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Patients with cancer, both hematologic and solid malignancies, are at increased risk for thrombosis and thromboembolism. In addition to general risk factors such as immobility and major surgery, shared by non-cancer patients, cancer patients are exposed to specific thrombotic risk factors. These include, among other factors, cancer-induced hypercoagulation, and chemotherapy-mediated endothelial dysfunction as well as tumor-cell-derived microparticles. After an episode of thrombosis in a cancer patient, secondary thromboprophylaxis to prevent recurrent thromboembolism has long been established and is typically continued as long as the cancer is active or actively treated. On the other hand, primary prophylaxis, even though firmly established in hospitalized cancer patients, has only recently been studied in ambulatory patients. This recent change is mostly due to the emergence of direct oral anticoagulants (DOACs). DOACs have a shorter half-life than vitamin K antagonists (VKA), and they overcome the need for parenteral application, the latter of which is associated with low-molecular-weight heparins (LMWH) and can be difficult for the patient to endure in the long term. Here, first, we discuss the clinical trials of primary thromboprophylaxis in the population of cancer patients in general, including the use of VKA, LMWH, and DOACs, and the potential drug interactions with pre-existing medications that need to be taken into account. Second, we focus on special situations in cancer patients where primary prophylactic anticoagulation should be considered, including myeloma, major surgery, indwelling catheters, or immobilization, concomitant diseases such as renal insufficiency, liver disease, or thrombophilia, as well as situations with a high bleeding risk, particularly thrombocytopenia, and specific drugs that may require primary thromboprophylaxis. We provide a novel algorithm intended to aid specialists but also family practitioners and nurses who care for cancer patients in the decision process of primary thromboprophylaxis in the individual patient.

This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib-dexamethasone in patients with primary relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg; VD; n = 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD; n = 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12.6 vs 9.9 months, P = 0.192), and the hazard ratio for disease progression was in favor of VD (hazard ratio = 0.71, 95% confidence interval = 0.43-1.19, P = 0.196). The overall response rate was 74% with VD and 70% with VCD. Most adverse events were similar in frequency between arms; however, grade ≥ 3 peripheral neuropathy was more frequent in the VCD versus VD arm (15 vs 4%). Infection rate was higher in the VCD arm (64 vs 52%); however, grade ≥3 infection rates were comparable (19 vs 17%). Further trials are needed to determine whether addition of cyclophosphamide to VD at a different dose/schedule confers clinical benefit. This study was terminated prematurely, with insufficient sample size to adequately compare the arms; the results should, therefore, be considered descriptive. This trial is registered: EudraCT Number 2008-003213-27; ClinicalTrials.gov NCT00813150.

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

Cancer can trigger thromboembolism. There is a 4-10% chance of finding an asymptomatic occult cancer in patients with idiopathic venous thromboembolism (VTE). Current guidelines recommend limited cancer screening with history, physical examination, and screening examinations according to age after idiopathic VTE. Recent studies found that a more extensive screening program, including endoscopy and computed tomography, may increase the cancer detection rate. The Hemostasis Working Group of the German Society of Hematology and Oncology recommends a more extensive screening program after idiopathic VTE., (© 2015 S. Karger GmbH, Freiburg.)

Background: Laparoscopic splenectomy has been proposed to be the standard therapy for adult patients with medically refractory immune thrombocytopenia (ITP). However, due to inconsistent definitions of response, variable rates of long term response have been reported. Furthermore, new medical treatment options are currently challenging the role of splenectomy. The aims of this study were to (1) analyze long term response after splenectomy according to recently defined consensus criteria, (2) identify possible predictive response factors., Methods: A case series of 72 consecutive patients with ITP undergoing laparoscopic splenectomy was retrospectively studied using univariate and multivariate analysis as well as logrank tests., Results: Median follow-up was 32 (2-110) months. Mortality was 0% and morbidity was 8.2%. Response to splenectomy was achieved in of 63/72 patients (87.5%). Loss of response occurred in 19/63 (30.2%) in median after 3 (range 2-42) months. Preoperative platelet counts after boosting with steroids and immunoglobulins as well as the postoperative rise in platelet counts were statistically significant factors for response upon both univariate and multivariate analysis, whereas age, gender, body mass index, ASA classification, disease duration, accessory spleens, splenic weight, conversion to open surgery, or perioperative complications were not. Patients with a postoperative rise in platelet counts >150,000/μL had a significant better chance on stable long term response than those with a smaller increment (P < 0.001)., Conclusions: Laparoscopic splenectomy is an effective and safe treatment option in order to obtain stable long term response in patients with ITP. Perioperative platelet counts are predictive factors of long term response., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Malassezia spp. form part of the normal human cutaneous flora and are implicated in several mild, but recurrent cutaneous diseases, such as pityriasis versicolor, Malassezia folliculitis, seborrhoeic dermatitis, and, with lesser frequency, a range of other dermatological disorders. Malassezia spp. have also been associated with cutaneous and systemic diseases in immunocompromised patients including folliculitis, seborrhoeic dermatitis, catheter-related fungaemia and a variety of deeply invasive infections. In this review, we provide an overview of the epidemiology, risk factors, pathogenesis, clinical manifestations, diagnosis, treatment and outcome of cutaneous and invasive Malassezia infections in immunocompromised patients.

