Comparative pharmacokinetics of a tumour-targeting therapy candidate rh-IFNα2a-NGR with rh-IFNα2a administered intravenously in mice and rats.

OBJECTIVES: rh-IFNα2a-NGR is a promising anti-tumor candidate. The aim of present study was to compare pharmacokinetics of rh-IFNα2a-NGR with rh-IFNα2a. METHODS: Pharmacokinetics and elimination were investigated after intravenous administration to mice and rats. Compared tumor and tissue distribution profiles between rh-IFNα2a-NGR and rh-IFNα2a were illustrated in the tumor transplanted mice of SP2/0 myeloma. Double antibody sandwich ELISA method was used to assess the level of both rh-IFNα2a-NGR and rh-IFNα2a in serum, tissue, bile and urine. KEY FINDINGS: After a single intravenous administration, the pharmacokinetic characters of rh-IFNα2a-NGR and rh-IFNα2a were described using a two-compartment model. No significant differences were observed between the two drugs in pharmacokinetic and elimination data. However, the concentration of rh-IFNα2a-NGR in tumor was 5.34 times and 1.52 times as high as that of rh-IFNα2a at 0.5 h (P < 0.01) and 1 h. In addition, immunohistochemical stain displayed rh-IFNα2a-NGR was predominantly located in tumor vascular tissues. CONCLUSIONS: rh-IFNα2a-NGR could be an agent for tumor vascular-targeting therapy and these findings provided references for further clinical study.

Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.

IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

[Intracranial tumor behavior of plasma cell neoplasms. Report of 2 cases and literature review]. / Comportamiento tumoral de neoplasias intracraneales de células plasmáticas. Reporte de 2 casos y revisión de la bibliografía.

BACKGROUND: Multiple myeloma is a plasmatic cell neoplasm that is characterized by skeletal destruction, renal failure, anemia and hypercalcemia. The skull plasmacytomas represent less than 1% of the head and neck tumors, they can be the primary lesion or occur as a secondary manifestation of multiple myeloma in 20-30% of the patients, or they can even manifest several years later after the diagnosis of plasmacytoma. Although some of the lesions may be surgically accessible, the aggressive natural behavior will complicate the evolution of the patients. We present two cases of Mexican women with intracranial plasmacytomas, one of them associated with multiple myeloma. CLINICAL CASES: The first case was a 24 year-old woman diagnosed with a multiple myeloma with plasmacytic-plasmablastic bone infiltration that was removed in 90%. She presented a local recurrence that required a second intervention for removal. The second case was a 62 year-old female with a malignant intracranial tumor of plasma cells that was totally resected. Both patients received adjuvant treatment based on chemotherapy and radiation therapy with favorable results. The patients died at 5 and 1.5 years respectively due to renal failure secondary to systemic disease. CONCLUSIONS: We propose chemotherapy and radiation therapy as an essential part of treatment for this condition, as the aggressive behavior of the neoplasms can complicate the evolution, despite being surgically accessible.

Antecedentes: el mieloma múltiple es una neoplasia de células plasmáticas caracterizada por destrucción ósea, insuficiencia renal, anemia e hipercalcemia. Los plasmacitomas de los huesos del cráneo representan menos de 1% de los tumores de cabeza y cuello. Se manifiestan como lesión primaria o secundaria a mieloma múltiple en 20-30%, incluso pueden aparecer varios años después del diagnóstico. Los autores comunicamos dos casos de pacientes mexicanas con lesiones plasmocíticas intracraneales, asociadas con mieloma múltiple.Casos clínicos: el primer caso es el de una paciente de 24 años de edad, con diagnóstico de mieloma múltiple e infiltración ósea que fue extirpado en 90%. Experimentó una recidiva local que requirió otra intervención para su remoción. El segundo caso es el de una mujer de 62 años de edad con un tumor intracraneal de células plasmáticas que se resecó en su totalidad. Ambas recibieron terapia adyuvante con quimio y radioterapia con resultados favorables. Las pacientes fallecieron a los 5 y 1.5 años, respectivamente, por insuficiencia renal como consecuencia de la enfermedad sistémica. Conclusiones: se propone a la quimioterapia y radioterapia como parte esencial del tratamiento de este tumor porque su comportamiento natural agresivo puede complicar la evolución, a pesar de ser accesibles quirúrgicamente.

