Sclerotherapy for Benign Cystic Lesions of the Head and Neck: Systematic Review of 474 Cases.

OBJECTIVE: The role of sclerotherapy for vascular lesions of the head and neck is well established. However, the efficacy of sclerotherapy for benign cystic lesions of the head and neck is less clear. The objective of this review is to determine the efficacy and safety of sclerotherapy for benign cystic lesions of the head and neck. DATA SOURCES: PubMed/MEDLINE, Cochrane Library, and Embase. REVIEW METHODS: The PRISMA guidelines (Preferred Reporting Systems for Systematic Reviews and Meta-analyses) were followed for this systematic review. Studies of patients with benign head and neck cystic masses treated primarily with sclerotherapy were included. Thirty-two studies met criteria for inclusion. RESULTS: A total of 474 cases of sclerotherapy were reviewed. Agents comprised OK-432, ethanol, doxycycline, tetracycline, and bleomycin. Lesions in the analysis were ranula, thyroglossal duct cyst, branchial cleft cyst, benign lymphoepithelial cyst, parotid cyst, thoracic duct cyst, and unspecified lateral neck cyst. A total of 287 patients (60.5%) had a complete response; 132 (27.9%) had a partial response; and 55 (11.6%) had no response. OK-432 was the most widely utilized agent, with a higher rate of complete response than that of ethanol (62.0% vs 39.4%, P = .015). Fifty-three cases (11.2%) required further surgical management. One case of laryngeal edema was reported and managed nonoperatively. CONCLUSION: Sclerotherapy appears to be a safe and efficacious option for benign cystic lesions if malignancy is reliably excluded. Efficacy rates are comparable to those of sclerotherapy for vascular malformations. The rate of serious complications is low, with 1 incident of airway edema reported in the literature.

Evaluation of pleural lesions after pleurodesis with OK-432 by fluorodeoxyglucose-positron emission tomography/CT.

OBJECTIVE: This study aimed to determine changes in FDG-PET/CT after pleurodesis with OK-432 and to investigate differences in the changes between non-malignant and malignant lesions. METHODS: Study participants were 17 patients with a history of malignant chest disease who underwent FDG-PET/CT after pleurodesis using OK-432 and in whom pleural lesions were determined to be non-malignant (n = 8) or malignant (n = 9). FDG uptake (SUVmax) was counted on all pleural lesions. CT findings (CT attenuation, shape) of pleural lesions with increased FDG uptake were evaluated. RESULTS: The number of patients with increased FDG uptake in the pleura differed significantly between the non-malignant group (3/8) and malignant group (9/9) (p < 0.01) The mean SUVmax of non-malignant lesions with increased FDG uptake was 2.3 ± 0.7 vs. 6.2 ± 2.2 in malignant lesions, for a significant difference (p < 0.01). The mean CT attenuation of lesions was 36 ± 11 HU in the non-malignant group and 34 ± 14 HU in the malignant group, a difference that was not significant (p = 0.91). There was a significant difference in nodular and linear shapes between non-malignant and malignant lesions (p < 0.01). All non-malignant lesions were linear. CONCLUSIONS: Positive FDG uptake was shown in non-malignant pleural lesions as well as in malignant pleural lesions after pleurodesis using OK-432. Combined analysis of FDG accumulation and CT morphology is helpful to distinguish between benign and malignant lesions.

Promising abscopal effect of combination therapy with thermal tumour ablation and intratumoural OK-432 injection in the rat osteosarcoma model.

Treatment options for metastatic osteosarcoma are limited. The present study aimed to evaluate whether radiofrequency ablation (RFA) combined with intratumoural OK-432 injection induces systemic anti-tumour immunity in rat osteosarcoma model. Eighty of 145 rats were assigned to four groups to evaluate overall survival and tumour size: control (no treatment), RFA-only, OK-432, and RFA-OK-432. The remaining 65 were assigned for histological examination. Maximum diameters of tibial and lung tumours were determined. Tumour samples were histologically examined using haematoxylin-eosin and immunohistochemical staining. Overall survival was significantly prolonged in the RFA-OK-432 group compared to the RFA-only and OK-432 groups. Only rats in the RFA-OK-432 group exhibited significant decreases in maximum tumour diameter after treatment. Ki-67-positive tumour cells in the RFA-OK-432 group were significantly stained negative on immunohistochemical analysis as opposed to those in the RFA-only and OK-432 groups. The number of CD11c+, OX-62+, CD4+, and CD8 + cells significantly increased in the RFA-OK-432 group compared to the RFA-only group. RFA with intratumoural OK-432 injection resulted in distant tumour suppression, prolonged survival, and increased dendritic cells, cytotoxic T cells, IFN-γ, and TNF-α, whereas RFA or OK-432 alone did not produce this effect. This combination may induce an abscopal effect in human osteosarcoma.

