Experiencia con OK-432 en malformaciones vasculares linfáticas en un hospital del norte de México / Experience with OK-432 in lymphatic vascular malformations in a hospital from northern Mexico

Resumen Introducción: Las malformaciones vasculares linfáticas (MVL), anteriormente llamadas linfangiomas, son malformaciones congénitas que se presentan en uno de cada 6,000 a 16,000 nacimientos. El sistema de clasificación más útil para el manejo del linfangioma se basa en el tamaño de los quistes. La resolución espontánea es infrecuente, por lo que el tratamiento expectante no se recomienda. El tratamiento clásico es la cirugía de escisión, pero puede afectar a estructuras vecinas o haber recidivas, por lo que se empezaron a estudiar sustancias esclerosantes, como el OK-432. La mayoría de los estudios incluyen pocos pacientes; los más grandes realizados en México se enfocan a lesiones específicas (macroquísticas) o únicamente a una región anatómica. Hasta la fecha, no existen estudios del uso de este fármaco en la población del norte de México. Método: Se describe la experiencia con OK-432 mediante un estudio retrospectivo, descriptivo, en los pacientes con MVL, de 2011 a 2016, en un hospital de referencia del norte de México. Resultados: Veintiséis pacientes con MVL recibieron tratamiento con OK-432. La mayoría fueron macroquísticos (69%), microquísticos (19%) y mixtos (12%). Del total de pacientes, 11 presentaron curación total. El 72% de la población estudiada tuvo una reducción de > 50% del tamaño de las lesiones con solo dos aplicaciones de tratamiento; no se presentaron recidivas. Se reportaron complicaciones en dos pacientes (hiperpigmentación de la piel). Conclusiones: El manejo con OK-432 demostró ser efectivo para el tratamiento de las MVL en un hospital de referencia del norte de México.

Abstract Background: Lymphatic vascular malformations (LVM) or formerly called lymphangiomas are congenital malformations present in about 1 out of 6000 to -16000 births. The most relevant classification system for lymphangioma management is based on the size of the cysts. Spontaneous resolution is uncommon; thus, expectant management is not recommended. The classic treatment is excisional surgery, but it can affect adjacent structures or have relapses, so, sclerosing substances like OK-432 are being studied. The majority of the studies are small in number of patients and are from Japan; the largest studies in Mexico are focused on specific lesions (macrocystic) or a determined anatomical region. To date, there are no studies of the population of the north of Mexico. Methods: The experience with OK-432 was described through a retrospective, descriptive study in patients with LVM, from 2011 to 2016, in a reference hospital of northern Mexico. Results: A total of 26 patients with LVM were treated with OK-432. The majority of the lesions were macrocystic (69 %), microcystic (19 %) and mixed (12 %). From the total number of patients, 11 fully healed, and 72 % of the study population had >50 % reduction in lesion size, with only 2 applications. There were no recurrences. Complications were reported in 2 patients who had skin hyperpigmentation. Conclusions: OK-432 probed to be an effective treatment for LVM in a reference hospital in the north of Mexico.

Tratamento intralesional de malformações linfáticas com ênfase na escleroterapia com picibanil (OK-432): revisão sistemática / Intralesional treatment of lymphatic malformations with emphasis on Picibanil (OK-432) sclerotherapy: a systematic review

INTRODUÇÃO: Conduziu-se revisão sistemática retrospectiva da literatura incluindo estudos relatando o uso de picibanil para tratar malformações linfáticas (ML). MÉTODOS: A pesquisa foi realizada com estudos publicados no PubMed de janeiro de 1990 a 14 de abril de 2013. Na estratégia de busca, usou-se os descritores "OK-432" ou "Picibanil" e "lymphatic malformation". Os seguintes elementos foram comparados aos de outras modalidades relatadas e, então, compilados: mecanismo de ação, indicações, contraindicações, eficácia, administração, efeitos colaterais, complicações, vantagens e desvantagens. RESULTADOS: Foram encontrados 44 estudos, 27 dos quais atenderam aos critérios de inclusão. O picibanil é uma preparação liofilizada de uma cepa de baixa virulência de Streptococcus pyogenes inativada pela penicilina G. Seu mecanismo de ação ainda não definido claramente, mas especula-se que provoque uma resposta inflamatória controlada com adesão das paredes dos cistos. O picibanil é indicado quase que unanimemente para o tratamento da ML macrocística, cuja resposta é mais efetiva do que em lesões microcísticas ou mistas. Em geral, o picibanil é administrado por meio de punção com visualização direta ou guiada por ultrassonografia, com o paciente sob anestesia geral. A preparação comumente utilizada consiste em 0,1 mg de picibanil em 10 ml de soro fisiológico. Os efeitos colaterais são, em geral, leves; sendo dor, inchaço e febre os mais frequentemente relatados. CONCLUSÃO: Os estudos apresentam pouca evidência científica. A revisão sistemática identificou que o picibanil é útil no tratamento da ML de qualquer tipo, mas tem resultados melhores em lesões macrocísticas. A eficácia foi comparável à de outras terapias. Não foi apresentada nenhuma contraindicação específica. Embora o mecanismo de ação ainda não tenha sido determinado, o picibanil trata-se de opção de tratamento.

