Guido Tricot

University of Iowa | UI · Department of Internal Medicine

Purpose: That the malignant clone of Waldenström's macroglobulinemia (WM) demonstrates significant intraclonal heterogeneity with respect to plasmacytoid differentiation indicates the mechanistic complexity of tumorigenesis and progression. Identification of WM genes by comparing different stages of B cells may provide novel druggable targets. Ex...

Background Neutropenic fever (NF) is a known and common complication of autologous hematopoietic stem cell transplantation (ASCT). Early risk assessment may help direct treatment. We retrospectively analyzed the role of serial serum C-reactive protein (CRP) levels in predicting NF and assessed the clinical value of CRP within 14 days after transpla...

Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In...

Tandem autologous transplants are generally the preferred therapy for newly diagnosed intermediate- and high-risk myeloma patients. More Jehovah’s Witnesses (JW) are receiving single autologous peripheral blood stem cell transplants (PBSCTs). However, tandem autologous transplants have not been reported in JW patients. We performed a retrospective...

Background Aerobic glycolysis, a hallmark of cancer, is characterized by increased metabolism of glucose and production of lactate in normaxia. Recently, pyruvate kinase M2 (PKM2) has been identified as a key player for regulating aerobic glycolysis and promoting tumor cell proliferation and survival. Methods Tandem affinity purification followed...

Many cancers, including multiple myeloma (MM), retain more cytosolic iron to promote tumor cell growth and drug resistance. Higher cytosolic iron promotes oxidative damage due to its interaction with reactive oxygen species generated by mitochondria. The variation of mitochondrial biogenesis in different stages of MM disease was evaluated using gen...

Leukemia accepted article preview online, 12 April 2017. doi:10.1038/leu.2017.115.

Background: Multiple myeloma (MM) risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with MM. We undertook a pooled analysis of eight case-control studies to further evaluate anthropometric MM risk factors, including young adult BMI. Methods: We conducted multivariable logist...

Supplementary material

High-dose chemotherapies to treat multiple myeloma (MM) can be life-threatening due to toxicities to normal cells and there is a need to target only tumor cells and/or lower standard drug dosage without losing efficacy. We show that pharmacologically-dosed ascorbic acid (PAA), in the presence of iron, leads to the formation of highly reactive oxyge...

The addition of cytotoxic drugs to high-dose melphalan as a preparative regimen for autologous stem cell transplantation in multiple myeloma has not resulted in superior activity. Although novel agents have significantly improved outcome in multiple myeloma, their role in preparative regimens remains largely unknown. We have evaluated the toxicity...

Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma (MM). Methods: We performed association testing of common variation in eight regions in 1,264 MM patients and 1,479 controls of European ancestry (EA) and 1,305 MM patients and 7,078 controls of Africa...

Family clusters of multiple myeloma (MM) suggest disease heritability. Nevertheless, patterns of inheritance and the importance of genetic versus environmental risk factors in MM aetiology remain unclear. We pooled data from eleven case-control studies from the International Multiple Myeloma Consortium to characterize the association of MM risk wit...

Response to treatment in patients with a plasma cell disorder is typically measured by evaluating the bone marrow and myeloma markers, including monoclonal protein spike and immunofixation (IFE) in blood and urine, and serum free light chains (sFLCs). Stringent complete response criteria for Multiple Myeloma (MM) patients require a normal FLC ratio...

The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM data sets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (similar to 15%) of newly diagnosed cases,...

Comparative genetic and biological studies on malignant tumor counterparts in human beings and laboratory mice may be powerful gene discovery tools for blood cancers, including neoplasms of mature B-lymphocytes and plasma cells such as Burkitt lymphoma (BL) and multiple myeloma (MM). We used EMSA to detect constitutive NF-κB/STAT3 activity in BL- a...

In most myeloma patients, even after several rounds of intensive therapy, drug resistant tumor cells survive and proliferate aggressively leading to relapse. In the present study, gene expression profiling of tumor cells isolated from myeloma patients after sequential rounds of chemotherapy, revealed for the first time that heparanase, a potent pro...

Despite the development of several new agents for multiple myeloma (MM) therapy over the last decade, drug resistance continues to be a significant problem. Patients with relapsed/refractory disease have high mortality rates and desperately need new precision approaches that directly target specific molecular features that are prevalent in the refr...

Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associatio...

The human intestine contains 10 bacteria, which outnumber the mammalian cells 10-fold. Certain other commensal or infectious agents, like helminthic parasites, become members of this microbial ecosystem, especially in populations living under less hygienic conditions. Intestinal microbes, also called the microbiome or microbiota, shape the host imm...

The transcription factor forkhead box M1 (FOXM1) is a validated oncoprotein in solid cancers, but its role in malignant plasma cell tumors such as multiple myeloma (MM) is unknown. We analyzed publicly available MM datasets and found that overexpression of FOXM1 prognosticates inferior outcome in a subset (~15%) of newly diagnosed cases, particular...

Our appreciation of the different molecular subtypes¹ and the complex genomic architecture of myeloma² has been recently enhanced by whole-exome and whole-genome DNA sequencing, indicating that myeloma cells typically harbor dozens of non-synonymous mutations.3, 4 Although myeloma is associated with recurrent mutations in a number of genes, includi...

Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversi...

CKS1B is significantly upregulated in multiple myeloma (MM) and associated with poor prognosis. The identification of novel therapies is essential for effective treatment of patients resistant to chemotherapy. The NEDD8 inhibitor MLN4924 selectively targets SCFSkp2 activation and offers a more specific approach to protein degradation inhibition tha...

A single center retrospective study was performed to characterize CMV DNAemia episodes in CMV sero+ adults with multiple myeloma who received one or two auto-PBHSCT and contemporary chemotherapeutics per a structured protocol (N=59). Plasma CMV DNA load was measured weekly and as needed and calibrated to the international standard. Single and tande...

Iron homeostasis is disrupted in multiple myeloma (MM), a difficult-to-cure plasma cell malignancy with lytic bone lesions. Here we systematically analyzed iron gene expression signature and demonstrated that mRNA expression of iron exporter Ferroportin (FPN1) is significantly downregulated in myeloma cells and correlates negatively with clinic out...

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental design: BI-505 was given intravenously, every two weeks, at escalating doses from 0.0004 to 20 mg/kg, with...

Background: Peripheral blood stem cell (PBSC) rescue following myeloablative therapy is a mainstay of cancer therapy. To evaluate the ability of the Spectra Optia Apheresis System (SO), a newly developed apheresis device, the device was studied in multiple myeloma patients undergoing a first autologous PBSC transplant. Aim: To demonstrate that n...

Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma, yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population cells from human myeloma cell lines and multiple myeloma primary sam...

Background: Rapid evaluation and antibiotic therapy for febrile bone marrow transplant (BMT) patients is critical to decrease morbidity and mortality from infection, but identifying these patients in a large medical system can be challenging. This study measures the effect of computerized triage support implemented in an Emergency Department (ED) e...

Background: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association we conducted a pooled analysis of nine case-control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigaret...

We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expre...

The serine/threonine kinase Nek2 is commonly found upregulated in a wide variety of neoplasms including diffuse large B cell lymphoma and multiple myeloma. High expression of Nek2 is implicated in the induction of chromosomal instability, promotion of cell proliferation, and drug resistance in tumor cells as well as a marker for poor clinical outco...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Following therapy, essentially all multiple myeloma patients relapse due to a population of chemoresistant cells leading to eventual patient death. Our lab has identified heparanase, an endoglycosidase, as a master regulator of aggressive myeloma disease. In the present study th...

Background: Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients. Materials and methods: To investigate the role of Nek2 in bortezomib res...

The Supplementary Material provides further detail about the small molecule Nek2 inhibitors used in the studies. The first Supplementary Figure depicts the structural binding mode of HCI-2389 in the ATP-binding pocket of Nek2 and rationalizes the irreversible bond between the small molecule and Cys22 on Nek2. The second Supplementary Figure shows t...

We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expre...

Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, Phase IIa study to investigate the safety and efficacy of intravenous (IV) busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplant. Because a safe Bu e...

Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in...

Background Levofloxacin is routinely used for the prevention of invasive bacterial infections during autologous peripheral blood stem cell transplantation (APBSCT). However, increasing rates of bacterial sepsis were noted at our institution among multiple myeloma (MM) patients undergoing outpatient APBSCT with melphalan-based chemotherapy and levof...

s: AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities - May 17-20, 2013; Bellevue, WA Unprecedented progress in our understanding of the biologic and molecular genetic underpinnings of multiple myeloma (MM) has recently led to the development of novel targeted therapeutic agents, including proteasome inhibitors,...

