TTYH3 is a prognostic biomarker and associates with immune cell infiltrations of lung adenocarcinoma / TTYH3 es un biomarcador pronóstico y se asocia con infiltraciones de células inmunitarias del adenocarcinoma de pulmón

SUMMARY: We investigated Tweety Family Member 3 (TTYH3) level in lung adenocarcinoma (LUAD) and its relationship with immune infiltration in tumors by bioinformatics. Differential expressions of TTYH3 in lung cancer were analyzed with Oncomine, TIMER, GEO, UALCAN and HPA. Relationship of TTYH3 mRNA/protein levels with clinical parameters was analyzed by UALCAN. Co-expressed genes of TTYH3 in LUAD were analyzed using Cbioportal. Its relationship with LUAD prognosis was analyzed by Kaplan-Meier plotter. GO and KEGG analysis were performed. Correlation between TTYH3 and tumor immune infiltration were tested by TIMER, TISIDB and GEPIA. We found that TTYH3 was significantly increased in LUAD tissues. TTYH3 high expression was closely related to poor overall survival, post progression survival and first progression in LUAD patients. TTYH3 mRNA/protein levels were significantly associated with multiple pathways. Specifically, TTYH3 up-regulation was mostly related to biological regulation, metabolic process, protein blinding, extracellular matrix organization and pathways in cancer. Moreover, TTYH3 was positively associated with immune cell infiltration in LUAD. Finally, TTYH3 was highly expressed in LUAD as revealed by meta-analysis. TTYH3 is closely related to the prognosis of LUAD and immune cell infiltration, and it can be used as a prognostic biomarker for LUAD and immune infiltration.

Investigamos por bioinformática el nivel de Tweety Family Member 3 (TTYH3) con adenocarcinoma de pulmón (LUAD) y su relación con la infiltración inmune en tumores. Las expresiones diferenciales de TTYH3 en cáncer de pulmón se analizaron con Oncomine, TIMER, GEO, UALCAN y HPA. Con UALCAN se analizó la relación de los niveles de ARNm/proteína de TTYH3 con los parámetros clínicos. Los genes coexpresados de TTYH3 en LUAD se analizaron utilizando Cbioportal. Su relación con el pronóstico LUAD se analizó mediante plotter de Kaplan- Meier. Se realizaron análisis GO y KEGG. TIMER, TISIDB y GEPIA probaron la correlación entre TTYH3 y la infiltración inmune tumoral. Encontramos que TTYH3 aumentó significativamente en los tejidos LUAD. La alta expresión de TTYH3 estuvo estrechamente relacionada con una supervivencia general deficiente, supervivencia posterior a la progresión y primera progresión en pacientes con LUAD. Los niveles de ARNm/ proteína de TTYH3 se asociaron significativamente con múltiples vías. Específicamente, la regulación positiva de TTYH3 se relacionó principalmente con la regulación biológica, el proceso metabólico, el cegamiento de proteínas, la organización de la matriz extracelular y las vías en el cáncer. Además, TTYH3 se asoció positivamente con la infiltración de células inmunitarias en LUAD. Finalmente, TTYH3 se expresó altamente en LUAD como lo reveló el metanálisis. TTYH3 está estrechamente relacionado con el pronóstico de LUAD y la infiltración de células inmunitarias, y se puede utilizar como biomarcador pronóstico para LUAD y la infiltración de células inmunitarias.

Tumor cell lysate with low content of HMGB1 enhances immune response of dendritic cells against lung cancer in mice / 南方医科大学学报

OBJECTIVE@#To assess the effect of tumor cell lysate (TCL) with low high-mobility group B1 (HMGB1) content for enhancing immune responses of dendritic cells (DCs) against lung cancer.@*METHODS@#TCLs with low HMGB1 content (LH-TCL) and normal HMGB1 content (NH-TCL) were prepared using Lewis lung cancer (LLC) cells in which HMGB1 was inhibited with 30 nmol/L glycyrrhizic acid (GA) and using LLC cells without GA treatment, respectively. Cultured mouse DCs were exposed to different doses of NH-TCL and LH-TCL, using PBS as the control. Flow cytometry was used to detect the expressions of CD11b, CD11c and CD86 and apoptosis of the stimulated DCs, and IL-12 levels in the cell cultures were detected by ELISA. Mouse spleen cells were co-cultured with the stimulated DCs, and the activation of the spleen cells was assessed by detecting CD69 expression using flow cytometry; TNF-β production in the spleen cells was detected with ELISA. The spleen cells were then co-cultured with LLC cells at the effector: target ratios of 5:1, 10:1 and 20:1 to observe the tumor cell killing. In the animal experiment, C57/BL6 mouse models bearing subcutaneous LLC xenograft received multiple injections with the stimulated DCs, and the tumor growth was observed.@*RESULTS@#The content of HMGB1 in the TCL prepared using GA-treated LLC cells was significantly reduced (P < 0.01). Compared with NH-TCL, LH-TCL showed a stronger ability to reduce apoptosis (P < 0.001) and promote activation and IL- 12 production in the DCs. Compared with those with NH-TCL stimulation, the DCs stimulated with LH-TCL more effectively induced activation of splenic lymphocytes and enhanced their anti-tumor immunity (P < 0.05). In the cell co-cultures, the spleen lymphocytes activated by LH-TCL-stimulated DCs showed significantly enhanced LLC cell killing activity (P < 0.01). In the tumor-bearing mice, injections of LH-TCL-stimulated DCs effectively activated host anti-tumor immunity and inhibited the growth of the tumor xenografts (P < 0.05).@*CONCLUSION@#Stimulation of the DCs with LH-TCL enhances the anti-tumor immune activity of the DCs and improve the efficacy of DCbased immunotherapy for LLC in mice.

The halo sign: HRCT findings in 85 patients / Sinal do halo: achados de TCAR em 85 pacientes

ABSTRACT Objective: The halo sign consists of an area of ground-glass opacity surrounding pulmonary lesions on chest CT scans. We compared immunocompetent and immunosuppressed patients in terms of halo sign features and sought to identify those of greatest diagnostic value. Methods: This was a retrospective study of CT scans performed at any of seven centers between January of 2011 and May of 2015. Patients were classified according to their immune status. Two thoracic radiologists reviewed the scans in order to determine the number of lesions, as well as their distribution, size, and contour, together with halo thickness and any other associated findings. Results: Of the 85 patients evaluated, 53 were immunocompetent and 32 were immunosuppressed. Of the 53 immunocompetent patients, 34 (64%) were diagnosed with primary neoplasm. Of the 32 immunosuppressed patients, 25 (78%) were diagnosed with aspergillosis. Multiple and randomly distributed lesions were more common in the immunosuppressed patients than in the immunocompetent patients (p < 0.001 for both). Halo thickness was found to be greater in the immunosuppressed patients (p < 0.05). Conclusions: Etiologies of the halo sign differ markedly between immunocompetent and immunosuppressed patients. Although thicker halos are more likely to occur in patients with infectious diseases, the number and distribution of lesions should also be taken into account when evaluating patients presenting with the halo sign.

RESUMO Objetivo: O sinal do halo consiste em uma área de opacidade em vidro fosco ao redor de lesões pulmonares em imagens de TC de tórax. Pacientes imunocompetentes e imunodeprimidos foram comparados quanto a características do sinal do halo a fim de identificar as de maior valor diagnóstico. Métodos: Estudo retrospectivo de tomografias realizadas em sete centros entre janeiro de 2011 e maio de 2015. Os pacientes foram classificados de acordo com seu estado imunológico. Dois radiologistas torácicos analisaram os exames a fim de determinar o número de lesões e sua distribuição, tamanho e contorno, bem como a espessura do halo e quaisquer outros achados associados. Resultados: Dos 85 pacientes avaliados, 53 eram imunocompetentes e 32 eram imunodeprimidos. Dos 53 pacientes imunocompetentes, 34 (64%) receberam diagnóstico de neoplasia primária. Dos 32 pacientes imunodeprimidos, 25 (78%) receberam diagnóstico de aspergilose. Lesões múltiplas e distribuídas aleatoriamente foram mais comuns nos imunodeprimidos do que nos imunocompetentes (p < 0,001 para ambas). A espessura do halo foi maior nos imunodeprimidos (p < 0,05). Conclusões: As etiologias do sinal do halo em pacientes imunocompetentes são bastante diferentes das observadas em pacientes imunodeprimidos. Embora halos mais espessos ocorram mais provavelmente em pacientes com doenças infecciosas, o número e a distribuição das lesões também devem ser levados em conta na avaliação de pacientes que apresentem o sinal do halo.