Efficacy assessment of interferon-alpha-engineered mesenchymal stromal cells in a mouse plasmacytoma model.

Bone marrow mesenchymal stromal cells (BM-MSCs) may survive and proliferate in the presence of cycling neoplastic cells. Exogenously administered MSCs are actively incorporated in the tumor as stromal fibroblasts, thus competing with the local mesenchymal cell precursors. For this reason, MSCs have been suggested as a suitable carrier for gene therapy strategies, as they can be genetically engineered with genes encoding for biologically active molecules that can inhibit tumor cell proliferation and enhance the antitumor immune response. We used BM-MSCs engineered with the murine interferon-alpha (IFN-α) gene (BM-MSCs/IFN-α) to assess in a mouse plasmacytoma model the efficacy of this approach toward neoplastic plasma cells. We found that IFN-α can be efficiently produced and delivered inside the tumor microenvironment. Subcutaneous multiple administration of BM-MSCs/IFN-α significantly hampered the tumor growth in vivo and prolonged the overall survival of mice. The antitumor effect was associated with enhanced apoptosis of tumor cells, reduction in microvessel density, and ischemic necrosis. By contrast, intravenous administration of BM-MSCs/IFN-α did not significantly modify the survival of mice, mainly as a consequence of an excessive entrapment of injected cells in the pulmonary vessels. In conclusion, BM-MSCs/IFN-α are effective in inhibiting neoplastic plasma cell growth; however, systemic administration of engineered MSCs needs to be improved to make this approach potentially suitable for the treatment of multiple myeloma.

Biological impact of vascular endothelial growth factor on vessel density and survival in multiple myeloma and plasmacytoma.

We compared the differences in a number of angiogenesis-related immunohistochemical parameters, including microvascular density (MVD) and tumor cell activity, between multiple myeloma (MM) and solitary plasmacytoma (SP). Tissue sections from tumors of MM and SP were immunohistochemically stained and analyzed using ImageJ image analysis software for the expression of vascular endothelial growth factor (VEGF), VEGF receptors (Flt-1 and Flk-1), inducible nitric oxide (iNOS), and anti-apoptotic (Bcl-2) protein. Tumor tissues were cytologically graded as high-, intermediate-, or low-grade. Two pathologists determined the MVD of each section independently by recording the average number of CD34+ blood vessels in 500 unit fields. The arithmetic means for MVD were statistically analyzed using the Student's t-test and the significance level was calculated at P-value <0.001. The results indicate a direct correlation between upregulation of iNOS/VEGF in high-grade tumors. For MM, an increase in MVD is also correlated with a high-grade. Tumor survival signaling by Bcl-2 in both SP and MM emphasizes the fact that VEGF has a bimodal role that is mainly angiogenic in MM and tumorigenic, promoting tumor cell survival in SP.

Plasmocitoma solitario de cabeza: presentación de dos casos

Se trata de un tumor de baja frecuencia constituido de células plasmáticas que pueden aparecer a nivel de cabeza y cuello. Estos constituyen menos del 1 por ciento de las neoplasias malignas de esta región. Deben ser diferenciados del mieloma múltiple, lo que puede ser dificultoso porque un variable porcentaje va asociado a un desarrollo más tardío de esta patología. Describimos dos casos de plasmocitoma solitario parietal. La clínica, diagnóstico y los problemas terapéuticos(radioterapia, cirugía o combinación de ambos) son discutidos y revisados en la literatura

Solitary plasmocytoma is a rare plasmactic cell tumor occurring in the head and neck. These constitute, less than 1% of all head and neck malignancies. They must be differentiated from multiple myeloma because a varying percentage may be associated at a later date with the development of multiple myeloma. We describe two cases of plasmocytomas, both in parietal bone. The clinical, diagnosis and therapeutic problems (radiation, surgery or a combination of both) are discussed and reviewed in the literature

Tumor necrosis factor receptor 2-mediated tumor suppression is nitric oxide dependent and involves angiostasis.

