Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

Image-Guided Transvaginal and Transabdominal Drain Placement for Surgical Navigation in a Patient with Tubo-Ovarian Abscess and Obstructed Hemivagina and Ipsilateral Renal Anomaly Syndrome.

BACKGROUND: We describe a minimally invasive, image-guided technique for obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome complicated by tubo-ovarian abscess (TOA). CASE: A 15-year-old female adolescent with OHVIRA syndrome presented with TOA. Magnetic resonance imaging of the abdomen/pelvis showed a loculated pelvic mass and fluid collection near the obstructed left hemivagina. Tissue quality and ill-defined surgical planes prevented surgical excision. A transabdominal drain was placed via laparoscopic port by Interventional Radiology. She later underwent transvaginal and transabdominal drain placement into the hemivaginal collection using computed tomography and ultrasound guidance, allowing for surgical excision of the vaginal septum, drainage and excision of the TOA, and neosalpingostomy. SUMMARY AND CONCLUSION: Because of the anatomic complexity in OHVIRA syndrome, preoperative minimally invasive techniques with Interventional Radiology collaboration can assist intraoperative anatomic navigation for successful surgical treatment.

A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo.

Matrix metalloproteinases (MMPs) play a critical role in cancer pathogenesis, including tumor growth and osteolysis within the bone marrow microenvironment. However, the anti-tumor effects of MMPs are poorly understood, yet have significant implications for the therapeutic potential of targeting MMPs. Host derived MMP-7 has previously been shown to support the growth of bone metastatic breast and prostate cancer. In contrast and underscoring the complexity of MMP biology, here we identified a tumor-suppressive role for host MMP-7 in the progression of multiple myeloma in vivo. An increase in tumor burden and osteolytic bone disease was observed in myeloma-bearing MMP-7 deficient mice, as compared to wild-type controls. We observed that systemic MMP-7 activity was reduced in tumor-bearing mice and, in patients with multiple myeloma this reduced activity was concomitant with increased levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Our studies have identified an unexpected tumour-suppressive role for host-derived MMP-7 in myeloma bone disease in vivo, and highlight the importance of elucidating the effect of individual MMPs in a disease-specific context.

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer.

Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired AI resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is upregulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen-independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand-independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI-resistant cancers. In addition, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI-resistant breast cancer treatment.

Persistence of Influenza A (H1N1) Virus on Stainless Steel Surfaces.

UNLABELLED: As annual influenza epidemics continue to cause significant morbidity and economic burden, an understanding of viral persistence and transmission is critical for public health officials and health care workers to better protect patients and their family members from infection. The infectivity and persistence of two influenza A (H1N1) virus strains (A/New Caledonia/20/1999 and A/Brisbane/59/2007) on stainless steel (SS) surfaces were evaluated using three different surface matrices (2% fetal bovine serum, 5 mg/ml mucin, and viral medium) under various absolute humidity conditions (4.1 × 10(5) mPa, 6.5 × 10(5) mPa, 7.1 × 10(5) mPa, 11.4 × 10(5) mPa, 11.2 × 10(5) mPa, and 17.9 × 10(5) mPa) for up to 7 days. Influenza A virus was deposited onto SS coupons (7.07 cm(2)) and recovered by agitation and sonication in viral medium. Viral persistence was quantified using a tissue culture-based enzyme-linked immunosorbent assay (ELISA) to determine the median (50%) tissue culture infective dose (TCID50) of infectious virus per coupon. Overall, both strains of influenza A virus remained infectious on SS coupons, with an approximate 2 log10 loss over 7 days. Factors that influenced viral persistence included absolute humidity, strain-absolute humidity interaction, and time (P ≤ 0.01). Further studies on the transfer of influenza A virus from fomites by hand and the impact of inanimate surface contamination on transmission should be performed, as this study demonstrates prolonged persistence on nonporous surfaces. IMPORTANCE: This study tested the ability of two influenza A (H1N1) virus strains to persist and remain infectious on stainless steel surfaces under various environmental conditions. It demonstrated that influenza A (H1N1) viruses can persist and remain infectious on stainless steel surfaces for 7 days. Additional studies should be conducted to assess the role played by contaminated surfaces in the transmission of influenza A virus.

MS2 Coliphage as a Surrogate for 2009 Pandemic Influenza A (H1N1) Virus (pH1N1) in Surface Survival Studies on N95 Filtering Facepiece Respirators.