Acarbose versus trans-chalcone: comparing the effect of two glycosidase inhibitors on obese mice

Objective Acarbose and trans-chalcone are glucosidase inhibitors whose beneficial effects have been demonstrated in diabetes. The present study aimed at investigating their potential effects in obesity.Materials and methods NMRI male mice (n = 48) were subjected to a high fat diet for four weeks, which induced an initial state of obesity. One control group was given normal rodent diet. Obese animals were then switched to normal rodent diet, and divided to four groups (n = 12 in each): untreated, sham (receiving grape seed oil), and experimental groups receiving acarbose and trans-chalcone (12 mg/kg) during eight weeks. Body weight, blood glucose and other biochemical parameters including triglycerides (TG), cholesterol, HDL, AST, and ALT were measured, as well as leptin, adiponectin, TNF-α, and total antioxidant capacity (TAC). Histological studies were performed on adipose cells and liver tissue samples.Results All factors were affected in a positive manner by acarbose, save for body weight, blood sugar and leptin levels, on which acarbose effects, although observable, were not statistically significant. Grape seed oil, used as a solvent for trans-chalcone was found to possess significant effect on TG and TAC, and had beneficial effects on other factors including liver enzymes and cholesterol. Trans-chalcone effects were significant on HDL, leptin and ALT. All compounds seemed to be able to affect fat deposition in liver tissue, and decrease the size of adipose tissue cells to some extent.Conclusion In conclusion, the tested compounds were able to affect lipid accumulation in tissues and influence adipokines, which may result in an enhanced state with regard to inflammation and oxidative stress. Arch Endocrinol Metab. 2015;59(3):202-9.

Myeloid-derived suppressor cells and associated events in urethane-induced lung cancer

OBJECTIVES: Myeloid-derived suppressor cells contribute to the immunosuppressive microenvironment during tumor development and limit the efficacy of cancer immunotherapy. Identifying myeloid-derived suppressor cells and associated factors is the first step in creating strategies to reverse the suppressive effects of these cells on the immune system. METHODS: To induce lung cancer, we administered 2 doses of urethane to BALB/c mice and observed these animals for 120 days. After this period, we evaluated the percentage of myeloid-derived suppressor cells in the blood, lung and bone marrow. The expression of alpha-smooth muscle actin, transforming growth factor-β, Toll-like receptor 2, Toll-like receptor 4, and interleukin-6 was also determined in the lung tissue. RESULTS: Myeloid-derived suppressor cells were increased in all evaluated tissues after lung cancer development in association with increased Toll-like receptor 4 expression and decreased interleukin-6 expression in the lung. We observed alpha-smooth muscle actin and transforming growth factor-β expression in lung nodules. CONCLUSIONS: We believe that the early diagnosis of cancer through determining the blood levels of myeloid-derived suppressor cells followed by the depletion of these cells should be further investigated as a possible approach for cancer treatment. .

Papel da imuno-histoquímica no diagnóstico do câncer de pulmão: [revisão] / Role of immunohistochemistry in the diagnosis of lung cancer: [review]

O propósito da imuno-histoquímica é reconhecer antígenos e assim identificar e classificar células específicas dentro de uma população celular morfologicamente heterogênea (ou aparentemente homogênea). A visualização do complexo antígeno-anticorpo é possível pela adição de um fluorocromo conjugado ao anticorpo, que pode então ser observado ao microscópio, ou alternativamente uma enzima, cujo produto de reação pode igualmente ser visualizado. A imuno-histoquímica pode ser aplicada na rotina diagnóstica complementar do câncer de pulmão para a identificação de marcadores biológicos diagnósticos e prognósticos. Os painéis imuno-histoquímicos mínimos necessários para a complementação diagnóstica serão discutidos nesta revisão.

The role of immunohistochemistry is to recognize antigens and, consequently, to identify and classify specific cells within a cell population whose morphology is heterogenous or apparently homogenous. The visualization of the antigen-antibody complex is made possible through the addition of either a fluorochrome conjugate or an enzyme to the antibody, which is then viewed under microscopy. Immunohistochemistry can be used in the routine diagnosis of lung cancer, in order to identify biological markers (diagnostic and prognostic). The essential immunohistochemistry panels will be discussed in this review.

