo.This study was funded by Karyopharm Therapeutics, Inc. M Gounder: reports an institutional research grant from Karyopharm, personal fees from Karyopharm, Epizyme, Springworks, Daiichi, Bayer, Amgen, Tracon, Flatiron, Medscape, Physicians Education Resource, Guidepoint, GLG and UpToDate; and grants from the National Cancer Institute, National Institutes of Health (P30CA008748) – core grant (CCSG shared resources and core facility). ARA Razak: consulting/Ad board: Merck & Adaptimmune Research support: Karyopharm Therapeutics, Deciphera, Blueprint Medicines, Pfizer, Adaptimmune, Merck, Roche/Genentech, Bristol-Myers Squibb, Medimmune, Amgen, GSK, AbbVie, Iterion Therapeutics. AM Gilligan: employee of Karyopharm Therapeutics, Inc. H Leong: employee of Karyopharm Therapeutics, Inc. X Ma: employee of Karyopharm Therapeutics, Inc. N Somaiah: consultant for Deciphera, Blueprint, Bayer Research Support from Ascentage, Astra-Zeneca, Daiichi-Sankyo, Deciphera, Eli Lilly, Karyopharm and GSK. SP Chawla: consultant for Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer, NKMax, InhibRx. Grants or contracts from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer, InhibRx, NKMax. G Grignani: consultant for Eli Lilly, Novartis, Glaxo, Pharmamar, EISAI, Bayer, Merck. SM Schuetze: consultant – NanoCarrier, UpToDate. Research funding to institution – Adaptimmune, Amgen, Blueprint, Glaxo-SmithKline, Karyopharm. B Vincenzi: Consultant for Pharmamar Eisai, Lilly, Abbott, Novartis, Accord AJ Wagner: consultant for Daiichi-Sankyo, Deciphera, Eli Lilly, Epizyme, NovoCarrier, Mundipharma, and Research Support to My Institution from Aadi Bioscience, Daiichi-Sankyo, Deciphera, Eli Lilly, Karyopharm and Plexxikon. RL Jones: consultant for Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, Springworks, Tracon, Upto Date. J Shah: employee of Karyopharm Therapeutics, Inc. S Shacham: employee of Karyopharm Therapeutics, Inc. M Kauffman: employee of Karyopharm Therapeutics, Inc. RF Riedel: ownership - Limbguard, LLC (Spouse); Institutional Clinical Research Support - AADi, AROG, Blueprint, Daiichi-Sankyo, Deciphera, Glaxo-SmithKline, Karyopharm, Ignyta, Immune Design, NanoCarrier, Oncternal, Philogen, Plexxikon, Roche, Springworks, Tracon; Consultant/Advisor - Bayer, Blueprint, Daiichi-Sankyo, Deciphera, Ignyta, NanoCarrier. S Attia: reports research funding from Desmoid Tumor Research Foundation and research funding to their institution from: AB Science, TRACON Pharma, Bayer, Novartis, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Peer reviewe

Standardizing Clinical Trials Workflow Representation in UML for International Site Comparison

BACKGROUND: With the globalization of clinical trials, a growing emphasis has been placed on the standardization of the workflow in order to ensure the reproducibility and reliability of the overall trial. Despite the importance of workflow evaluation, to our knowledge no previous studies have attempted to adapt existing modeling languages to standardize the representation of clinical trials. Unified Modeling Language (UML) is a computational language that can be used to model operational workflow, and a UML profile can be developed to standardize UML models within a given domain. This paper's objective is to develop a UML profile to extend the UML Activity Diagram schema into the clinical trials domain, defining a standard representation for clinical trial workflow diagrams in UML. METHODS: Two Brazilian clinical trial sites in rheumatology and oncology were examined to model their workflow and collect time-motion data. UML modeling was conducted in Eclipse, and a UML profile was developed to incorporate information used in discrete event simulation software. RESULTS: Ethnographic observation revealed bottlenecks in workflow: these included tasks requiring full commitment of CRCs, transferring notes from paper to computers, deviations from standard operating procedures, and conflicts between different IT systems. Time-motion analysis revealed that nurses' activities took up the most time in the workflow and contained a high frequency of shorter duration activities. Administrative assistants performed more activities near the beginning and end of the workflow. Overall, clinical trial tasks had a greater frequency than clinic routines or other general activities. CONCLUSIONS: This paper describes a method for modeling clinical trial workflow in UML and standardizing these workflow diagrams through a UML profile. In the increasingly global environment of clinical trials, the standardization of workflow modeling is a necessary precursor to conducting a comparative analysis of international clinical trials workflows