Background: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of BIBF 1120, a triple angiokinase inhibitor administered once-daily in patients with advanced multiple myeloma., Patients and Methods: This Phase I study included 17 patients. Planned dose escalations of BIBF 1120 were 100, 200, 250 and 300 mg. Safety and pharmacokinetic (PK) assessments were performed., Results: Two DLTs (200 and 250 mg) occurred due to increased gamma-glutamyltransferase levels (CTC grade 3). The 250 mg dose was well tolerated; no dose escalation beyond 250 mg was made. The most common adverse events included diarrhoea, nausea and vomiting. No detectable deviation from dose linear PKs was observed. Regarding tumour control, two patients had stable disease for > or = 4 months., Conclusion: BIBF 1120 was safe and well tolerated up to 250 mg/day. The MTD was not reached.

The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, gammadelta T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human gammadelta T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived gammadelta T cells (Vgamma2+Vdelta2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated gammadelta T cells pulsed with human leukocyte antigen-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen Bam H1 Z fragment leftward open reading frame or the tumor-associated latent EBV antigen latent membrane protein 2a (LMP2a) with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3CD8 cytolytic effector memory T cells. Furthermore, gammadelta T APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced gammadelta T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous gammadelta T cells to induce LMP2a-specific autologous cytotoxic T lymphocytes was confirmed in 2 patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human gammadelta T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease.

Purpose: Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic potential in the poor-prognosis t(4;14) subset; t(4;14) results in overexpressed and activated fibroblast growth factor receptor 3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM., Experimental Design: We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone., Results: RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic pathways (e.g., decrease of Mcl-1, down-regulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stress-activated protein/c-Jun NH(2)-terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N-ras-mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14)+ MM., Conclusions: Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably Ras mutational status.

While the effects of single growth factors on endothelial cells (ECs) have been extensively studied, the importance of induction of growth factors such as PDGF-BB (platelet derived growth factor) in ECs and its impact on tumor cell functions are only partly understood. Human umbilical vein endothelial cells (HUVECs) were cultured under serum-free conditions and stimulated by 20 ng/ml VEGF (vascular endothelial growth factor) or 20 ng/ml bFGF (basic fibroblastic growth factor). As determined by real-time PCR, both VEGF and bFGF induced a significant (up to 4-fold) increase in PDGF-B RNA expression which was time- and dose-dependent (p<0.05). Similarly, conditioned medium (CM) from lung cancer cells (A549) which is known to contain multiple growth factors including VEGF and bFGF also induced PDGF-B RNA expression. Using ELISA assays, VEGF and bFGF significantly increased PDGF-BB protein secretion in HUVECs (p<0.01). By addition of BIBF 1000, a novel inhibitor of the VEGF and bFGF receptor kinases, the effect of VEGF on PDGF-B RNA induction was significantly antagonized (p<0.01). Furthermore, we studied the biological significance of EC-derived PDGF-BB on lung cancer cells. Interestingly, HUVEC-derived CM significantly stimulated migration of A549 cells (p<0.001) with a trend to further increased migration with the use of VEGF-stimulated (PDGF-BB rich) CM (p=0.2). Collectively, endothelial and lung cancer cells seem to interact via various paracrine pathways, e.g. by the reciprocal induction of VEGF and PDGF-BB. Thus, targeting key molecules would result in expression alterations of multiple factors and alter the biological functions of both stromal and tumor cells.

A phase 2 trial was performed to study the combination of bortezomib (VELCADE) with intermediate-dose dexamethasone (DEX), and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM were enroled to receive eight 3-week treatment cycles with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, followed by three 5-week cycles with bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.