INTRODUCTION: We performed a retrospective systematic review of studies reporting the use of Picibanil for treatment of lymphatic malformations (LMs). METHODS: We searched the PubMed database for available studies, including those published between January 1990 and April 14, 2013. The search strategy involved the use of the keywords "OK-432" or "Picibanil" and "lymphatic malformation." Information was compiled regarding the reported mechanism of action, indications, contraindications, efficacy, administration, side effects, complications, and advantages and disadvantages compared to those of other modalities. RESULTS: Forty-four studies were found, of which 27 fulfilled the inclusion criteria. Picibanil is a lyophilized preparation of a low-virulence strain of Streptococcus pyogenes inactivated with penicillin G. Its mechanism of action is unclear, but it has been speculated that it causes a controlled inflammatory response with adhesion of cyst walls. Picibanil is almost unanimously indicated for the treatment of macrocystic LMs, which show a greater effectiveness response compared to that shown by microcystic or mixed LMs. Picibanil is usually administered by puncturing, either with direct visualization or guided by ultrasound, with the patient under general anesthesia. The most widely used preparation comprises 0.1 mg of Picibanil in 10 mL of saline. Side effects are mostly mild, with pain, swelling, and fever being the most frequently reported. CONCLUSION: The studies had low scientific evidence. A systematic review found that Picibanil is useful against any LM, with better results in macrocystic lesions. Efficacy was comparable to that of other therapies. No specific contraindication was presented. Although the mechanism of action has not been established, the inclusion of Picibanil as a treatment option is warranted.

Avaliação de consumo alimentar, medidas antropométricas e tempo de menopausa de mulheres na pós-menopausa / Food consumption in postmenopausal women and its relation with anthropometric measurements and time since menopause

OBJETIVO: Avaliar o hábito alimentar e nutricional de mulheres na pós-menopausa e compará-los com o perfil antropométrico, faixa etária e tempo de menopausa. MÉTODOS: No período de junho a agosto de 2011, 148 mulheres na pós-menopausa residentes no Estado de São Paulo (região Sudeste do Brasil) foram avaliadas com um questionário estruturado contendo dados socioeconômicos, clínicos, antropométricos e alimentares. Avaliou-se nível de atividade física, variáveis bioquímicas, Índice de Massa Corporal (IMC), circunferência abdominal (CA) e consumo alimentar (energia, proteínas, carboidratos e gorduras, fibra, colesterol, vitaminas A e C, minerais, cálcio e ferro) de acordo com a faixa etária e o tempo de pós-menopausa (TPM). RESULTADOS: A média de IMC foi 29,0±5,6 kg/m2 e da CA, 95,7±12,9 cm. O consumo médio calórico diário atingiu 1.406,3±476,5 kcal. A ingestão e a adequação calórica foram significantemente mais apropriadas entre as mulheres eutróficas e com CA<88 cm. O mesmo ocorreu quanto ao consumo de proteínas (p<0,001 e p=0,006, respectivamente). Na análise por faixa etária ou TPM não houve diferenças significantes, exceto a média do consumo proteico, maior no grupo com 5 anos ou menos de menopausa (p=0,048). CONCLUSÃO: O perfil antropométrico de mulheres na pós-menopausa mostrou predominância de sobrepeso ou obesidade. O consumo alimentar apresentou-se adequado quanto às calorias e percentuais de macronutrientes, entre as eutróficas e com CA<88 cm. .