Center of Excellence in Research Reporting in Neurosurgery - Diagnostic Ontology

Motivation: Evidence-based medicine (EBM), in the field of neurosurgery, relies on diagnostic studies since Randomized Controlled Trials (RCTs) are uncommon. However, diagnostic study reporting is less standardized which increases the difficulty in reliably aggregating results. Although there have been several initiatives to standardize reporting, they have shown to be sub-optimal. Additionally, there is no central repository for storing and retrieving related articles. Results: In our approach we formulate a computational diagnostic ontology containing 91 elements, including classes and sub-classes, which are required to conduct Systematic Reviews - Meta Analysis (SR-MA) for diagnostic studies, which will assist in standardized reporting of diagnostic articles. SR-MA are studies that aggregate several studies to come to one conclusion for a particular research question. We also report high percentage of agreement among five observers as a result of the interobserver agreement test that we conducted among them to annotate 13 articles using the diagnostic ontology. Moreover, we extend our existing repository CERR-N to include diagnostic studies. Availability: The ontology is available for download as an.owl file at: http://bioportal.bioontology.org/ontologies/3013

The Selective Role of Open and Endoscopic Approaches for Sinonasal Malignant Tumours

Endoscopic endonasal surgery has been demonstrated to be effective in the treatment of selected cases of sinonasal cancers. However, in cases of locally advanced neoplasms, as well as recurrences, the most appropriate approach is still debated. The present review aims to summarize the current state of knowledge on the utility of open approaches to resect sinonasal malignant tumours. Published comparative studies and meta-analyses suggest comparable oncological results with lower morbidity for the endoscopic approaches, but selection biases cannot be excluded. After a critical analysis of the available literature, it can be concluded that endoscopic surgery for selected lesions allows for oncologically safe resections with decreased morbidity. However, when endoscopic endonasal surgery is contraindicated and definitive chemoradiotherapy is not appropriate, craniofacial and transfacial approaches remain the best therapeutic option.Peer reviewe

Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein-Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

PURPOSE: Lenalidomide, thalidomide, and pomalidomide (LTP) are immunomodulatory agents approved for use in multiple myeloma, but in some settings, especially with alkylating agents, an increase in Hodgkin’s lymphoma (HL) and other secondary primary malignancies (SPM) has been noted. Some of these malignancies have been linked to Epstein-Barr virus (EBV), raising the possibility that immunomodulatory drugs disrupt latent EBV infection. EXPERIMENTAL DESIGN: We studied the ability of LTP to reactivate latently infected EBV-positive cell lines in vitro and in vivo, and evaluated the EBV viral load in archived serum samples from patients who received a lenalidomide, thalidomide and dexamethasone (LTD) combination. RESULTS: Treatment of EBV-infected B-cell lines with LTP at physiologically relevant concentrations induced the immediate early gene BZLF1, the early gene BMRF1, and the late proteins VCA and BCFR1. This occurred in the potency order pomalidomide>lenalidomide>thalidomide, and the nucleoside analogue ganciclovir enhanced the cytotoxic effects of lenalidomide and pomalidomide in Burkitt’s lymphoma cells in vitro and in vivo. EBV reactivation was related to phosphatidylinositol-3 kinase (PI3K) stimulation and Ikaros suppression, and blocked by the PI3K-δ inhibitor idelalisib. Combinations of lenalidomide with dexamethasone or rituximab increased EBV reactivation compared to lenalidomide alone and, importantly, lenalidomide with melphalan produced even greater reactivation CONCLUSIONS: We conclude LTP may reactivate EBV-positive resting memory B-cells thereby enhancing EBV lytic cycle and host immune suppression

Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma

Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase-3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies