Efficacy of OK-432 sclerotherapy for different types of lymphangiomas: a review and meta-analysis

Abstract Objective This study aims to perform a meta-analysis to figure out the efficacy of OK-432 sclerotherapy between Macrocystic (MAC) lymphangiomas and Microcystic (MIC) lymphangiomas. Methods We conducted a systematic review and meta-analysis to clarify the relationship between OK-432 and lymphangiomas. PubMed and ISI Web of Science were searched from inception to May 2022. Joanna Briggs Institute (JBI) manual was used to evaluate the risk of bias. We calculated pooled Relative Risks (RR) and 95% Confidence Interval (95% CI) using random effects model to evaluate the relations between OK-432 and lymphangiomas. Results A total of 11 studies (including 352 cases) about OK-432 sclerotherapy for lymphangioma were included in the current meta-analyses. The results suggested that the efficacy of OK-432 was significantly in MAC lesions than in MIC (RR = 1.51, 95% CI 1.298-1.764), with significant moderate degrees of heterogeneity among 11 studies (I2 = 51.2%, p = 0.025). Subgroup analyses suggested that there was significant association in both retrospective studies (RR = 1.26, 95% CI 1.03-1.53) and classification (by 1 cm) (RR = 1.37, 95% CI 1.04-1.80) were associated with the efficacy of OK-432. Conclusion To our knowledge, our study represents the first meta-analysis examining the efficacy of OK-432 in the treatment of different types of LMs. However, the regional differences and the age differences of the subjects are the main limitations of this study and should be avoided in further research. Our results suggested that OK-432 sclerotherapy for macrocystic lymphangiomas was more effective.

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.

Intralesional Injection of OK-432 in Cystic Hygroma

Background: Lymphangiomas are congenital malformations of the lymphatic system with characteristic dilated endothelium-lined spaces. It is vulnerability to infection or chemical irritants cause spontaneous reduction in size and in some cases complete resolution. Intralesional injection of OK-432 or Picibanil (lyophilized incubation mixture of Group A Streptococcus pyogenes of human origin) is slowly gaining recognition as its safety and efficacy standards have shown to avoid complications resulting from surgical interventions. The objective of this study was to evaluate the clinical outcomes of cystic hygroma patients who received OK-432 injections. Methods: In between 2011 and 2013, six patients with cystic hygroma received intralesional injection of OK-432. All the patients were assessed clinically and radiologically either via ultrasound, computer tomography (CT) or magnetic resonant imaging (MRI) prior to and after receiving the injections. Patients’ response towards treatment was classified as total shrinkage, marked shrinkage (greater than 50% reduction in size), slight shrinkage (less than 50% reduction in size) or non-responsive to treatment. Results: Mean duration of follow-up was 12 months. Total shrinkage was achieved in one patient, marked shrinkage in three patients and one patient experienced mild shrinkage. Only one out of the six patients showed no response to treatment. None of the patients in this study experienced serious complications or adverse effects post intralesional injection of OK-432. Conclusions: Intralesional OK-432 injection is an effective and safe alternative in treating cystic hygroma.

Surgical Treatment of Difficult Cervicofacial Lymphangioma in Children / 소아외과

PURPOSE: Cervical lymphangiomas are rare lymphovascular malformations arising in the neck, which form huge fluid-containing cysts. Treatment of the malformation consists of surgery and sclerotherapy. However, the optimal approach is still controversial. Here, we describe a series of cervical lymphangiomas which have been treated with surgical approaches. METHODS: We retrospectively investigated the medical records of 82 patients who had been diagnosed with cervicofacial lymphangioma from 2001 to 2012 in our center. A closed suction drainage with negative pressure was placed on the operative lesion following excision to prevent reaccumulation of lymphatic fluid and the drainage tube was removed after injecting OK-432 through the tube. RESULTS: Twelve patients underwent surgical excision of cervical lymphangioma. The median patient age was 3 months at the time of the operation. The patients have been followed-up over a period of 34 months. When lesions were located near vital organs such as the trachea or carotid artery or did not respond to repetitive OK-432 injections, surgical treatment might bring good outcomes. However, swallowing difficulty, lip palsy, or dyslalia due to adjacent nerve damage temporarily appeared as postoperative complications. Five children had tracheostomy due to tracheal or subglottic stenosis and 2 patients had gastrostomy due to aspiration while they eat after surgery. CONCLUSION: Surgery for cervicofacial lymphangioma should be conducted carefully in selective cases. A well thought-out surgical plan with a multidisciplinary surgical team approach and placement of closed suction drainage tube after surgery and adjuvant OK-432 sclerotherapy through drainage tube seem to be helpful for good outcome.