Avaliação clínica e laboratorial da trombose venosa em pacientes com câncer de pulmão / Clinical and laboratory evaluation of venous thrombosis in patients with lung cancer

INTRODUÇÃO: A trombose é um fenômeno frequente nos pacientes portadores de neoplasias e está relacionada com o prognóstico dos mesmos. No entanto, até os dias de hoje, a real incidência de trombose e os mecanismos relacionados ainda não estão totalmente elucidados. MÉTODOS: O presente estudo acompanhou, de forma prospectiva e consecutiva, 120 pacientes portadores de adenocarcinoma de pulmão em diferentes estágios da doença. Nestes pacientes foram testados ao diagnóstico e a cada 6 meses, marcadores da coagulação (TAP, PTT, fibrinogênio, D-dímero, proteína C, antitrombina, fatores (VIII e IX) e plaquetas) além de parâmetros imunológicos (presença de anticorpos anticardiolipina, anticoagulante lúpico, anti B2 glicoproteína l, níveis de interleucinas (1 e 6) e fator de necrose tumoral). Os mesmos foram acompanhados a cada 3 meses (no caso de sintomas) com pesquisa de trombose em membros inferiores e superiores (e no caso de suspeita, pesquisa de embolia pumonar). Daqueles pacientes dos quais se obteve o bloco de diagnóstico, também foi feito estudo da expressão de fator tecidual e receptores PAR1. RESULTADOS: Trombose foi um evento frequente (24% dos pacientes) e esteve relacionada com uma pior sobrevida. Em análise univariável, a presença de altos níveis de interleucina-6, fatores VIII e IX, fibrinogênio, além de presença de anticorpo anticoagulante lúpico, estiveram relacionados com o aumento de eventos trombóticos. Porém, em análise multivariável, apenas o anticoagulante lúpico manteve-se como fator de risco. Por outro lado, a presença de anticorpos anti B2 glicoproteína l do tipo IgM não só reduziu o risco de eventos trombóticos como também aumentou a sobrevida dos pacientes. A presença da expressão de fator tecidual esteve mais frequente nas fases avançadas da doença, enquanto a expressão de PAR foi maior em estados iniciais. Ambos não mostraram influenciar de forma significativa o risco de trombose e mortalidade...

INTRODUCTION: Thrombosis is a frequent event on cancer patients and are related to their prognosis. However, until now the real incidence and their mechanism are still not fully elucidated. METHODS: We studied prospectively and consecutively 120 patients with lung adenocarcinoma in different disease stages. Those patients made blood evaluation at diagnosis and each 6 month each for clotting (TAP, TPP, fibrinogen, D-dimmer, Protein C, antithrombin, platelets and clotting factors VIII and IX) than immunologic markers (anticardiolipin antibodies, lupus anticoagulant, anti B2 glicoproteín I, interleukin 1 and 6 and Tumor Necrosing Factor Levels). The same patients were submitted to limb and arms Doppler scan each 3 month to screening for thrombosis and if suspected of pulmonary embolism it was screened). From those patients of witch paraffin block of tumor biopsy were obtained, immunohistochemical analysis were made to detect tissue factor and PAR1 expression. RESULTS: Thrombosis were a frequent event (24% of patients), and were related to survival (independently if symptomatic or not). Univariable analysis showed that high levels of interleukin 6, fibrinogen, factors VIII or XI and lupus anticoagulant detection increases thrombosis risk. However in multivariable analysis, only lupus anticoagulant antibodies maintain as risk factor of thrombosis. But, despite be from antiphospholipid family, IgM anti B2 glicoproteín l decreased thrombosis risk and increase patients' survival as compared for those patients without those antibodies. Tissue factor expression was more evident on advanced stage of disease and PAR expression in early stages. However neither tissue factor nor PAR changes in a significantly manner patient's survival (however, the number of patients samples studied is small). CONCLUSION: Venous thrombosis is very frequent in lung adenocarcinoma patients. In our study, we show interaction between both systems (clotting and immunologic)...

