The use of natural killer cell activity and PPD test in the prediction of results in intravesical BCG treatment of patients with nonmuscle-invasive bladder cancer.

PURPOSE: To predict the efficacy of intravesical BCG therapy in patients with nonmuscle-invasive bladder tumors (NIBC) by using components of the cellular immune response such as the tuberculin skin test (PPD) and natural killer (NK) activity measurement. METHODS: Ninety-nine patients who were started on intravesical BCG therapy for NIBC were evaluated prospectively. Patients who were included in the intermediate, high, and very high-risk groups according to the EAU NMIBC Scoring System and who had never received intravesical BCG therapy previously were included. The clinical and demographic characteristics of the patients (age, gender, EAU NMBIC risk group, EORTC progression and recurrence scores, CUETO progression and recurrence scores, presence and types of comorbidity) were recorded. NK activity was measured and the PPD test was applied 3 days before the start of intravesical BCG therapy. The results of PPD were measured in millimeters 72 h after the test. RESULTS: PPD values measured before BCG treatment, as an independent variable, were found to be significantly lower in patients with recurrence. A significant correlation was detected between NK activity results obtained before BCG treatment and recurrence after treatment, when the cutoff was 200-500 pg/dl. There was no significant relationship between the time to recurrence and PPD and NKA measurements. CONCLUSION: We conclude that the results of PPD test and NK activity measurement performed before starting intravesical BCG therapy in NIBC may be a marker that can be used to predict the risk of recurrence under treatment.

Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain.

Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST-/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36-0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20-440) per 100,000 person-years), both probable de novo infections. CONCLUSION: A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective. WHAT IS KNOWN: • The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain. • Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease. WHAT IS NEW: • A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone. • Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.

[The study of ocular tuberculosis during the 19th and early 20th century].

During the 19th and early 20th century the achievements in the study of ocular tuberculosis were of great significance. The development of pathological anatomy in those years helped physicians to understand the histological image and the pathophysiology of the disease and allowed the scientists to detect the specific anatomical structures of the eye, where the disease could be present. The physicians of those years tried to describe the clinical image of the disease and to give value information, in order to facilitate the diagnosis. Despite major efforts made in the field of clinical approach to ocular tuberculosis, the treatment of the disease in those years was not very effective. Nevertheless, the physicians of the time used every new pharmacological or not pharmacological treatment to fight the disease.

A phase I study on combined therapy with proton-beam radiotherapy and in situ tumor vaccination for locally advanced recurrent hepatocellular carcinoma.

BACKGROUND: Proton-beam radiotherapy (PBT) has been shown to be effective to hepatocellular carcinoma (HCC) as a nonsurgical local treatment option. However, HCC still remains as one of the most difficult cancers to be cured because of frequent recurrences. Thus, methods to inhibit the recurrence need to be explored. To prevent the HCC recurrence, we here report on a prospective phase I study of 'in situ' tumor vaccination using CalTUMP, a newly developed immunoadjuvant consisting of BCG extract bound to hydroxyapatite and microparticulated tuberculin, following local PBT for HCC. METHODS: Patients with locally advanced recurrent HCC, which had been heavily pretreated with various treatments, were enrolled. PBT was performed with the conventional method to the target HCC. Subsequently, CalTUMP was injected into the same irradiated-tumor three times at one-week intervals. Three dose-levels of CalTUMP (1/10, 1/3, and 1/1) were administered to 3 patients each. Vital signs, blood samples, ultrasound, and computed tomographic scans were monitored to evaluate the safety. RESULTS: Three intratumoral injections of CalTUMP following PBT (median dose: 72.6 GyE) were accomplished in 9 patients. Transient low-grade fever and minor laboratory changes were observed in 7 patients after CalTUMP injections. No other treatment-related adverse events were observed. Median progression-free survival was 6.0 months (range: 2.1-14.2) and 4 patients were progression-free for more than 1 year. CONCLUSIONS: Intratumoral injection of CalTUMP following PBT was feasible and safe in patients with heavily pre-treated HCC. Further clinical studies to evaluate the efficacy of this in situ tumor vaccination are warranted.

Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women.

Immunotherapy for treatment of recalcitrant warts was used through different modalities including intralesional injection of purified protein derivative (PPD), which is an extract of Mycobacterium tuberculosis, used for testing exposure to tuberculin protein, either from a previous vaccination or from the environment. This method is used to evaluate the efficacy of a new approach of intradermal injection of PPD in the treatment of anogenital warts in pregnant women. A total of 40 pregnant women, aged 20-35 years, and presented with anogenital warts were enrolled in this study. Human papillomavirus (HPV) typing was done using the GP5+/GP6+ PCR assay. The patients were treated with weekly injections of PPD given intradermally in the forearms, and evaluated for the response regularly. HPV type-6 was the predominant genotype (67.5%). Overall, the improvement in this study was 85% and was related to the extent of tuberculin reactivity. Nineteen (47.5%) patients demonstrated complete clearance, 15 (37.5%) had partial response, and three (7.5%) had minimal response. Three (7.5%) cases did not respond to treatment. Side effects were minimal and insignificant. Treatment of anogenital warts in pregnant women with intradermal injection of PPD was found to be a unique, safe, and effective modality of immunotherapy.