PURPOSE: To evaluate eating in postmenopausal women and its relation to anthropometry, age and time since menopause in São Bernardo do Campo residents. METHODS: During the period from June to August of 2011, 148 postmenopausal women residents in state of São Paulo (Southeast region of Brazil) were evaluated using a structured questionnaire containing socioeconomic, clinical, anthropometric and food data. The level of physical activity, biochemical variables, Body Mass Index (BMI), abdominal circumference (AC) and dietary intake (energy, protein, carbohydrates and fats, fiber, cholesterol, vitamins A and C, minerals, calcium and iron) were analyzed according to age and time after menopause. RESULTS: Mean BMI was 29.0≤5.6 kg/m2 and abdominal circumference was 95.7±12.9 cm. The average daily caloric consumption was 1,406.3±476.5 kcal. The calorie intake was significantly more appropriate in normal-weight women and women with AC<88 cm. The same was observed for protein intake (p<0.001 and p=0.006, respectively). No association was observed with age or duration of the postmenopausal period, except for average protein consumption that was higher in the group with five years or less of menopause (p=0.048). CONCLUSION: The anthropometry of postmenopausal women showed a predominance of overweight and obesity. Dietary intake was adequate in relation to the percentage of calories and macronutrients and calories among most normal-weight women and women with AC<88 cm. .

Cross-sectional study comparing different therapeutic modalities for cystic lymphangiomas in children

OBJECTIVE: Here, we describe our experience with different therapeutic modalities used to treat cystic lymphangiomas in children in our hospital, including single therapy with OK-432, bleomycin and surgery, and a combination of the three modalities. METHODS: We performed a retrospective, cross-sectional study including patients treated from 1998 to 2011. The effects on macrocystic lymphangiomas and adverse reactions were evaluated. Twenty-nine children with cystic lymphangiomas without any previous treatment were included. Under general anesthesia, patients given sclerosing agents underwent puncture of the lesion (guided by ultrasound when necessary) and complete aspiration of the intralesional liquid. The patients were evaluated with ultrasound and clinical examinations for a maximum follow-up time of 4 years. RESULTS: The proportions of patients considered cured after the first therapeutic approach were 44% in the surgery group, 29% in the bleomycin group and 31% in the OK-432 group. These proportions were not significantly different. Sequential treatment increased the rates of curative results to 71%, 74% and 44%, respectively, after the final treatment, which in our case was approximately 1.5 applications per patient. CONCLUSION: The results of this study indicate that most patients with cystic lymphangiomas do not show complete resolution after the initial therapy, regardless of whether the therapy is surgical or involves the use of sclerosing agents. To achieve complete resolution of the lesions, either multiple operations or a combination of surgery and sclerotherapy must be used and should be tailored to the characteristics of each patient. .

Uso de OK-432 (Picibanil) como alternativa no quirúrgica para el manejo de ránulas y mucoceles / The use of OK-432 (Picibanil) as a non-surgical alterantive for the management of ranula and mucoceles

Mucocele y ránula, son términos clínicos aplicados para describir un pseudoquiste asociado con extravasación mucosa en los tejidos circundantes, donde se hallen glándulas salivales menores. Estas lesiones ocurren como resultado de un trauma del conducto excretor de laglándula salival o por la obstrucción de flujo salival por otra lesión asociada, como un sialolito o un tapón bacteriano. Estas patologías se originan en una glándula salival menor y son también conocidos como fenómeno de retenciónmucosa o reacción de escape mucoso.El manejo de estas lesiones es quirúrgico en todos los casos, sin embargo, presenta algunas dificultades propias del evento, complicacionespostquirúrgicas y secuelas permanentes en el paciente; en la actualidad se ha manejado este tipo de lesiones con otro tipo de terapéutica, como escleroterapia, uso de toxina Botulínicatipo A, LASER, o el OK-432 (Picibanil), que es una mezcla de Streptococo Pyogenes del grupo A mermado en su virulencia y penicilina G en polvo liofilizado que funciona como agente esclerosante para linfangiomas y agenteantineoplásico. En este trabajo se presenta una revisión bibliográficaacerca de esta patología y una nuevaopción de tratamiento con este medicamento, sus indicaciones y contraindicaciones, así como su administración, reacciones secundarias y complicaciones durante el manejo de lesiones reactivas asociadas a las glándulas salivales menores.

Percutaneous Treatment of Renal Cysts with OK-432 Sclerosis

PURPOSE: The aim of this study was to demonstrate OK- 432 sclerotherapy efficacy for treatment of simple renal cysts. MATERIALS AND METHODS: Twenty patients with 25 symptomatic or large simple cysts were treated by ultrasonography (US)-guided percutaneous aspiration and injection of OK-432 (8 men and 12 women, mean age 63.6 years, SD 9.5). Six patients presented with flank pain, 14 presented with renal mass; renal cyst location was right, left, or bilateral sided in 9, 8, and 8 kidneys, respectively. Patients were evaluated by clinical assessment, US, or CT scan 3 months following the procedure. Complete and partial success was defined as symptom resolution with either total cyst ablation or greater than 70% reduction, respectively. Failure was defined as 30% of cyst size recurrence and/or persistent symptoms. RESULTS: Average reduction was 93.0%. Complete and partial resolution occurred in 11 (44.0%) and 13 (52.0%) cysts, respectively. One case was defined as failure, with a 64.2% size reduction from 10.9cm to 3.9cm (volume reduction rate 95.4%). Renal pain improved in all patients, regardless of complete or partial resolution. Minor complications occurred in 3 patients, 2 developed leukocytosis and 1 had mild fever (< 38.5 degrees C) following aspiration and sclerotherapy. Successful treatment was achieved with conservative measures and NSAID therapy. CONCLUSION: Percutaneous treatment of simple renal cysts with OK-432 sclerotherapy was found to be a safe, effective and minimally invasive procedure.