Tumor necrosis factor (TNF) binds to two different receptors. Although most of its functions are attributed to TNF receptor 1 (TNFR1), the independent role of TNFR2 is still largely unknown. Using TNFR single or double knock-out mice, we show here that the expression of TNFR2 alone on host cells was sufficient to suppress the growth of TNF-secreting tumors in both immune competent and T/B lymphocyte-deficient severe combined immunodeficiency (SCID) mice. Histologic studies showed that TNF recruited, via TNFR2, large numbers of macrophages and efficiently inhibited angiogenesis in the tumor. In vitro, TNF activated TNFR1-deficient macrophages to produce nitric oxide (NO). Treatment of TNFR1 knock-out mice with L-NAME, a specific NO synthase inhibitor, almost completely eliminated TNF-induced angiostasis and tumor suppression. Moreover, L-NAME acted only during the first few days of tumor growth. Our results show for the first time that TNFR2 expressed on host innate immune cells is sufficient to mediate the antitumor effect of TNF, and NO is necessary for this process, possibly by inhibition of angiogenesis in the tumor.

[Plasmacytoma with multiple hypervascular lesions revealed by angiography in a patient with multiple myeloma].

A 68-year-old woman suffering from a left iliac tumor and severe back pain was admitted to another hospital in May 1999. The bone X-ray, CT scan and MRI demonstrated a 7 cm x 5 cm left iliac tumor with osteolysis and she was transferred to our hospital. Angiography demonstrated multiple hypervascular lesions in the left ilium, lumbar vertebrae, left ischium, left pubis and left rib. The tumor was resected and diagnosed as a plasmacytoma. Immunoelectrophoresis did not show any M-protein in the serum and urine, but the patient was diagnosed as having a non-secretory or low producing multiple myeloma because of the presence of 42.8% of abnormal plasma cells in the bone marrow aspirate. Her symptoms improved following 3 courses of MCNU-VMP therapy and the bone marrow plasma cells decreased to less than 5%. She was discharged and treated as an outpatient but relapsed and died of chemotherapy-resistant myeloma. We report this case because macro-angiogenesis in a multiple myeloma demonstrated by angiography is rare and interesting.

Response to thalidomide in multiple myeloma: impact of angiogenic factors.

Thalidomide has antiangiogenic and immunomodulatory effects, mediated by several cytokines such as vascular endothelial growth factor (VEGF), fibroblastic growth factor (FGF-2), hepatocyte growth factor (HGF), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Although extramedullary plasmacytomas (EMP) have a high vascularization, the response of these patients to thalidomide is controversial. Thirty-eight patients with refractory/relapsed MM were treated with thalidomide. Eleven patients had EMP when therapy was initiated. Serum specimens were obtained in patients before treatment was started and at the time of maximum response in responding patients or at thalidomide discontinuation in non-responders. Serum levels of VEGF, HGF and FGF-2 were determined in 18 patients whereas IL-6 and TNF-alpha were measured in 19 patients. Sixteen of the 38 patients (42%) responded to thalidomide. The response rate was significantly higher in patients without EMP (59% vs 0%, p = 0.0006 ). VEGF serum levels were significantly higher in responding patients. In contrast, baseline serum levels of HGF were significantly lower in responders. Neither VEGF nor HGF serum levels showed correlation with the presence of EMP. Baseline TNF-alpha serum levels were significantly lower in responding patients and in those without EMP. The serum levels of FGF-2 and IL-6 did not correlate with response to treatment or presence of EMP.

A nitric oxide synthase inhibitor, N(G)-nitro-l-arginine-methyl-ester, exerts potent antiangiogenic effects on plasmacytoma in a newly established multiple myeloma severe combined immunodeficient mouse model.