Tubercúlides: revisão sobre tema polêmico / Tuberculids: revision on controversial theme

Tubercúlides representam uma forma de reação de hipersensibilidade a antígenos bacterianos liberados de um foco de infecção distante. A maioria dos pacientes é caracterizada por apresentar PPD forte reator e evidência de passado de tuberculose pulmonar e(ou) contactante. O tratamento é baseado na terapia de dessensibilização com tuberculina, drogas antituberculosas e corticóides.

Tuberculids represent a form of hypersensitivity reaction to tuberculosis antigens released from a distant focus of infection. Most of patients are characterized by displaying a markedly positive Mantoux skin test and evidence of past tuberculosis infection or contacts of patient with tuberculosis. The treatment is based on tuberculin desensitizing therapy, antituberculous drugs and corticosteroids.

Prognostic value of tuberculin and BCG immunoreactivity in stage I high-risk malignant melanoma (EORTC protocol 18781).

BACKGROUND: Since the immune system is considered to be a major determinant in the outcome of malignant melanoma, vaccination with BCG (bacillus Calmette-Guérin) or more recently with interleukins is used in this condition, although the effects of this immunotherapy are unclear. OBJECTIVE: The present study was to elucidate clinical aspects and the prognostic relevance of the cellular and humoral immune responses of melanoma patients treated with two different BCG vaccines. METHODS: A subgroup of patients from a multicenter adjuvant trial with BCG in stage I (pT3-4N0M0) high-risk melanoma was prospectively subjected to detailed analysis regarding tuberculin (PPD, purified protein derivate) skin test reactivity, local, regional and systemic reactions to BCG vaccination, PPD antibody response and disease-free survival. Patients were randomized into three arms and received either no adjuvant treatment (22 patients), BCG RIV (40 patients) or BCG Pasteur (44 patients). All patients were followed for up to 10 years (median follow-up 6 years). RESULTS: Patients treated with BCG Pasteur mounted a stronger antibody response, experienced stronger regional and systemic reactions to vaccination and converted more frequently to positive PPD skin tests, compared to controls and to patients vaccinated with BCG RIV. All BCG-treated patients who developed an antibody response had a longer disease-free interval (p = 0.05), with slightly higher significance for BCG Pasteur-treated patients (p = 0.02). CONCLUSIONS: Cellular as well as humoral immune responses to PPD and BCG thus identify stage I malignant melanoma patients with an overall better prognosis.

Respuesta a la tuberculina en escolares de Barquisimeto / Answer to the tuberculin in scholastics in Barquisimeto

Se practicó la prueba de Mantoux en 194 escolares de 6 a 12 años de edad de Barquisimeto para evaluar la respuesta al PPD en ralación con la vacunación BCG y el estado nutricional. Se encontraron 23 (11,06 por ciento)escolares sin vacunación y 171 (88,14 por ciento) vacunados y se consideraron sólo 167 con una cicatriz del BCG para evaluar la vacunación del nacimiento. La repuesta negativa al PPD fue alta en vacunados (94,01 por ciento) y no vacunados (86,96 por ciento) y positiva en 2 (1,20 por ciento) vacunados, con un tamaño promedio de induración similar (p>0,05 entre ambos grupos. El 18,05 por ciento de escolares fueron desnutridos y no presentaron diferencia (p>0.05) respecto al porcentaje de reactores y tamaño de induración al PPD con los escolares normales. En conclusión, el BCG del nacimiento no es efectivo, en términos de reactividad tuberculínica, después de los 6 años de edad y el estado nutricional de los escolares no alteró la respuesta al PPD.

Um caso de angeíte tuberculosa? / One case of tuberculosis angiitis?

O caso clínico aqui relatado refere-se a uma paciente com diagnóstico clínico-patológico de vasculite liverdóide, apresentando eritema nodoso, história de contato com tuberculose, PPD forte reator e resposta positiva à dessensibilizaçäo com tuberculina. A ausência de outros sinais clínicos ou alteraçöes laboratoriais que sugiram outra etiologia e a pouca resposta a outros tipos de tratamento por parte da paciente também reforçam a hipótese de tuberculose. Entretanto, com näo houve remissäo permanente do quadro, consideramos tratar-se de uma paciente hiperégica, na qual a vasculite livedóide e o eritema nodoso säo manifestaçöes de reaçäo de hipersensibilidade a vários antígenos, incluindo do M.tuberculosis

Reacción tuberculina en niños asegurados menores de un año: comparación de calidad del PPD y dosis de vacuna aplicada / Determinate tuberculin in children: compare the quality of National PPD Vs. Import PPD and to vacune BCG