Sarcoma sinovial monofásico primario de pulmón: reporte de un caso y revisión de la literatura / Single primary synovial sarcoma of the lung: a case report and review of the literature

El sarcoma sinovial es una entidad morfológica, clínica y genéticamente distinta y se puede apreciar en cualquier ubicación. Es un tumor mesenquimal de células fusiformes con una diferenciación epitelial variable. No existe una terapia estandarizada, generalmente el tratamiento es quirúrgico, con una resección total de la lesión, aplicándose en algunos casos radioterapia adyuvante. Los sarcomas sinoviales han mostrado quimiosensibilidad a la ifosfamida y a la doxorrubicina con una respuesta aproximada del 24 por ciento. Se presenta caso de una paciente de 32 años de edad quien presenta tumor en lóbulo inferior de pulmón izquierdo. Se le realizan estudios de extensión, paraclínicos y biopsia por punción dirigida por fluoroscopia que reportó neoplasia epitelial maligna poco diferenciada. Se diagnostica como cáncer de pulmón estadío I realizándose lobectomía inferior izquierda cuya biopsia y estudios inmunohistoquímicos diagnostica un sarcoma sinovial monofásico. Evoluciona satisfactoriamente refiriéndose a los servicios de oncología médica y radioterapia para tratamiento adyuvante.

Synovial Sarcoma is morphologic, clinical organization and genetically different and is possible to be appreciated in any location. Is mesenquimal tumor fusiform cell with variable epithelial differentiation. Treatment, standardized therapy does not exist; the treatment is generally surgical, with total resection of the injury, being applied in some cases adjuvant radiotherapy. Synovial sarcomas has shown chemo sensibility to ifosfamide one and doxorrubicin with an approximated answer of 24 %. A case of a patient of 32 years of age appears that presents displays tumor in inferior lobe of left lung. Studies of extension, paraclinics are made to him and biopsy by punction directed by fluoroscopy that reported neoplasia epithelial vitiates little differentiated. It is diagnosed as lung cancer stage I being made left inferior lobotomy whose inmunohystochemestry biopsy and studies diagnose Synovial sarcoma single-phase. It evolves satisfactorily talking about to the services of medical oncology and radiotherapy for adjuvant treatment.

value of immunohistochemical expression of TTF-1, CK7 and CK20 in the diagnosis of primary and secondary lung carcinomas

To study the value of immunohistochemical staining of thyroid transcription factor-1 TTF-1, cytokeratin 7 CK7, and cytokeratin 20 CK20 in the differentiation between primary and secondary pulmonary carcinomas. Forty-three cases of lung carcinoma, 14 squamous cell carcinoma, 12 adenocarcinoma, 8 small cell carcinoma, 3 mesothelioma, and 6 metastatic tumors, were collected from the files of the Pathology Department, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia between 2004 and 2006. All cases were stained immunohistochemically following Avidin biotin method using monoclonal antibodies to TTF-1, CK7, and CK20. Immunohistochemical staining of 43 cases of lung carcinoma revealed nuclear immunoreactivity for TTF-1 in all primary adenocarcinoma, and small cell carcinoma, while cases of squamous cell carcinoma were negative. Mesotheliomas were negative to TTF-1, CK7, and CK20. Metastatic tumors except for one case metastatic from the thyroid gland were negative to TTF-1. Cytokeratin 7 was positively expressed in primary tumors of lung, as well as metastatic tumors from the thyroid and breast. Cytokeratin 20 was negative in all primary lung tumors, while positive in metastatic carcinomas from the colon. Thyroid transcription factor-1 is a sensitive marker for diagnosis of primary pulmonary adenocarcinoma, and differentiation between poorly differentiated squamous cell carcinoma and small cell carcinoma and adenocarcinoma. Cytokeratin 20 could be a marker for metastatic tumors from the colon to the lung since it was negative in all primary lung tumors

Imunofenotipagem e rearranjo gênico em doenças pulmonares linfocíticas e linfoproliferativas / Immunophenotyping and gene rearrangement analysis in lymphoid/lymphoproliferative disorders of the lungs