Anti-tumor effects of OK432 optimized umbilical vein endothelial cell vaccine in murine breast cancer / 中国药理学通报

Aim To investigate the anti-EAC breast cancer effects of viable human umbilical vein endothe-lial cells ( HUVECs) vaccine. Methods Subconflu-ent HUVECs were mixed with OK432 to prepare HU-VECs-OK432 vaccine, and the anti-tumor efficacy of HUVECs-OK432 was investigated using a subcutaneous tumor model of EAC breast cancer. ELISA, splenic lymphocyte proliferation assay and cytotoxic T lympho-cytes ( CTL ) killing assay were adopted to detect the humoral and cellular immune responses after HUVECs-OK432 immunization. Results HUVECs-OK432 im-munization significantly inhibited the growth of EAC tumor in mice in the prophylactic procedures. High ti-ter of anti-HUVEC antibody was elicited by HUVECs-OK432 immunization. The proliferation activity of splenocytes from mice immunized with HUVECs-OK432 was significantly increased. T lymphocytes iso-lated from HUVECs-OK432-immunized mice were dose dependently killing HUVECs in vitro. Conclusion Strong humoral and cellular immune responses targeting HUVEC are elicited by HUVECs-OK432 immuniza-tion, which results in a significant inhibition on the growth of EAC tumor in mice.

Lymphatic Malformations of the Orbit

OBJECTIVES: Lymphatic malformations of the orbit are rare lesions that constitute approximately 1% to 8% of all orbital masses. They are difficult to treat since they do not remain within anatomic boundaries and tend to penetrate into normal orbital structures. The aim was to analyze clinical courses and therapy options in patients with lymphatic malformations of the orbit. METHODS: Thirteen patients with orbital lymphatic malformations confirmed by magnetic resonance imaging between 1998 and 2009 were enrolled in this study. Patients' charts were retrospectively reviewed to analyze clinical courses and treatment options. RESULTS: Four patients suffered from isolated intraorbital lymphatic malformations without conjunctival involvement, in three of them the masses were completely resected, in one patient close controls were performed. Three patients had isolated intraorbital lymphatic malformations with conjunctival involvement. Surgical volume reduction of the exterior parts of the lymphatic malformation were performed without any complications and satisfying outcome in these cases. Six patients suffered from intra- and periorbital lymphatic malformations. In 3 patients a watch-and-wait strategy was initiated. In the other 3 patients a surgical therapy was performed, one patient additionally received sclerotherapy with OK-432; however, these 3 patients suffered from residual lymphatic malformations. CONCLUSION: The presented cases underline the inconsistencies in the malformations behavior and underscore the inability to make specific recommendations regarding treatment. The treatment decision should be based on the size and location of the lymphatic malformation. The untreated patient must be watched for signs of visual detoriation, which may signal the need for therapeutic intervention.

Successful pleurodesis with OK-432 in preterm infants with persistent pleural effusion / 소아과

OK-432 (picibanil) is an inactivated preparation of Streptococcus pyogenes that causes pleurodesis by inducing a strong inflammatory response. Intrapleural instillation of OK-432 has recently been used to successfully treat neonatal and fetal chylothorax. Here we report a trial of intrapleural instillation of OK-432 in two preterm infants who were born with hydrops fetalis and massive bilateral pleural effusion. Both cases showed persistent pleural effusion, refractory to conservative treatment, up to postnatal days 26 and 46, respectively. An average of 80 to 140 mL of pleural fluid was drained daily. In case 1, the infant was treated with OK-432 during the fetal period at gestation 28 weeks and 4 days of gestation, but showed recurrence of pleural effusion and progressed into hydrops. Within two to three days after OK-432 injection, the amount of pleural fluid drainage was dramatically decreased and there was no reaccumulation. We did not observe any side effects related to OK-432 injection. We suggest that OK-432 should be considered as a therapeutic option in infants who have persistent pleural effusion for more than four weeks, with the expectation of the early removal of the chest tube and a good outcome.

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.