Uso de OK-432 em crianças com linfangioma / OK-432 therapy for lymphangioma in children

OBJETIVO: Relatar a experiência no uso do OK-432 para tratamento de linfangiomas em crianças. MÉTODOS: Estudo retrospectivo de 19 crianças com linfangioma tratadas com OK-432 no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP, durante o período de 1999 a 2003. RESULTADOS: Todos os pacientes apresentaram alguma resposta ao OK-432, 12 pacientes apresentaram regressão total, sete apresentaram regressão parcial variando de 50 por cento a 80 por cento. Os pacientes apresentaram febre após a aplicação da droga com duração de 2 a 10 dias. Não se observaram cicatrizes após a aplicação do OK-432. CONCLUSÕES: A droga OK-432 é segura, eficaz e pode ser utilizada como primeira escolha no tratamento de pacientes com linfangiomas devido à excelente resposta, podendo tornar desnecessária a realização de cirurgia. Em pacientes com resposta parcial, podem ser realizadas novas aplicações de OK-432 ou cirurgia menos mutilante, devido à redução das dimensões da lesão.

The observation of immunosuppressor(s) derived from cultured tumor cells and its partial neutralization with OK-432.

Malignant tumors such as brain tumors have been reported to be associated with immunosuppression caused by certain tumor-secreted cytokines. The reversion of tumor-derived immunosuppression has not been described. The use of OK-432, an immunomodulatory agent prepared from Su-strain of Streptococcus pyogenes A3, to activate peripheral blood mononuclear cells from a patient with glioblastoma multiforme has demonstrated a sharp rise in proliferative response. This proliferative response was compromised in the presence of living and irradiated autogeneic cancer cells. The conditioned media from cultured cells of glioblastoma multiforme, astrocytoma, and cholangiocarcinoma were tested for immunosuppressive ability. We found that conditioned media from 3 of 4 cases of glioblastoma, all 3 cases of astrocytoma, and 1 case of cholangiocarcinoma exhibited immunosuppressive activity toward the proliferative response of allogeneic peripheral blood mononuclear cells to phytohemagglutinin. This is the first report that cholangiocarcinoma produces soluble immunosuppressor(s). Our finding suggested that soluble substance(s) as well as direct cell-cell contact between tumor cells and mononuclear cells play roles in the observed tumor-derived immunosuppression.

Sclerotherapy with OK-432 for recurrent cystic thyroid nodule

We have adopted OK-432 as a sclerosing agent in the treatment of cystic predominant thyroid nodules and have analyzed our findings to assess the efficacy of intralesional instillation of OK-432. From 1992 through 1993, 48 patients with recurrent or progressive cystic thyroid nodules after 2 or 3 aspirations alone, and whom were cytologically negative for malignancy, were used for this study. The OK-432 solution was prepared by dissolving 0.1 mg of OK-432 in 2 ml of physiologic saline and it was instilled in the amount of 1/10-to-1/5 of the aspirated cystic fluid. A repeated course of therapy was given up to 3 times when sufficient resolution was not obtained 4-to-6 weeks after treatment. The mean number of treatment sessions per patient was 1.5. Throughout the follow-up period from 30-to-45 months (mean, 38 months), 32 (66.7%) patients experienced an almost complete disappearance ( 0.5 cm in diameter) of the initial cyst size, and none of these patients required further treatment. The remaining 4 (8.3%) patients showed insufficient resolution despite 3 courses of therapy and 2 of these patients underwent thyroidectomy, in which the lesion proved benign in both cases. All of the patients tolerated the sclerotherapy well. No significant local complications attributed to this treatment were observed. However, a low-grade fever was observed in 26 (54.2%) patients for 2 to 5 days after instillation, which subsided with symptomatic treatment. On the basis of our experience, OK-432 sclerotherapy appears to be safe, simple and effective, and can be a useful alternative treatment for cystic thyroid nodules.