Research on influenza viruses regarding transmission and survival has surged in the recent years due to infectious emerging strains and outbreaks such as the 2009 Influenza A (H1N1) pandemic. MS2 coliphage has been applied as a surrogate for pathogenic respiratory viruses, such as influenza, as it's safe for personnel to handle and requires less time and labor to measure virus infectivity. However, direct comparisons to determine the effectiveness of coliphage as a surrogate for influenza virus regarding droplet persistence on personal protective equipment such as N95 filtering facepiece respirators (FFRs) are lacking. Persistence of viral droplets deposited on FFRs in healthcare settings is important to discern due to the potential risk of infection via indirect fomite transmission. The objective of this study was to determine if MS2 coliphage could be applied as a surrogate for influenza A viruses for studying persistence when applied to the FFRs as a droplet. The persistence of MS2 coliphage and 2009 Pandemic Influenza A (H1N1) Virus on FFR coupons in different matrices (viral media, 2% fetal bovine serum, and 5 mg ml-1 mucin) were compared over time (4, 12, 24, 48, 72, and 144 hours) in typical absolute humidity conditions (4.1 × 105 mPa [18°C/20% relative humidity (RH)]). Data revealed significant differences in viral infectivity over the 6-day period (H1N1- P <0.0001; MS2 - P <0.005), although a significant correlation of viral log10 reduction in 2% FBS (P <0.01) was illustrated. Overall, MS2 coliphage was not determined to be a sufficient surrogate for influenza A virus with respect to droplet persistence when applied to the N95 FFR as a droplet.

An in vitro evaluation of disinfection protocols used for needleless connectors of central venous catheters.

UNLABELLED: A repeatable and sensitive method to evaluate the effect of three antiseptics and two disinfection techniques on viable micro-organisms on luer-activated catheter needleless connectors (NCs) was developed. NCs were inoculated with Staphylococcus epidermidis or Klebsiella pneumoniae and disinfected with 3·15% chlorhexidine gluconate + 70% isopropanol (CGI), 70% isopropanol (IPA) or 10% PVP povidone-iodine (PI) antiseptic pads using: (i) scrubbing the NC septum and threaded external surfaces or (ii) wiping only the surface of the septum. Treatments were also evaluated against NCs pretreated with human serum and exposed for 18 h to Staph. epidermidis prior to testing. Viable cells were quantified by plate count. The method for inoculation and recovery of luminal micro-organisms was repeatable (SD, 0·31; n = 28). IPA disinfection provided an approximate 3 log10  CFU reduction; CGI and PI provided 3-4 log10 reductions. PI and CGI were more effective than IPA (P < 0·05), but differences between CGI and PI were not significant for either disinfection method. IPA, but not CGI and PI was also less effective (P < 0·05) against NCs inoculated with Kl. pneumoniae than Staph. epidermidis. Pretreatment with serum and prolonged Staph. epidermidis inoculation removed the advantage seen with CGI and PI; log10 reductions were 1·80, 1·73 and 2·50 for CGI, PI and IPA, respectively. PI or CGI may be more effective than IPA for NC disinfection but effectiveness may be reduced on NCs contaminated with blood or serum. SIGNIFICANCE AND IMPACT OF THE STUDY: sensitive and repeatable protocol was developed to evaluate antiseptics for disinfecting catheter needleless connectors (NCs). Povidone-iodine (PI) and chlorhexidine gluconate plus isopropanol (CGI) were more effective than isopropanol (IPA) for reducing Staphylococcus epidermidis contamination of NCs. The effectiveness of PI and CGI was reduced on NCs pre-exposed to human serum and prolonged bacterial inoculation. IPA was also less effective against NCs contaminated with Klebsiella pneumoniae.

Persistence of the 2009 pandemic influenza A (H1N1) virus on N95 respirators.

In the United States, the 2009 pandemic influenza A (H1N1) virus (pH1N1) infected almost 20% of the population and caused >200,000 hospitalizations and >10,000 deaths from April 2009 to April 2010. On 24 April 2009, the CDC posted interim guidance on infection control measures in health care settings explicitly for pH1N1 and recommended using filtering face respirators (FFRs) when in close contact with a suspected- or confirmed-to-be-infected individual, particularly when performing aerosol-generating procedures. The persistence and infectivity of pH1N1 were evaluated on FFRs, specifically N95 respirators, under various conditions of absolute humidity (AH) (4.1 × 10(5) mPa, 6.5 × 10(5) mPa, and 14.6 × 10(5) mPa), sample matrices (2% fetal bovine serum [FBS], 5 mg/ml mucin, and viral medium), and times (4, 12, 24, 48, 72, and 144 h). pH1N1 was distributed onto N95 coupons (3.8 to 4.2 cm(2)) and extracted by a vortex-centrifugation-filtration process, and the ability of the remaining virus to replicate was quantified using an enzyme-linked immunosorbent assay (ELISA) to determine the log10 concentration of the infectious virus per coupon. Overall, pH1N1 remained infectious for 6 days, with an approximately 1-log10 loss of virus concentrations over this time period. Time and AH both affected virus survival. We found significantly higher (P ≤ 0.01) reductions in virus concentrations at time points beyond 24 to 72 h (-0.52-log10 reduction) and 144 h (-0.74) at AHs of 6.5 × 10(5) mPa (-0.53) and 14.6 × 10(5) mPa (-0.47). This research supports discarding respirators after close contact with a person with suspected or confirmed influenza infection due to the virus's demonstrated ability to persist and remain infectious.