Background: The major obstacles that impair successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies remain graft-versus-host disease (GvHD) and tumor relapse. Improved survival after allogeneic HSCT therefore requires more effective control of GvHD while preserving graft-versus-tumor (GvT) effects., Methods: Allogeneic parent-into-F1 murine transplant models (BALB/c or C57BL/6 --> F1[BALB/cxC57BL/6]) were used to evaluate the interrelation of GvHD and GvT effects targeting tumor-specific antigens or alloantigens on MethA tumor cells., Results: Compared with syngeneic F1-into-F1 controls (F1[H-2(b/d)] --> F1: MethA[H-2d]), significant T cell-mediated GvT effects occurred in both allogeneic transplant models, even in the absence of histoincompatibilities between donor cells and host tumor (BALB/c[H-2d] --> F1: MethA[H-2d]). Selective inhibition of type-1 (Th-1/Tc1) immune responses with TAK-603 after HSCT nearly abolished GvHD in both allogeneic transplant models. While GvT effects directed against alloantigens (C57BL/6[H-2b] --> F1: MethA[H-2d]) remained unaffected during type-1-immune suppression, GvT effects targeted against tumor-associated antigens (BALB/c[H-2d] --> F1: MethA[H-2d]) were not evident. CONCLUSIONS.: Our data show that GvHD and GvT effects are in principle separable from each other by selective type-1 inhibition in transplantation models with major histocompatibility complex disparities between tumor, host, and donor. In contrast, in situations that only allow for GvT effects that exclusively target tumor-associated antigens (TAAs), type-1 inhibition results in complete abrogation not only of GvHD but also desired GvT reactions. These differences in GvT effects targeting alloantigens or TAAs and their interrelation to GvHD should be considered in future studies aimed at separating GvT reactions from GvHD.

In acute myeloid leukemia (AML), receptor tyrosine kinase ligands promote growth and survival and contribute to AML-associated marrow neoangiogenesis. We have tested simultaneous inhibition of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor signaling by novel indolinone derivatives using 14 myeloid, including 11 human leukemic, cell lines. Compounds inhibited colony formation of all cell lines in a dose-dependent fashion. Inhibitory concentrations for 50% of the colony formation/survival (IC50) for BIBF1000 were <100 nmol/L for 3 of 11,

The ubiquitin-proteasome pathway is the major cellular degradative system for various proteins critical for proliferation, survival and homing of myeloma cells. Bortezomib is the first specific and reversible proteasome inhibitor for clinical application in humans. Phase I studies have defined the maximum tolerated dose and suggested activity against multiple myeloma. From single agent phase II studies, a rate of at least partial responses ranging from 27% for relapsed and refractory to 38% for second-line patients was derived. In comparison with pulsed dexamethasone, bortezomib enabled a higher response rate, a longer time to myeloma progression and a longer survival for patients after one to three prior lines of therapy. Preclinical and clinical phase I studies as well as initial phase II studies combining bortezomib with conventional chemotherapy or thalidomide support the assumption that bortezomib sensitizes myeloma cells to these drugs resulting in additive or synergistic activity.

In multiple myeloma (MM), both vascular endothelial (VEGF) and basic fibroblast growth factor (bFGF) promote tumor growth and survival. We have used the novel indolinone BIBF 1000 to study effects of simultaneous inhibition of VEGF, FGF and transforming growth factor-beta on MM cells and their interactions with bone marrow stroma cells (BMSCs). Both, in the absence and presence of myeloma-stroma cell contacts, BIBF 1000 abrogated BMSC-derived secretion of interleukin-6 (IL-6). In addition, BIBF 1000 directly induced apoptosis in t(4;14)-positive cell lines as well as in CD138+ marrow cells from patients with t(4;14) myeloma. To a similar extent, BIBF 1000 induced apoptosis in MM.1S and MM.1R cells carrying the translocation t(14;16). In case of MM.1S and other dexamethasone-sensitive t(14;16) cell lines, BIBF 1000 and dexamethasone had additive proapoptotic effects. Induction of apoptosis by BIBF 1000 was associated with inhibition of the mitogen-activated protein kinases (MAPK) pathway in t(4;14) and inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway in t(14;16) cells. Apoptotic effects did not occur in t(4;14)-or t(14;16)-positive MM cells carrying n- or k-Ras mutations. The data provide the rationale for clinical evaluation of this class of targeted kinase inhibitors in MM with focus on defined cytogenetic subgroups.

Fifteen patients with advanced multiple myeloma were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 every 3 weeks for eight cycles in combination with dexamethasone. One patient (7%) achieved a complete response, 10 (67%) a partial response, and one (7%) a minor response (MR) resulting in an overall response rate (> or = MR) of 80% (9/9 with > or = 2nd untreated and 3/6 with refractory relapse). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters including deletion of chromosome 13. Adverse events, mainly myelosuppression, neuropathy and fatigue, were manageable.

