Subglottic extramedullary plasmacytoma with light chain multiple myeloma masquerading as adult-onset asthma.

Extramedullary plasmacytoma (EMP) arises outside the bone marrow and can be associated with multiple myeloma (MM). A 55-year-old gentleman, who presented with dyspnea and expiratory wheeze, was diagnosed and treated for asthma. A subsequent relapse 6 months later prompted an Otolaryngology consult. Preliminary findings showed a benign-looking nodular lesion at the subglottis. Work-up at our institution revealed an Fludeoxyglucose (FDG) avid left subglottic lesion with multiple bone metastases on a Positron Emission Tomography / Computed Tomography (PET/CT). The patient underwent a panendoscopy and laser excision of the subglottic lesion with subglottic jet ventilation. Histology showed an EMP. Further work-up revealed the presence of kappa light chain MM with adverse cytogenetics. Patient was treated systemically with lenalidomide, bortezomib, and dexamethasone for four cycles with rapid improvement in his symptoms. We review the literature about EMP of the subglottis with MM. We present the first case of subglottic laryngeal EMP with MM managed via CO2 laser excision.

Active immunization with EPF suppresses the formation of immune ascites in BALB/c mice.

The production of early pregnancy factor (EPF) is not confined to pregnancy--EPF has been detected as a product of tumour and transformed cells in vivo and in vitro. In this study, EPF (or an EPF-like substance) was detected also in the serum of BALB/c mice, 7 days after intraperitoneal (i.p.) administration of the mineral oil pristane. Furthermore, EPF was present in serum from mineral oil-induced plasmacytoma-susceptible mice throughout the latent period potentially leading to tumour development, peaking around the time neoplastic cells were identified in ascites. Since mineral oil-induced granuloma is essential to development of immune ascites, involvement of EPF in this process was investigated. Active immunization of BALB/c mice with EPF was shown to suppress the production of immune ascites, induced by multiple i.p. injections of antigen in complete Freund's adjuvant. Of the mice immunized with EPF (n = 19), only 47% produced ascites, compared with 94% of mice receiving saline or human chorionic gonadotrophin and 100% of mice receiving keyhole limpet haemocyanin. Further investigations revealed that ascites was only produced in mice that maintained free-circulating EPF. These mice displayed the classic mineral oil-induced granuloma covering the tissues of the peritoneum. In contrast, the serum of mice that did not produce ascites tested negative for EPF and the peritonea of these mice were devoid of the oil granuloma. These studies suggest that EPF is involved in the initiation and maintenance of the inflammatory response of the peritoneum to mineral oil.

A synthetic thymic hormone, THF-gamma 2, repairs immunodeficiency of mice cured of plasmacytoma by melphalan.

BALB/c mice cured of large MOPC-315 plasmacytomas by melphalan remain deficient in their spleen T-cell functions. This was manifested by impairment of the allogeneic and the antibody responses in vitro to SRBC and in decreased numbers of T-cells including their subsets CD4 and CD8. IL-2 production and specific cytotoxicity against MOPC-315 tumor cells were, on the other hand, maintained. Treatment of these cured mice by in-vivo administration of THF-gamma 2, an octapeptide from calf thymus, repaired these deficits. This was evidenced by in vitro tests with spleen cells which manifested an increased allogeneic response and elevated generation of primary antibody response, restoration of T-cell subpopulations to normal and an enhanced IL-2 production above normal levels. The potential use of THF-gamma 2 as supportive therapy in cancer treatment is suggested.

Effectiveness of low-dose melphalan treatment against a nonimmunogenic primary induced mouse plasmacytoma.

The fourth i.p. passage of the plasmacytoma "PR" induced by repeated i.p. injections was used for testing chemotherapy with melphalan. The development of "PR" ascitic tumours was slower and the survival time of inoculated mice was longer than that of MOPC-315 inoculated mice. Moreover, the myeloma protein secreted by the "PR" tumour cells, differed from MOPC-315 secreted myeloma protein in its electrophoretic mobility (fast gamma-2) and its characteristics as IgG immunoglobulin. Chemotherapy by a single injection of melphalan 7.5 mg/kg was effective in preventing the development of both MOPC-315 ascitic tumours and "PR" ascitic tumours. Mice cured from MOPC-315 tumours, however, developed antitumour response as shown by resistance to challenge with a high tumourigenic dose and by development of cytotoxic response in vitro against MOPC-315 tumour cells by spleen cells taken from the cured mice. On the other hand, mice cured from "PR" tumour by melphalan were highly susceptible to challenge and their spleen cells were not able to develop a cytotoxic response in vitro against target "PR" tumour cells.