Large-eddy simulation of human-induced contaminant transport in room compartments.

UNLABELLED: A large-eddy simulation is used to investigate contaminant transport owing to complex human and door motions and vent-system activity in room compartments where a contaminated and clean room are connected by a vestibule. Human and door motions are simulated with an immersed boundary procedure. We demonstrate the details of contaminant transport owing to human- and door-motion-induced wake development during a short-duration event involving the movement of a person (or persons) from a contaminated room, through a vestibule, into a clean room. Parametric studies that capture the effects of human walking pattern, door operation, over-pressure level, and vestibule size are systematically conducted. A faster walking speed results in less mass transport from the contaminated room into the clean room. The net effect of increasing the volume of the vestibule is to reduce the contaminant transport. The results show that swinging-door motion is the dominant transport mechanism and that human-induced wake motion enhances compartment-to-compartment transport. PRACTICAL IMPLICATIONS: The effect of human activity on contaminant transport may be important in design and operation of clean or isolation rooms in chemical or pharmaceutical industries and intensive care units for airborne infectious disease control in a hospital. The present simulations demonstrate details of contaminant transport in such indoor environments during human motion events and show that simulation-based sensitivity analysis can be utilized for the diagnosis of contaminant infiltration and for better environmental protection.

Risk factors for foot-and-mouth disease in sedentary livestock herds in selected villages in four regions of Bhutan.

AIMS: To identify livestock husbandry practices important for transmission of foot-and-mouth disease (FMD) in the herds and villages of four regions in Bhutan. To consider using this information to enhance the current prevention and control programme, a consideration arising from the failure to control FMD in spite of a control programme in place. METHODS: Between March and May 2009, 383 livestock farmers originating from 80 villages in four districts of Bhutan were interviewed, using a structured questionnaire, about the livestock management practices and incidence of FMD in their herds. Multivariable logistic regression was used to quantify the risk factors that predicted the outcome variable 'farmer-diagnosed FMD in Bhutan'. RESULTS: Sixty-two percent (49/79) of the villages and 87/355 (24%) of herds surveyed had at least one outbreak of FMD within the 5 years preceding the survey. The odds of having FMD in a herd increased substantially (OR=39.2; p<0.0001) when cattle mixed with herds from other nearby villages compared with those where mixing did not occur. Those cattle herds mixing with six or more other herds within the same village were 5.3 times (p<0.0001) more likely to have had FMD than those mixed with fewer than six herds. Farmers who fed kitchen waste to cattle were 14.1 times (p<0.0001), and those who sent their animals for grazing in the forest were 3.1 times (p=0.014), more likely to report FMD in their herds than those who did not. Farmers who kept their cattle always housed in a shed during the day (OR=0.033) or at night (OR=0.29) were less likely to report FMD than those who did not (p<0.04). CONCLUSIONS: Mixing of cattle at grazing areas was identified as a risk factor for FMD. This indicates that spread from infected herds and villages, through close contact, could be an important source of disease for non-infected herds in Bhutan. Therefore, quarantining of early cases in affected herds or villages could reduce the spread of disease within and between villages. This study also highlights the potential role of feeding kitchen waste to cattle as a risk factor for FMD. The findings from this study could be considered for strengthening of the FMD control programme in Bhutan.

Large eddy simulation and zonal modeling of human-induced contaminant transport.