Cure of hematologic malignancies after allogeneic hematopoietic stem cell transplantation is partially attributable to immunocellular antitumor reactions termed graft-versus-tumor (GvT) effect. GvT effects are heterogeneous with respect to effector cell populations, target antigens, and their interrelation with graft-versus-host disease (GvHD). In the present study, allogeneic parent-into-F1 murine transplantation models (BALB/c or C57BL/6 --> [C57BL/6 x BALB/c]F1) with different tumors derived from either parental strain were used to evaluate tumor-specific GvT effects. Compared with syngeneic F1-into-F1 controls, significant CD8+ T cell-mediated GvT effects occurred in both allogeneic transplantation models, even in the absence of histoincompatibilities between donor cells and host tumor. Identical genetic background of donor and tumor precluded allorecognition of tumor cells, indicating that tumor-associated antigens (TAAs) were targeted. With allowance made for selective major histocompatibility complex (MHC) disparities between donor cells and normal host tissue, GvHD was identified as a driving force for TAA-specific GvT effects. Adoptive transfer of the effector cells into secondary tumor-bearing recipients confirmed sustained antitumor activity and specificity of the T-cell response. The results provide experimental proof of a donor CD8+ T cell-mediated TAA-specific antitumor response in vivo that is driven by GvHD. It may represent one of the mechanisms contributing to GvT effects observed in allogeneic transplant recipients.

Sixty patients with advanced multiple myeloma received 2-6 monthly treatment courses combining hyperfractionated cyclophosphamide (300 mg/m2 i.v. over 3 h q 12 h x 6, d 1-3) with pulsed dexamethasone (20 mg/m2/d p.o., d 1-4, 9-12, 17-20) and once daily thalidomide at individually escalating doses (100-400 mg/d) depending on tolerability (HyperCDT). Responding patients were maintained on daily thalidomide and monthly dexamethasone pulses. Complete, partial and minor response rates were 4%, 68% and 12% respectively; overall response rate was 84% (efficacy analysis). Median event-free and overall survival was 11 and 19 months respectively. During at least one treatment cycle, 67% of patients experienced grade 4 neutropenia resulting in 17% grade 3 and 9% grade 4 infections. Side-effects, presumably related to thalidomide, included neuropathy (40% grade 2, 16% grade 3), constipation (17%), oedema (5%), bradycardia (5%), skin reactions (3%), cerebrovascular events (5%) and deep vein thromboses (8%). Thromboses were not related to known thrombophilic risk factors. Four patients with prior myeloma therapy > 50 months developed myelodysplastic syndrome or secondary acute myeloid leukaemia 2-4 months after study entry. HyperCDT is a highly active and reasonably well-tolerated salvage regimen in advanced or refractory multiple myeloma.

Myeloma cells express basic fibroblast growth factor (bFGF), an angiogenic cytokine triggering marrow neovascularization in multiple myeloma (MM). In solid tumors and some lymphohematopoietic malignancies, angiogenic cytokines have also been shown to stimulate tumor growth via paracrine pathways. Since interleukin-6 (IL-6) is a potent growth and survival factor for myeloma cells, we have studied the effects of bFGF on IL-6 secretion by bone marrow stromal cells (BMSCs) and its potential reverse regulation in myeloma cells. Both myeloma-derived cell lines and myeloma cells isolated from the marrow of MM patients were shown to express and secrete bFGF. Cell-sorting studies identified myeloma cells as the predominant source of bFGF in MM marrow. BMSCs from MM patients and control subjects expressed high-affinity FGF receptors R1 through R4. Stimulation of BMSCs with bFGF induced a time- and dose-dependent increase in IL-6 secretion (median, 2-fold; P <.001), which was completely abrogated by anti-bFGF antibodies. Conversely, stimulation with IL-6 enhanced bFGF expression and secretion by myeloma cell lines (2-fold; P =.02) as well as MM patient cells (up to 3.6-fold; median, 1.5-fold; P =.002). This effect was inhibited by anti-IL-6 antibody. When myeloma cells were cocultured with BMSCs in a noncontact transwell system, both IL-6 and bFGF concentrations in coculture supernatants increased 2- to 3-fold over the sum of basal concentrations in the monoculture controls. The IL-6 increase was again partially, but significantly, inhibited by anti-bFGF. The data demonstrate a paracrine interaction between myeloma and marrow stromal cells triggered by mutual stimulation of bFGF and IL-6.