Successful Treatment of Steatocystoma Multiplex with OK-432 Sclerotherapy / 대한피부과학회지

Steatocystoma multiplex is a hamartomatous malformation of the pilosebaceous junction and this manifests as multiple, asymptomatic, yellowish or skin-colored cystic papules and nodules located most commonly on the upper anterior portion of the trunk, upper arms and axillae. Various treatment methods such as radical excision, simple surgery, CO2 laser, cryotherapy, needle aspiration and oral retinoids have been reported, but there is currently no standard treatment. OK-432 is a biological preparation consisting of lyophilized powder containing Streptococcus pyogenes Su strain cells (group A, type3) that were treated with benzylpenicillin potassium. This has been used for sclerotherapy in patients with lymphangioma. We herein report on a case of 36-year-old female with steatocystoma multiplex on the trunk and axillary area. She was successfully treated with intralesional infusion of OK-432 after aspiration of the oily contents without recurrence or any complications such as scarring, atrophy and skin necrosis. We suggest that this sclerotherapy is a cosmetically acceptable treatment option for the multiple lesions of steatocystoma multiplex.

Evaluation of Intralesional Injection Therapy for Pediatric Lymphangiomas Classified with MRI

Pediatric lymphangioma can occur at any site. However the neck is the most common site. There are two treatment modalities (surgical excision and intralesional injection) for lymphangiomas. But, the treatment guide line for lymphangioma has not been established, yet. The aim of this study is to establish the treatment guide line based on our experience with lymphangiomas. Medical records of 82 cases of lymphangioma were reviewed retrospectively. On MRI (magnetic resonance image) findings, lymphangiomas were divided into 4 groups by the proportion of the cyst bigger than 2 cm in diameter of the tumor; group A-proportion of cyst occupies more than 75%, group B-proportion of the cyst 50~75%, group C-25~50%, and D in less than 25%. All patients were treated with OK-432 intralesional injection as the initial treatment. The effective response rates of OK-432 in group A & B were 88.2% and 88.8%, respectively. Group C response was 38.0% and D only 20.0%. Twenty-three patients received surgical excision. The result of surgical excision was generally satisfactory. Surgical site infection occurred in 1 case and postoperative bleeding in 1 case. Theses results indicate that intralesional injection of OK-432 could be the first line therapy in group A & B. In group C, OK-432 would be better as the first line therapy than surgery. For the group D, surgical excision should be the first line of treatment.

A Case of Lymphangioma Treated by OK-432 (Picibanil(R)) Sclerotherapy / 대한피부과학회지

Lymphangioma is an uncommon, benign hyperproliferation of the lymphatic vessels, and this consists of dilated lymphatic channels lined by a normal, single layer of endothelial cells. Various methods have been tried for the treatment of lymphangioma, including cryotherapy, electrocauterization, surgical excision, laser therapy, radiotherapy and itralesional injection of sclerosing agents. Yet these methods have shown low success rates and various side effects. It has recently been reported that intralesional injection of OK-432 is a safe and effective alternative therapy for lymphangioma, and especially for macrocystic lesion. In this report, we describe a patient with lymphangioma on the upper labial mucosa and this patient was successfully treated with intralesional injection of OK-432 without any serious complications. To the best of our knowledge, this is the first such case reported on in the Korean dermatological literature.

Treatment of Simple Renal Cysts by Percutaneous Aspiration and OK-432 Sclerotherapy / 대한비뇨기과학회지

PURPOSE: Percutaneous aspiration with sclerotherapy has been widely used for the treatment of symptomatic or large simple renal cysts. Ethanol has been most commonly used as a sclerosing agent; however, a temporary percutaneous nephrostomy for multiple ethanol injections is necessary to achieve a low recurrence rate. Thus, we used OK-432 as a new sclerosing agent without a temporary percutaneous nephrostomy for multiple injections, and also compared our results with the results of previous studies. MATERIALS AND METHDOS: Between October 2005 and April 2006, 50 patients (63 simple renal cysts) who underwent percutaneous OK-432 sclerotherapy for simple renal cysts were evaluated. The simple renal cysts were aspirated under ultrasonography and fluoroscopy, after which OK-432 was injected into the cyst. Follow-up was performed with ultrasonography or CT scan after 3 months. Regression of the renal cyst or a >70% reduction in size with no symptoms was considered a treatment success. RESULTS: Among 63 renal cysts in 50 patients, complete regression occurred in 17(27.0%). Greater than a 90% reduction in size occurred in 8(12.7%), a 80-90% reduction in size occurred in 21(33.3%), and a 70-80% reduction in size occurred in 15(23.8%); a <70% reduction in size occurred in 2 (3%). The overall efficacies of success were 96.8%. After the procedure, there were only some minor complications, such as mild fever, local pain, and liver function test elevation that subsided with symptomatic treatment. CONCLUSIONS: Percutaneous OK-432 sclerotherapy is simple, safe, and effective and can be an alternative first-line therapy of simple renal cysts.