Angiogenesis is one of critical factors in sustaining the growth, invasion and metastasis of certain solid tumours and haematological malignancies such as multiple myeloma (MM). In the present study, we examined the anticancer potential of an inhibitor of nitric oxide synthase (NOS), NG-nitro-l-arginine methyl ester (L-NAME), in a novel severe combined immunodeficient mouse model (KHM mouse) that harbours the highly sanguineous plasmacytoma cell line KHM-4, derived from a patient with highly chemoresistant MM. KHM mice were intraperitoneally administered with either L-NAME, doxorubicin, melphalan, or paclitaxel. A significant reduction in tumour sizes was noted in L-NAME-administered KHM mice while no significant reduction was observed in melphalan- or doxorubicin-administered mice. A profound decrease in angiogenesis was observed in tumour tissues from L-NAME- and paclitaxel-administered KHM mice. A marked decrease in human vascular endothelial cell growth factor (VEGF) levels was identified in tumour tissues from L-NAME-administered KHM mice, strongly suggesting that L-NAME suppressed VEGF production by tumour cells through its inhibition of NOS in tumour cells, resulting in reduced neovasculization in mice leading to the regression of tumour sizes. The present data represent the first observations that certain NOS inhibitors potentially serve as experimental agents for the treatment of chemoresistant MM and plasmacytoma.

Prognostic value of angiogenesis in solitary bone plasmacytoma.

Angiogenesis plays an important role in the biology of multiple myeloma (MM) and has prognostic importance in this disease. Solitary plasmacytoma is a localized plasma cell malignancy that progresses to MM in a significant number of patients. We examined if angiogenesis is increased in solitary plasmacytoma and if it can help identify patients likely to progress to myeloma. We studied angiogenesis in plasmacytoma biopsy samples and bone marrow biopsies from 25 patients. High-grade angiogenesis was present in 64% of plasmacytomas. In contrast, bone marrow angiogenesis was low in all patients. Patients with high-grade angiogenesis in the plasmacytoma sample were more likely to progress to myeloma and had a shorter progression-free survival compared with patients with low-grade angiogenesis (P =.02). Angiogenesis is increased in solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma.

Breast plasmacytoma.

An unusual case of breast plasmacytoma associated with a multiple myeloma is reported. Breast plasmacytoma is exceedingly rare. We identified 37 cases published between 1928 and 1999, and reviewed the clinical features of this unusual presentation of plasmacytoma.

Hypervascular presentation of multiple myeloma involving the skull, demonstrated on encephaloscintigraphy.

We present two cases of myelomatous involvement of the skull. Correlative studies with routine radiography, angiography, and encephaloscintigraphy were performed. The areas of involvement of the skull were confirmed as autopsy. A mixed pattern of photon-deficient and photon-abundant lesions was noted. The clinician should be aware of such mixed patterns.

Angiography in the diagnosis and management of extracranial vascular lesions of the head and neck.

The angiographic features of various lesions of the head and neck are presented. Angiographically, cavernous hemangiomas display large venous lakes with calcified phleboliths. Arteriovenous malformations reveal massive tumor stain with well delineated feeding vessels from multiple systems. Chemodectomas and juvenile nasopharyngeal angiofibromas are clearly vascular with homogenous tumor staining in the capillary phase. Angiography of cavernous hemangioma, AVM, chemodectoma, and angiofibroma is diagnostic and may preclude the need for tissue biopsy. Angiographically neurilemmomas are less vascular with non-homogenous tumor stain. Carcinomas are typically avascular. The use and benefits of arterial embolization in the management of these lesions is presented.

Solitary renal plasmacytoma with palisading tumor vascularity.

A solitary extramedullary plasmacytoma of the kidney associated with contralateral myeloma kidney is reported. The tumor demonstrated extensive palisading tumor vessels, heretofore thought to be characteristic of renal lymphoma. Plasmacytoma as the etiology of a renal mass should be considered when there is nonfunction of a normal-appearing contralateral kidney.