Para contribuir a esclarecer las controversias sobre la utilidad de la Vacuna BCG y del PPD, realizamos la presente investigación con los objetivos de determinar la prevalencia de respuesta Tuberculínica en Niños menores de un año vacunados con BCG; comparar la calidad del PPD Nacional Vs. PPD Importado, y determinar la relación: dosis de Vacuna BCG y negatividad de respuesta tuberculínica. El estudio se efectuó en dos aspectos. Evaluación de calidad del PPD en 66 niños vacunados, aplicándose en forma aleatoria el tipo de PPD; Evaluación de dosis de vacuna con dos grupos BCG 1cc (72 niños) y otro BCG 0.05 cc (48 niños), todos los niños nacidos en el Hospital y Vacunados en las primeras semanas de vida. Los resultados indican que no existe diferencia significativa entre PPD Nacional e Importado, ni entre dosis de Vacuna BCG (0.1-0.05cc) confirmándose la alta negatividad Tuberculínica 90-94 por ciento en Niños asegurados menores de un año vacunados con BCG.

Síndrome de hiperreatividade tuberculínica: revisäo e estudo de novos casos / Tuberculinic hiperreativity syndrome: review and study of new cases

Os autores, baseados em experiência de 28 casos selecionados, abordam um tema bastante polêmico - as síndromes de hiperreatividade tuberculínica (SHT). Procuram enfocar dentro do contexto clínico-tuberculínico, as peculiaridades mais exuberantes e significativas, objetivando, com isto, conglomerar parâmetros patodiagnósticos destas entidades alergo-bacterianas, visando a um posicionamento clínico definitivo e a um tratamento hipossensibilizante à luz dos novos conhecimentos da quimioprevençao anti-tuberculose moderna.

A novel strategy for targeting CD4+ PPD-reactive T cells against tumour cells using PPD monoclonal antibody heteroconjugates.

We have constructed PPD monoclonal antibody heteroconjugates specific for a tumour-associated antigen of C57BL/6 melanomas or for human complement component C3d fixed de novo to murine fibrosarcoma cells (MC6A). The ability of our heteroconjugates to target CD4+ PPD-reactive T cells against the appropriate tumour targets was then determined in vitro. Heteroconjugate-treated B16-F10 and MC6A tumour targets were both able to present PPD to the specific T cells, resulting in activation and concomitant lymphokine secretion. Secreted lymphokines were then demonstrated to cause significant tumour cytolysis and cytostasis in vitro. Preliminary experiments in vivo suggest that this targeting system may provide the basis for a future immunotherapeutic strategy.

Encuesta epidemiológica rural de histoplasmina y tuberculina en la población de La Fuente, Estado Nueva Esparta, Venezuela / A rural epidemiologic research of histoplasmine and tuberculine in the population of La Fuente, Nueva Esparta State, Venezuela

Se realizó una encuesta epidemiológica de Histoplasmina y Tuberculina a 175 personas, integrantes de la población de la Escuela Dr. Luis Navarro Rivas. La Fuente, Estado Nueva Esparta. Se consideró procedencia, visita a cuevas, viajes fuera de la isla y presencia de animales domésticos. A los casos positivos, se les realizó radiografía de tórax, inmunodifusión e inmunoelectroforesis. En el ánalisis de nuestros resultados, no se observó una positividad marcada en las pruebas intradérmicas realizadas en esta población. Hubo un predominio de Histoplasmina positiva en mayores de 15 años y ningún preescolar mostró positividad a la prueba. La totalidad de los positivos coincidieron con calcificaciones pulmonares radiológicas. Ni todos los casos de Histoplasmina positiva mostraron banda M a la inmunodifusión, de los cuales uno sólo se puede considerar autóctono

[Effect of the combined use of BCG, PPD, a protein-containing preparation from allogenic tissue and cyclophosphamide in the development of methylcholanthrene-induced tumors]. / Vliianie sochetannogo primeneniia BTsZh, PPD, beloksoderzhashchego preparata iz allogennoi tkani i tsiklofosfana na razvitie opukholei, indutsirovannykh metilkholantrenom.

The organism resistance to the appearance of 20-methylcholanthrene-induced tumours may be enhanced by application of different immunologic factors (BCG, PPD, low-molecular allogenic protein) in combination with a single administration of cyclophosphane (CPh). The positive effect was observed both when CPh was applied prior to the immunologic impact (3 or 7 days before) and after it (3 or 8 days later). In the last case the effect was more stable.

Multiple cutaneous malignant melanomas with features of primary melanoma.

A case report and review of the literature regarding multiple primary melanomas, and a discussion of the histologic differentiation between cutaneous primary melanomas and dermal metastases are presented. This report concerns a patient who, following wide surgical resection of a 1.3 mm thick primary melanoma with satellite lesions, developed eight additional primary lesions and more than 50 dermal metastases. The primary nature of the lesions was confirmed by detailed pathologic study. The patient was rendered free of disease over a two-year period of intralesional injection of Bacillus Calmette-Guerin (BCG) and purified tuberculin protein. This was accompanied by substantial improvement in immune function tests. Although this patient represents an uncommon clinical entity, treatment results suggest that aggressive intralesional immunotherapy may complement surgical resection in achieving successful palliation of patients with multiple primary melanomas.