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.

Sclerotherapy of Ranula with Intracystic Injection of OK-432 / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES : Although surgery is the first choice of therapy for ranula, sometimes complete excision is very difficult. Therefore, nonsurgical therapies with less associated morbidity have been required for the treatment of ranula. This study examined the effectiveness of intracystic injection of OK-432 for treatment of ranula. SUBJECTS AND METHOD : Total 32 patients with ranula (24, intraoral type ; 8, plunging type) were treated with OK-432 sclerotherapy. Aspirated mucus of ranula was replaced with an equal volume of OK-432 solution of 0.01 mg/mL. The size of ranula was compared before and after sclerotherapy. RESULTS : Twenty five of 32 patients (78%) showed a complete response after sclerotherapy : higher in plunging ranula (88%) than in intraoral ranula (75%). Rupture of ranula developed in 8 of 25 patients (32%) with intraoral ranula within a few days after injection. Recurrence occurred in 3 patients during follow-up period of median 12 months (range 9-22 months) after last injection. There were no major side effects, scarring, or increased morbidity to surgery of the OK-432 injected lesions. CONCLUSION : The intracystic injection of OK-432 is highly effective as a primary treatment modality of ranula.

Efficacious Pleurodesis with OK-432 Plus Autoblood or OK-432 Against the Pneumothorax with Persistent Air Leak / 결핵및호흡기질환

BACKGROUND: This report reviews our experience with persistent air leaks in the peumothorax that were not considered candidates for surgical treatment in order to evaluate the efficacy and risks of the OK-432 plus autoblood or OK-432 pleurodesis. MATERIAL AND METHODS: From March 2004 to July 2005, 8 consecutive patients who had an air leak in the pneumothorax over 5 days and had been treated with OK-432 plus autoblood or OK-432 pleurodesis. The patients were not considered candidates for surgical treatments because the chest CT findings revealed severe chronic lung disease with multiple bullae and/or bullous changes. A prolonged air leak with/without dead space was treated with either OK-432 plus autoblood or OK-432 pleurodesis. The efficacy and side effects of OK-432 pleurodesis were assessed by determining the duration of the air leak, the number of pleurodesis, the patients' symptoms, measurements of the white blood cell count and the c-reactive protein level. RESULTS: All of eight patients were male and the mean age was 72.4 +/- 8.5. The mean number of pleurodesis was 1.9 +/- 1.1 and the mean duration of the air leak was 4.6 +/- 4.6 days after pleurodesis. Side effects after pleurodesis were encountered in 7 patients, which included a chilling sensation in 7 cases, chest pain in 5 cases, headache in 3 cases, local heat sensation in 2 cases, and fever in 1 case. Leukocytosis was observed in 6 patients, and the mean of WBC count and CRP were 14500 +/- 2100 and 21.9 +/- 11.4mg/dL, respectively. CONCLUSION: Either OK-432 plus autoblood or OK-432 pleurodesis has acceptable side effects, and can be considered a treatment option for persistent air leaks in the pneumothorax that are not candidates for surgical treatment.

Efficacious Pleurodesis with OK-432 Plus Autoblood or OK-432 Against the Pneumothorax with Persistent Air Leak / 결핵및호흡기질환

BACKGROUND: This report reviews our experience with persistent air leaks in the peumothorax that were not considered candidates for surgical treatment in order to evaluate the efficacy and risks of the OK-432 plus autoblood or OK-432 pleurodesis. MATERIAL AND METHODS: From March 2004 to July 2005, 8 consecutive patients who had an air leak in the pneumothorax over 5 days and had been treated with OK-432 plus autoblood or OK-432 pleurodesis. The patients were not considered candidates for surgical treatments because the chest CT findings revealed severe chronic lung disease with multiple bullae and/or bullous changes. A prolonged air leak with/without dead space was treated with either OK-432 plus autoblood or OK-432 pleurodesis. The efficacy and side effects of OK-432 pleurodesis were assessed by determining the duration of the air leak, the number of pleurodesis, the patients' symptoms, measurements of the white blood cell count and the c-reactive protein level. RESULTS: All of eight patients were male and the mean age was 72.4 +/- 8.5. The mean number of pleurodesis was 1.9 +/- 1.1 and the mean duration of the air leak was 4.6 +/- 4.6 days after pleurodesis. Side effects after pleurodesis were encountered in 7 patients, which included a chilling sensation in 7 cases, chest pain in 5 cases, headache in 3 cases, local heat sensation in 2 cases, and fever in 1 case. Leukocytosis was observed in 6 patients, and the mean of WBC count and CRP were 14500 +/- 2100 and 21.9 +/- 11.4mg/dL, respectively. CONCLUSION: Either OK-432 plus autoblood or OK-432 pleurodesis has acceptable side effects, and can be considered a treatment option for persistent air leaks in the pneumothorax that are not candidates for surgical treatment.