UNLABELLED: An immersed boundary method for particulate flow in an Eulerian framework is utilized to examine the effects of complex human motion on the transport of trace contaminants. The moving human object is rendered as a level set in the computational domain, and realistic human walking motion is implemented using a human kinematics model. A large eddy simulation (LES) technique is used to simulate the fluid and particle dynamics induced by human activity. Parametric studies are conducted within a Room-Room and a Room-Hall configuration, each separated by an open doorway. The effects of the average walking speed, initial proximity from the doorway, and the initial mass loading on room-to-room contaminant transport are examined. The rate of mass transport increases as the walking speed increases, but the total amount of material transported is more influenced by the initial proximity of the human from the doorway. The Room-Hall simulations show that the human wake transports material over a distance of about 8 m. Time-dependent data extracted from the simulations is used to develop a room-averaged zonal model for contaminant transport due to human walking motion. The model shows good agreement with the LES results. PRACTICAL IMPLICATIONS: The effect of human activity on contaminant transport may be important in applications such as clean or isolation room design for biochemical production lines, in airborne infection control, and in entry/exit into collective protection or decontamination systems. The large eddy simulations (LES) performed in this work allow precise capturing of the local wakes generated by time-dependent human motion and thus provide a means of quantifying contaminant transport due to wake effects. The LES database can be used to develop zonal models for the bulk effects of human-induced contaminant transport. These may be incorporated into multi-zone infiltration models for use in threat-response and exposure mitigation studies.

Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma.

The aim of this study was to identify risk factors associated with PFS in patients with Ewing sarcoma undergoing ASCT; 116 patients underwent ASCT in 1989-2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of PFS in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30-69) and 34% (95% CI 22-47) respectively. The 5-year probability of PFS in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3-30). PFS rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.

Immune responses to foot-and-mouth disease virus in pig farms after the 1997 outbreak in Taiwan.

This paper reports on a retrospective study of the antibody responses to structural and non-structural proteins of FMD virus O Taiwan 97 in six pig herds in Taiwan in the year after the 1997 Taiwanese FMD outbreak. All herds were vaccinated against FMD after the outbreak as part of the countrywide control program. Three of the herds had confirmed FMD infections (herds N, O and P) and three herds remained non-infected (herds K, L and M). The serum neutralizing antibody titers and the non-structural protein ELISA (NSP) antibody responses in sows and 1-month-old pigs in the infected herds were higher than in the non-infected herds, but over time a number of positive NSP reactors were detected. From the serological studies and the herd monitoring and investigations it was considered that the FMD NSP positive reactors may not have constituted a true reservoir of FMD virus infection especially in herds where susceptible pigs were no longer present post-exposure or post-vaccination. Pigs vaccinated with an unpurified FMD type O vaccines being used at that time also showed false positive responses for NSP antibodies.

Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity.

Cadmium (Cd) exposure results in injury to the proximal tubule characterized by polyuria and proteinuria. Kidney injury molecule-1 (Kim-1) is a transmembrane glycoprotein not normally detected in the mature kidney, but is upregulated and shed into the urine following nephrotoxic injury. In this study, we determine if Kim-1 might be a useful early biomarker of Cd nephrotoxicity. Male Sprague-Dawley rats were given daily injections of Cd for up to 12 weeks. Weekly urine samples were analyzed for Kim-1, protein, creatinine, metallothionein, and Clara cell protein CC-16. Significant levels of Kim-1 were detected in the urine by 6 weeks and continued to increase throughout the treatment period. This appearance of Kim-1 occurred 4-5 weeks before the onset of proteinuria, and 1-3 weeks before the appearance of metallothionein and CC-16. Higher doses of Cd gave rise to higher Kim-1 excretion. Reverse transcriptase-polymerase chain reaction (RT-PCR) expression analysis showed that Kim-1 transcript levels were increased after 6 weeks at the low dose of Cd. Immunohistochemical analysis showed that Kim-1 was present in proximal tubule cells of the Cd-treated rats. Our results suggest that Kim-1 may be a useful biomarker of early stages of Cd-induced proximal tubule injury.

Immune responses of pigs to commercialized emulsion FMD vaccines and live virus challenge.

The immune response to structural and non-structural proteins (NSPs) was studied on sequential serum samples in swine from O/Taiwan/97 FMDV challenge studies, outbreaks and after vaccination. The results showed that pigs vaccinated with a commercial vaccine prior to or after infection maintained high neutralizing antibody titers with gradual decline from peak titers over the duration of this study. However, neutralizing antibody titers in non-vaccinated pigs only reached moderate levels 2-4 weeks post infection and remained low thereafter. For the 3B and 3ABC NSP antibody ELISA responses, there were gradually decreasing levels of NSP antibody over time. In multiple vaccinations, all pigs showed significant increases in neutralizing antibodies after booster vaccination. For the 3B NSP antibody ELISA after vaccination, the mean S/P ratios for pigs vaccinated with all three FMD vaccines were all below the 0.23 cut-off value set by the manufacture, but some sera from individual vaccinated pigs gave results above this cut-off after primary or secondary vaccination. However, with the 3ABC NSP antibody ELISA, all sera from vaccinated pigs had negative results for NSP antibody for all time points.