Clinically significant serum parathyroid hormone (PTH) variations have been reported in multiple myeloma (MM) patients treated with proteasome inhibitors. To elucidate the association between serum PTH variations and proteasome inhibition in MM, the effect of PTH and PTHR1 ligands on the proteasome inhibitors bortezomib and carfilzomib in vitro and...

Increased aldehyde dehydrogenase (ALDH) activity has been found in murine and human hematopoietic stem cells and human multiple myeloma stem cells (MMSCs).1, 2, 3 ALDHs are a group of NAD(P)-dependent enzymes involved in drug resistance and retinoic acid metabolism, which are crucial for the protection of stem cells against toxic endogenous and exo...

(18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transge...

Recent findings suggest that alcohol consumption may reduce risk of multiple myeloma. To better understand this relationship, we conducted an analysis of six case-control studies participating in the International Multiple Myeloma Consortium (1,567 cases, 7,296 controls). Summary ORs and 95% confidence intervals (CI) relating different measures of...

Drug resistance is a major complication in cancer therapy but the molecular mechanisms driving both innate and acquired drug resistance still remain largely unknown for many anti-cancer agents. Microarray analyses on paired primary multiple myeloma samples at baseline and after therapy or at relapse showed that the mitotic kinase NEK2 was one of th...

We previously demonstrated that RARα2 expression is increased in CD138 selected plasma cells of relapsed multiple myelomas (MMs), and increased expression was linked to poor prognosis in newly diagnosed MM patients. In the present study, we demonstrate that increased RARα2 confers myeloma stem cell features. Higher expression of RARα2 was identifie...

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34(+) cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 mult...

We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used...

Using sequential gene expression profiling (GEP) samples, we defined a major functional group related to drug resistance that contains chromosomal instability (CIN) genes. One CIN gene in particular, NEK2, was highly correlated with drug resistance, rapid relapse, and poor outcome in multiple cancers. Overexpressing NEK2 in cancer cells resulted in...

The introduction of immunomodulatory drugs (IMiDs) has improved clinical outcome in patients with multiple myeloma (MM). However, their use has been associated with a higher risk of cardiovascular complications. The use of IMiDs with dexamethasone, chemotherapy, or in combination with erythropoietic agents enhances the risk of venous thromboembolis...

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenström's Macroglobulinemia/ Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth i...

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth in...

Cytomegalovirus (CMV) is an important pathogen after allogeneic transplantation. However, few studies have examined CMV reactivation after autologous peripheral blood stem cell transplantation (APBSCT) to treat multiple myeloma (MM), especially in the setting of the newer chemotherapeutic agents and/or 2 sequential APBSCTs (ie, tandem transplantati...

Background: MLN4924 binds to the NEDD8-activating enzyme (NAE), and promotes neddylation of SCF (Skp1-Cul1 / Cdc53-F-box protein) complex resulting in inhibition of proteasomal degradation of several substrates. CKS1B acts as an adaptor of SCF complexes involved in cell cycle progression and DNA damage repair in many cancers, including multiple mye...

Background: Patients with gene expression profiling-defined high-risk myeloma in relapse have poor outcomes with current therapies. We tested whether natural killer cells expanded by co-culture with K562 cells transfected with 41BBL and membrane-bound interleukin-15 could kill myeloma cells with a high-risk gene expression profile in vitro and in...

Bone disease is a key feature in multiple myeloma (MM) and can have a substantial impact on patient morbidity and quality-of-life. The pathogenesis of lytic bone disease in MM is complex and associated with increased osteoclast activity and impaired osteoblast function. Lytic lesions rarely heal in MM; however, the proteasome inhibitor bortezomib h...

Although MM is sensitive to both chemotherapy and radiation therapy, it remains incurable. However, treatment algorithms (based on published data and clinical experience) can be developed to optimize therapy, which include not only therapy for the underlying disease but also supportive therapy to enhance quality of life. Because myeloma is incurabl...

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and affects about 4 in 100,000 Americans. Even though much progress has been made in MM therapy, MM remains an incurable disease for the vast majority of patients. The existence of MM stem cell is considered one of the major causes of MM drug-resistance, lea...