A Case Report: Treatment of Orbital Lymphangioma with Intralesional OK-432 Injection

PURPOSE: To report the first domestic case of orbital lymphangioma treated with intralesional OK-432 injection. METHODS: Initial treatment with systemic corticosteroid had failed. After aspirating the blood, we injected OK-432 (0.05 mg) into the cystic space of the orbital lymphangioma. RESULTS: Although there were minor complications, such as fever and mild tenderness, the patient had an uneventful recovery. After 6 weeks, her visual axis was restored. CONCLUSIONS: We successfully treated this infant patient with an intralesional OK-432 injection. Based on this success, we suggest that treatment of orbital lymphangioma which is refractory to conservative treatment and difficult to resect, may include an intralesional OK-432 injection.

Toll-Like Receptor-Targeting Immunotherapy for Oral Cancer / Oral Science International

It is important to augment the anti-cancer host response in cancer treatment. Recent studies have suggested that the signaling that occurs via the Toll-like receptors (TLRs), which are newly identified receptor molecules recognizing many pathogens, are involved in the induction of anti-cancer immunity. OK-432, a penicillin-killed and lyophilized preparation of <i>Streptococcus pyogenes</i>, is being successfully used as an immunotherapeutic agent in many types of malignancies. However, the molecular mechanisms of OK-432, a whole bacterial preparation, and the active components which make it effective against cancer, remain uncertain. We have succeeded in isolating the active component of OK-432 (lipoteichoic acid-related molecule, OK-PSA) by affinity chromatography of a butanol extract of OK-432 on the CNBr-activated sepharose 4B bound TS-2 monoclonal antibody that neutralizes the interferon (IFN)-γ-inducing activity of OK-432. OK-PSA induced Th1-type cytokines both in human and in mice, and elicited an anti-cancer effect in tumor-bearing mice via TLR4. Furthermore, our clinical study revealed that TLR4 signaling is intimately involved in the anti-cancer effect achieved by OK-432 in patients with oral cancer. We elucidated that OK-432 is first captured and digested by phagocytes, such as dendritic cells and macrophages, and then its active component, OK-PSA, which is released from the phagocytes, stimulates TLR4 signaling. It is strongly suggested that OK-PSA is the molecule most responsible for the anti-cancer effect of OK-432, and that TLR4 may be a definite molecular target for cancer immunotherapy with OK-432/OK-PSA.

Clinical Manifestation and Treatment of Lymphangioma in Children: a Review of 117 Cases

Lymphangiomas or cystic hygromas are quite commonly seen in children. During a 22-year period, from January 1980 to December 2001, 117 patients with lymphangioma were treated and followed in the Department of Pediatric Surgery at Hanyang University Hospital. The male-to-female ratio was 1.9:1 (77:40) with a male preponderance. As for the age incidence at time of diagnosis, 10 (8.5 %) patients were noted under 1 month of age, 37 (31.6 %) were between 1 month and 1 year of age, 12 (10.3 %) between 1 and 2 years of age, so 59 (50.4 %) were under 2 years of age. Sixty one (52.1 %) lymphangioma-cases were located in the neck, including one case at the nape. Axilla was the second in frequency and the rest were scattered at various sites. The intrascrotal lymphangioma is very rare but we have experienced one case of primary intrascrotal lymphangioma. Eighteen (15.4 %) cases were located in the intraabdominal area, 10 in the mesentery, 2 in the greater omentum and 6 in the retroperitoneum. The chief complaints of intraabdominal lymphangioma were abdominal pain, intestinal obstruction, inguinal hernia, palpable mass, and/or abdominal distension. Among 77 histologically proven cases, 14 cases were cavernous lymphangiomas and the rest were cystic lymphangiomas. Bleeding in the lymphangioma was noted in 20 (17.1 %) cases of all. As for the treatment, a complete excision was performed in 77 (65.8 %) patients and AgNO3 sclerotherapy after incomplete excision was performed in 23 (19.7 %). Picibanil (OK-432) sclerotherapy was performed in 17 (14.5 %) patients. Recurrence rate was 7.7 % and mortality occurred in one case who had a large neck lymphangioma extending into the mediastinum.