The difference between 5-fluorouracil and melphalan in their ability to promote antitumor immune response against MOPC-315 plasmacytoma.

The anticancer chemotherapeutic drugs melphalan (L-phenylalanine mustard; L-PAM), 5-fluorouracil (5-FU), methotrexate (MTX), and daunorubicin (DAU) were tested for their toxic activity against MOPC-315 tumor cells in vitro. L-PAM, 5-FU, and DAU had a marked toxic effect whereas MTX did not affect the rate of thymidine incorporation in the tumor cells. L-PAM (7.5 mg/kg) induced permanent regression of large s.c. MOPC-315 plasmacytoma tumors, 5-FU (200-250 mg/kg) induced transient regression of MOPC-315 tumors with reappearance starting on the 6th day after the 5-FU injection and DAU (5 mg/kg) was not effective. L-PAM treatment restored the cytotoxic potential of spleen cells of tumor-bearing mice against target MOPC-315 tumor cells whereas spleen cells from tumor-bearing mice treated with 5-FU were unable to mount a cytotoxic response. L-PAM and 5-FU were also assayed for their effect in vitro on induction of suppressor T cells by ConA. L-PAM treatment in vitro markedly reduced the induction of suppressor T cells by ConA whereas 5-FU had no effect. It is suggested that anticancer chemotherapeutic drugs can be classified in "immunopromoting" (L-PAM as prototype) and "nonimmunopromoting" (5-FU as prototype) on the basis of their effect in vivo on established tumors and their effect on induction of suppressor T cells by ConA.

[Dynamics of the immunodepressive and antitumor activity of adriamycin]. / Dinamika immunodepressivnoi i protivoopukholevoi aktivnosti adriamitsina.

It was revealed in experiments on mice that the immunodepressive activity of adriamycin depends exponentially on the dose of the preparation and is marked both before and after the antigen stimulation. The degree of immunodepression, the kinetics of formation and attenuation of the immune response depend on the dose of adriamycin. The preparation possesses antitumoral activity in relation to the plasmacytoma MOPC-315.

A simple method for efficiently establishing 8-azaguanine-resistant mutant human leukemia and myeloma cell lines.

A simple and convenient method for efficiently establishing 8-azaguanine-resistant mutant leukemia and myeloma cell lines (for example, the T cell lines Jurkat and CCRF-CEM, human myeloid/macrophage-like cell lines HL60 and U937, Burkitt lymphoma line Raji and the human myeloma line RPMI 8226), is described. The method relies on culturing the cell lines in RPMI 1640 medium containing 8-azaguanine and supplemented with 15% heat-inactivated fetal calf serum and large amounts of amino acids and vitamins, and removes the necessity for pretreatment with mutagenic reagents such as ethyl methylsulfonate or X-irradiation. The possibility of obtaining mutant cell lines using the method described here is about 15 times greater than using media without high levels of amino acids and vitamins. Hybridomas produced between mitogen-activated human peripheral blood lymphocytes and an 8-azaguanine-resistant Jurkat mutant cell line (established by this method) were shown to produce soluble T cell-derived macrophage activating factor (MAF)-like material.

Cyclophosphamide-induced appearance of immunopotentiating T-cells in the spleens of mice bearing a large MOPC-315 tumor.

Following low-dose cyclophosphamide (CY) therapy (15 mg/kg) of mice bearing a large MOPC-315 tumor, the suppressive activity of their Sephadex G-10-adherent spleen cells (primarily macrophages) is overcome. Accordingly, when Sephadex G-10-adherent spleen cells from CY-treated tumor-bearing mice are added to the in vitro immunization culture of normal spleen cells, they do not suppress but actually bring about the generation of an augmented level of antitumor cytotoxicity. The ability to enhance the generation of antitumor cytotoxicity appears in the Sephadex G-10-adherent spleen cell population by Day 5 post-CY therapy of tumor-bearing mice and persists for at least 55 days; no such immunopotentiation is observed following administration of a low dose of CY to normal mice. In order for the immunopotentiating cells from CY-treated tumor-bearing mice to be effective in enhancing the generation of antitumor cytotoxicity, they must be added to the immunization culture of normal spleen cells no later than Day 3 (out of the 5 days) post-culture initiation. The CY-induced immunopotentiating activity resides in the T-cells, as is evident from the following observations. The immunopotentiating activity was abolished when the Sephadex G-10-adherent spleen cell population from CY-treated tumor-bearing mice was depleted of T-cells by anti-Thy 1.2 plus complement but not when this adherent spleen cell population was depleted of macrophages by carbonyl iron and magnet. Moreover, the immunopotentiating activity was also present in a population of CY-treated tumor-bearer spleen cells highly enriched for T-cells by passage through nylon wool columns. Thus, low-dose CY therapy overcomes the immunosuppressive activity of macrophages and induces the appearance of T-cell-mediated immunopotentiating activity, thereby leading to the development of an augmented level of antitumor cytotoxicity that can cooperate effectively with the tumoricidal activity of CY in the eradication of a late-stage, large s.c. tumor and extensive metastases.