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and w...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Bone disease is a key feature in multiple myeloma (MM) and can impact substantially on patient morbidity and quality-of-life. Our recent studies have demonstrated specific serum Parathyroid Hormone (PTH) variations associated with proteasome inhibitor response in multiple mye...

The development of therapy-related myelodysplasia (t-MDS) and acute myelogenous leukemia (t-AML) has been increasingly recognized as an important problem following high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) ([Stone et al., 1994]; [Deeg et al. 1998]; [Pedersen-Bjergaard et al., 2000]). The significance of t...

The ubiquitin-proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation alkaline phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX-171-003 and 29 patients in PX-171-004 studies, for patients with relapsed/refractory myeloma, were analyzed. All patients received 20 mg...

Increased risk of venous thromboembolism (VTE) has been described in multiple myeloma patients, particularly when exposed to immunomodulatory drugs. Epidemiological studies have shown that monoclonal gammopathy of undetermined significance (MGUS) patients also have an increased risk of VTE compared with normal individuals. Acquired activated protei...

Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE risk in MM is increased by various patient- and disease-related factors. The type of anti-MM therapy represents a key factor, with a substantially elevated VTE risk in patients treated wi...

Arsenic trioxide (ATO) is a well-known inhibitor of cell proliferation. Preclinical and clinical studies showed that ATO has anti-myeloma effects. However, the underlying mechanism remains elusive. In this study, the molecular mechanisms of ATO-induced myeloma apoptosis were explored on four myeloma cell lines of wild type or mutant p53 status and...

4989 Background Bone disease is present at diagnosis in almost all patients with multiple myeloma (MM) and can impact substantially on patient morbidity and quality of life. Decreased bone mineral density is also observed not only in MM but also in patients with monoclonal gammopathy of undetermined significance (MGUS). The pathogenesis of bone di...

We prospectively evaluated the bone changes associated with proteasome inhibition using single agent bortezomib in relapsed or refractory myeloma patients. Ten patients received bortezomib 1.3 mg/m(2) per days 1, 4, 8 and 11 for three 21-day cycles, and 6 patients received 1 mg/m(2) per day with the same schedule. Bone architecture and metabolism c...

Vaccination with idiotype (Id) protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. To improve the efficacy of DC vaccination in myeloma, we investigated the use of Id- and keyhole limpet haemocyanin (KLH)-pulsed, CD40 ligand-matured DCs administered intranodally. Nine patients with smo...

Bone has always been considered a target organ for neoplastic disorder. This review analyzed the close interaction between bone microenvironment and paraproteinemias. Paraproteinemias are a group of disorders characterized by the presence of a monoclonal protein measured in the blood or urine. Paraproteinemias include nonmalignant B cell disorders...

Here we demonstrate the crucial role of CKS1B in multiple myeloma (MM) progression and define CKS1B-mediated SKP2/p27(Kip1)-independent down-stream signaling pathways. Forced-expression of CKS1B in MM cells increased cell multidrug-resistance. CKS1B activates STAT3 and MEK/ERK pathways. In contrast, SKP2 knockdown or p27(Kip1) over-expression resul...

I congratulate Mayo Clinic Proceedings for undertaking an important and necessary effort in publishing the commentary by Hirsch1 on COIs and the accompanying editorial.2 I am a practicing physician involved with clinical research and treatment of AIDs and human immunodeficiency virus disease. In my 24 years of experience, I cannot overstate my gra...

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are considered the standard of care for many malignancies, including lymphoma, myeloma, and some leukemias. In many cases, mobilized peripheral blood has become the preferred source of hematopoietic stem cells. The efficacy of different mobilization regimens and transplantatio...

Purpose We conducted a retrospective analysis of the survival effect of venous thromboembolism (VTE) development in patients with multiple myeloma (MM). Methods Two identically designed, multicenter, double-blind, phase III clinical trials (MM-009 and MM-010) were conducted in Europe and the United States to assess the effect of lenalidomide in co...

Multiple myeloma is a differentiated clonal B-cell tumor, consisting in the early stages of the disease of slowly proliferating malignant plasma cells (myeloma cells). It is the second most common hematologic malignancy after non-Hodgkin’s lymphoma. Normal plasma cells are very hardy cells and usually the only type of cell to survive the effects of...