Comparison of sensitivity and specificity in three commercial foot-and-mouth disease virus non-structural protein ELISA kits with swine sera in Taiwan.

Three commercialized ELISA kits for the detection of antibodies to the non-structural proteins (NSPs) of FMD virus were compared, using sera from uninfected, vaccinated, challenged and naturally infected pigs. The kinetics of the antibody response to NSPs was compared on sequential serum samples in swine from challenge studies and outbreaks. The results showed that ELISA A (UBI) and ELISA B (CEDI) had better sensitivity than that of the 3ABC recombinant protein-based ELISA C (Chekit). The peak for detection of antibodies to NSPs in ELISA C was significantly delayed in sera from natural infection and challenged swine as compared to the ELISA A and B. The sensitivity of the three ELISAs gradually declined during the 6-month post-infection as antibodies to NSP decline. ELISA kits A and B detected NSP antibody in 50% of challenged pigs by the 9-10th-day and 7-8th-day post-challenge, respectively. ELISA B and C had better specificity than ELISA A on sequential serum samples obtained from swine immunized with a type O FMD vaccine commercially available in Taiwan. Antibody to NSPs before vaccination was not detected in swine not exposed to FMD virus, however, antibody to NSPs was found in sera of some pigs after vaccination. All assays had significantly lower specificity when testing sera from repeatedly vaccinated sows and finishers in 1997 that were tested after the 1997 FMD outbreak. However, when testing sera from repeatedly vaccinated sows or finishers in 2003-2004, the specificity for ELISAs A, B and C were significantly better than those in 1997. This effect was less marked for ELISA A. The ELISA B was the best test in terms of the highest sensitivity and specificity and the lowest reactivity with residual NSP in vaccinates.

LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis.

OBJECTIVE: Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. LIGHT is a transmembrane protein expressed and shed from the surface of activated T cells. Since activated T cells have been implicated in osteoclastogenesis in rheumatoid arthritis (RA), this study sought to determine whether LIGHT can regulate RANKL/cytokine-induced osteoclast formation, to identify the mechanism by which LIGHT influences osteoclastogenesis, and to investigate the presence of LIGHT in the serum of RA patients. METHODS: The effect of LIGHT on human and murine osteoclast formation was assessed in the presence and absence of neutralizing reagents to known osteoclastogenic factors. Serum levels of LIGHT in RA patients were measured by enzyme-linked immunosorbent assay. RESULTS: In the presence and absence of RANKL, LIGHT induced osteoclast formation from both human peripheral blood mononuclear cells and murine macrophage precursors, in a dose-dependent manner, whereas no inhibition was observed by adding osteoprotegerin, RANK:Fc, TNFalpha, or interleukin-8 or by blocking the LIGHT receptors herpesvirus entry mediator or lymphotoxin beta receptor. However, formation of osteoclasts was significantly decreased by the soluble decoy receptor for LIGHT, DcR3, and by blocking antibodies to the p75 component of the TNF receptor. A significant increase in LIGHT levels in the serum of RA patients compared with normal controls was also noted. CONCLUSION: Our results indicate that LIGHT promotes RANKL-mediated osteoclastogenesis and that it can induce osteoclast formation by a mechanism independent of RANKL. The increased concentration of LIGHT in patients with RA raises the possibility that LIGHT may play a role in immunopathogenic conditions that are associated with localized or systemic bone loss.

Expression of a lymphatic endothelial cell marker in benign and malignant vascular tumors.

Tumors of endothelial cell origin are relatively common. Soft tissue tumors and numerous subtypes of benign and malignant vascular tumors have been described; the histogenesis of many of these tumors is uncertain, and distinguishing between benign and malignant vascular tumors, some of which express lymphatic endothelial cell markers, can be problematic. In the present study, immunophenotypic expression of a novel hyaluronan receptor (LYVE-1), which is expressed by endothelial cells of normal lymphatic vessels but not blood vessels, was determined in benign and malignant vascular tumors. It was found that, except in lymphangiomas, intramuscular hemangiomas, and Masson's hemangiomas, endothelial cells in benign blood vessel tumors (including capillary and cavernous hemangiomas, glomus tumors, pyogenic granulomas, and epithelioid hemangiomas) were negative for LYVE-1, and that all angiosarcomas and Kaposi's sarcomas were positive for LYVE-1. Expression of LYVE-1 and other lymphatic endothelial cell markers in relatively few vascular neoplasms has implications for the histogenesis of these lesions, and may prove useful in distinguishing angiosarcoma and Kaposi's sarcoma from most common benign vascular tumors.