OBJETIVO: Determinar a utilidade, na prática rotineira, da análise da clonalidade dos linfócitos T e B nos tecidos pulmonares por reação em cadeia da polimerase no diagnóstico das doenças linfoproliferativas pulmonares. MÉTODOS: Avaliaram-se, mediante análise imunohistoquímica e rearranjo molecular dos genes, 8 casos de pneumonia intersticial linfocítica (PIL) e 7 casos de doenças linfoproliferativas pulmonares. RESULTADOS: Todos os 8 casos de PIL expressaram imunocoloração moderada a forte para CD3, em contraste com apenas 2 casos de linfoma e 1 caso de pseudolinfoma. Rearranjo gênico foi detectado em 4 de 8 casos de PIL, o que mudou o diagnóstico de PIL para linfoma, indicando, assim, a importância da detecção de rearranjo gênico em casos de PIL. Nesta situação, rearranjo gênico usando-se os pares de primers VH/JH e Vgama11/Jgama12 foi detectado em 3 e 1 casos de PIL, respectivamente, e não foram detectadas anormalidades gênicas usando-se as pares Dbeta1/Jbeta2 e Vgama101/Jgama12. Uma associação positiva foi detectada entre a intensidade de imunoexpressão CD20 e CD68 e rearranjo gênico usando-se o par de primers VH/JH. Antes do rearranjo gênico, 4 pacientes com PIL morreram rapidamente, enquanto que, após o rearranjo gênico, apenas 1 paciente com PIL morreu. CONCLUSÕES: A detecção de células B e T monoclonais por imunofenotipagem e reação em cadeia da polimerase mostrou impacto no diagnóstico de linfomas pulmonares em pacientes previamente diagnosticados com PIL. Portanto, imunofenotipagem e reação em cadeia da polimerase devem ser incluídas como métodos de 'padrão ouro' na rotina diagnóstica.

OBJECTIVE: To determine the usefulness, in routine practice, of using polymerase chain reaction to analyze B and T lymphocyte clonality in pulmonary tissue as a tool for the diagnosis of pulmonary lymphoproliferative disorders. METHODS: Immunohistochemistry and molecular gene rearrangement analysis were performed in order to assess 8 cases of lymphoid interstitial pneumonia (LIP) and 7 cases of pulmonary lymphoproliferative disorders. RESULTS: All 8 cases of LIP presented moderate to strong immunostaining for CD3, compared with only 2 cases of lymphoma and 1 case of pseudolymphoma (p = 0.02). Gene rearrangement was detected in 4 of the 8 cases, which changed the diagnosis from LIP to lymphoma, showing the importance of gene rearrangement detection in cases of LIP. In this situation, gene rearrangement using the VH/JH and Vgamma11/Jgamma12 primer pairs was detected in 3 cases and 1 case, respectively, and no gene abnormalities were found using the Dbeta1/Jbeta2 and Vgamma101/Jgamma12 primer pairs in any of the cases. A significant positive association was found between the intensity of CD20 and CD68 expression and gene rearrangement using the VH/JH primer pair. Prior to the gene rearrangement, 4 patients with LIP died quickly, whereas only one patient with LIP died after the gene rearrangement. CONCLUSIONS: Detection of monoclonal B and T cells by immunophenotyping and polymerase chain reaction had an impact on the diagnosis of pulmonary lymphomas in patients previously diagnosed with LIP. Therefore, immunophenotyping and polymerase chain reaction should be used as 'gold standard' techniques in routine practice.

Antitumor immunity induced by tumor cells engineered to express a membrane-bound form of IL-2

Transduction of cytokine gene into tumor cells is a promising method of tumor therapy, but the value is limited by accompanying side effects. To focus antitumor immune response to tumor antigen-specific CTL, we developed an antitumor vaccine by transfecting modified IL-2 gene in a membrane-bound form (mbIL-2) into B16F10 melanoma cells. The mbIL-2 clone showed reduced tumorigenicity and metastatic ability, and inhibited metastasis and prolonged the survival of mice against B16F10 cells. The inhibition of B16F10 metastasis by mbIL-2 was accompanied by the increment of CD8+ T cells. The metastasis of mbIL-2 clone was significantly increased in the CD8+ T cell-depleted mice, but not in CD4+ T cell depleted mice. Spleen cells immunized with the mbIL-2 clone showed higher CTL activity towards B16F10 cells than those immunized with control cells. The size of CD8+ T cell population in the lung of mice injected with the mbIL-2 clone was markedly greater than that of mice injected with B16F10 cells, but there was no detectible change in CD4+ and CD8+ T cell populations of lymph nodes and spleen. These results suggest that when the mbIL-2 clone is introduced into the blood stream, it migrates mainly to lung and activates CD8+ T cells in situ, possibly by direct priming. Such a tumor vaccine may ameliorate the toxic side effects encountered with conventional cytokine gene therapy.