Levels of corticotropin releasing factor-like immunoreactivity in mammalian hypothalamic and extrahypothalamic brain tissue as determined with a monoclonal antibody to the ovine material.

A monoclonal antibody to ovine corticotropin releasing factor (CRF) has been produced by fusion of a non-producing plasmacytoma cell line P3U1 with spleen cells of Balb/c mice immunized with the synthetic 41 amino acid peptide coupled covalently with rabbit myosin by a heterobifunctional reagent, N-succinimidyl 3-(2-pyridyldithio) propionate. A total immunizing dose of 500 micrograms resulted in a highly specific, high-affinity antibody with a Ka of 0.15 x 10(12) M-1, which was used to establish a specific RIA with a sensitivity of 10 pg/tube. Levels of corticotropin releasing factor-like immunoreactivity (CRF-LI) in a pg/mg of hypothalamic tissue ranged from 4-10 in ovine, 2.5-8 in bovine, 47.5-67.5 in mouse and 2.3-20 in human tissue. Moreover, CRF-LI was widely distributed in extrahypothalamic mouse brain at concentrations approximately one half those seen in hypothalamus.

Phospholipid modification retards intracellular transport and secretion of immunoglobulin G1 by mouse MOPC-31c plasmacytoma cells.

The intracellular transport and secretion of immunoglobulin G1(IgG1) by mouse MOPC-31C plasmacytoma cells were analyzed from the viewpoint of the roles of phospholipids. The membrane phospholipids were modified by culturing cells in a medium supplemented with choline analogues, N,N'-dimethylethanolamine or N-monomethylethanolamine, and accordingly the membranes were enriched in phosphatidyl-N,N'-dimethylethanolamine or phosphatidyl-N-monomethylethanolamine (Maeda, M., Tanaka, Y. and Akamatsu, Y. (1980) Biochem. Biophys. Res. Commun. 96, 876-881). The modified cells were pulse-labeled with L-[35S]methionine and the secretion of labeled IgG1 was chased. Half of the IgG1 was exported to the extracellular medium 1-1.5 h and 2-3 h after synthesis by choline- and dimethylethanolamine-supplemented cells, respectively. However, most of the newly synthesized IgG1 was not secreted by monomethylethanolamine-supplemented cells, even after 5 h; it remained within the cells. The sensitivity of intracellular IgG1 to endoglycosidase H was examined for probing the movement of IgG1 from the rough endoplasmic reticulum to the Golgi complex. Half of the newly synthesized IgG1 acquired resistance to endoglycosidase H after 30-45 min, 1-1.5 h and 2-3 h in choline-, dimethylethanolamine- and monomethylethanolamine-supplemented cells, respectively. Thus, the transport of IgG1 was markedly retarded by the modification with choline analogues, dimethylethanolamine or monomethylethanolamine, at least in the following two processes, from the rough endoplasmic reticulum to the Golgi complex and from the Golgi to the outside of cells. Modification with monomethylethanolamine was more effective than that with dimethylethanolamine in slowing down the transport of IgG1 and appeared to cause accumulation of IgG1 within the cells. A morphological study was also carried out for the three kinds of cell. The roles of phospholipids in the processes of membrane flow are discussed.

Transplantation of primary plasma cell tumor without 2,6,10,14- tetramethylpentadecane (pristane) treatment of the hosts.

Small inocula of primary plasma tumor cells which do not transplant i.p. unless recipients are conditioned with pristane do so readily when recipients are given i.p. injections of a peritoneal exudate induced by pristane inoculating, but free of pristane.

Receptors on immunocompetent cells. V. Cellular correlates of the "maturation" of the immune response.

During the course of the immune response to dinitrophenylated guinea pig albumin (DNP-GPA), a striking and parallel increase in avidity for epsilon-DNP-L-lysine occurs in the receptors on antigen-binding lymphocytes, antibody secreted by individual plaque-forming cells, and serum antibody molecules. A detailed analysis of the avidity distribution of antibody produced by plaque-forming cells indicates that this "immunologic maturation" is primarily due to a preservation of the high avidity subpopulation and a striking loss in the low avidity population rather than to sequential appearance of these cells. Moreover, the demonstration of the increased avidity of receptors of antigen-binding lymphocytes, which appear to be precursors of antibody-synthesizing cells, strongly suggests that the antigen-driven selectional process operates primarily on this cell type.