Activated natural killer cell-mediated immunity is required for the inhibition of tumor metastasis by dendritic cell vaccination

Immunization with dendritic cells (DCs) pulsed with tumor antigen can activate tumor-specific cytotoxic T lymphocytes (CTL), which is responsible for tumor protection and regression. In this study, we examined whether DCs pulsed with necrotic tumor lysates can efficiently prevent malignant melanoma tumor cell metastasis to the lung. DCs derived from mouse bone marrow were found to produce remarkably elevated levels of IL-12 after being pulsed with the tumor lysates. Moreover, immunization with these DCs induced CTL activation and protected mice from metastasis development by intravenously inoculated tumor cells. In addition, these DCs activated NK cells in vitro in a contact-dependent manner, and induced NK activities in vivo. Furthermore, NK cell depletion before DC vaccination significantly reduced the tumor-specific CTL activity, IFN-g production, and IFN-gamma- inducible gene expression, and eventually interfered with the antitumor effect of tumor-pulsed DCs. Finally, similar findings with respect to NK cell dependency were obtained in the C57BL/ 6J-bg/bg mice, which have severe deficiency in cytolytic activity of NK cells. These data suggest that the antitumor effect elicited by DC vaccination, at least in a B16 melanoma model, requires the participation of both cytolytic NK and CD8+ T cells. The findings of this study would provide important data for the effective design of DC vaccines for cancer immunotherapy.

Natural killer activity and antibody-dependent cellular cytotoxicity in patients with primary lung cancer

The NK activity and ADCC of peripheral blood mononuclear cell were examined to evaluate the contribution of ADCC and NK activity to host immune response against lung cancer. The NK activity and ADCC were examined in 58 patients with primary lung cancer and 40 healthy volunteers as normal controls. The NK activity of patients with lung cancer was significantly subnormal, but ADCC was at a normal level. The NK activity was decreased in non-small cell lung cancer (NSCLC), but not in small cell lung cancer (SCLC) compared to normal controls. According to stage, the NK activity in stage II, III-M0 and III-M1 NSCLC showed low levels compared to that of stage I NSCLC, but there was no difference of NK activity in patients with SCLC. The NK activity was not affected by performance status. There was no significant difference of ADCC in patients with lung cancer according to cell type, stage and performance compared with that of normal controls. The NK activity and ADCC were not changed after chemotherapy and operation respectively.

Reduction of interleukin 1 and interleukin 2 production by patients with advanced cancer

The concentrations of interleukin 1 (IL-1) and interleukin 2 (IL-2) produced in the supernatants of peripheral blood mononuclear cell cultures from patients with advanced cancer were measured to identify some of the causes of the immunological impairment characteristic of malignant disease. Mononuclear cells obtained from 19 cancer patients were stimulated to produce IL-1 and IL-2 and compared with those of healthy controls. A severe reduction of both IL-1 and IL-2 activity was observed. There was no correlation between the lower number of OKT4+ cells observed in these patients and the levels of IL-2 production. The removal of monocytes did not bring IL-2 levels to normal. Impaired IL-2 production could not be restored to normal by addition of IL-1. These results suggest that exogenous IL-01 and IL-2 may be useful in cancer immunotherapy

Primary well differentiated lymphocytic lymphoma of the lung: a clinical and immunohistochemical study of four cases

Four cases of well differentiated lymphocytic lymphoma with or without plasmacytoid differentiation of the lung are described. Two cases were single and the others were multiple. Histologic pictures of the lesion showed mass with perivascular, interstitial and alveolar extension in three cases and only interstitial and perivascular involvement in one. Histologically three cases were lymphoplasmacytic lymphoma and one was small lymphocytic lymphoma. Dutcher bodies, granulomas and germinal centers were also found in tumors. Immunohistochemical study revealed monoclonal lymphocytic proliferation in all cases in fresh frozen sections and in three in paraffin sections. Treatment is surgical resection. Chemotherapy is used for residual disease after surgery.