Dilemma in management of cervico-facial cystic hygroma.

Cervico facial cystic hygroma and tongue lymphagioma is rare representative of spectrum of lymphatic malformations. Conservative management with sclerosants alone has proven to be successful. However, sudden enlargement of these cervico facial lymphangiomas leads to catastrophic airway obstruction leading to debility in feeding and speech. Therefore, surgery is indicated in such case to prevent such a catastrophic problem. We report here the case of a 3-yearold boy with cervico facial hygroma involving the tongue. We successfully treated him with a combination of surgery and OK432 injection.

Sapylin (OK-432) alters inflammation and angiogenesis in vivo and vitro.

BACKGROUND: The occurrence of seroma formation and long-term wound healing remain challenging complications after modified radical mastectomy. Sapylin is a drug used to reduce seroma formation and enhance wound closure, but these results remain controversial. We aimed to investigate the potential mechanism. METHODS: A prospective, consecutive cohort study included 120 patients diagnosed with breast cancer who underwent modified radical mastectomy was designed. Patients were randomized into two group, using or not using OK-432 (sixty patients per group) during surgeries. Patients' drainage fluids were collected for three days after surgery. Inflammatory cytokines and chemokines were measured with ELISA assays. The proliferative, migratory, and angiogenic capacity of HUVEC and HFL1 cells HUVEC and HFL1 cells were measured after being treated with drainage fluids. RESULTS: Our clinic data showed that there was no statistical significance between the two groups in patient characteristics before surgery. However, the outcomes of patients in experimental group were significantly better than those in control group. In vitro studies, the results of ELISA assays showed that several cytokines, including IL-1a, IL-6, TGF-ß1, bFGF and VEGF were increased in the drainage fluids treated with Sapylin. The proliferative, migratory, and angiogenic capacity of HUVEC and HFL1 cells were significantly enhanced after being treated with Sapylin group drainage fluids. CONCLUSION: Sapylin could stimulate the body to secrete a variety of cytokines to promote wound healing by promoting endothelial cell proliferation and migration, angiogenesis and by increasing fibroblast migration and collagen deposition.

Vaccination of Urological Cancer Patients With WT1 Peptide-Pulsed Dendritic Cells in Combination With Molecular Targeted Therapy or Conventional Chemotherapy Induces Immunological and Clinical Responses.

The prognosis of metastatic or relapsed renal cell carcinoma (RCC) or bladder cancer (BC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with WT1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with molecular targeted therapy or conventional chemotherapy. Five eligible patients with metastatic or relapsed RCC and five eligible patients with BC were enrolled. No severe adverse events related to a vaccination were observed. Seven patients with RCC or non-muscle invasive BC had durable stable disease and three other patients had disease progression after DC vaccination. DC vaccination augmented WT1 specific immunity and the reduction of regulatory T cells which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a molecular targeted therapy or a conventional chemotherapy is safe and feasible for patients in advanced stage of RCC or BC.

OK-432 pleurodesis for the treatment of pneumothorax in patients with interstitial pneumonia.

BACKGROUND: Pneumothorax occasionally develops in patients with interstitial pneumonia (IP) and is often intractable. As there exists no well-established treatment for pneumothorax with IP, we evaluated the efficacy and safety of pleurodesis with OK-432, a lyophilized preparation of Streptococcus pyogenes Su strain that has been inactivated by benzylpenicillin. METHODS: We retrospectively evaluated the efficacy and safety of pleurodesis using OK-432 in 39 patients treated for IP-related pneumothorax between January 2006 and May 2017. Five to 10 Klinische Einheit (KE) of OK-432 was injected through the chest tube of each patient. Pleurodesis was considered successful if 1) the chest tube was removed without air leaks and 2) there was no recurrence of pneumothorax within 4 weeks after tube removal, and no additional treatment was required. RESULTS: OK-432 pleurodesis was performed 46 times in 39 patients. The median number of OK-432 intrapleural injections received was 1 (range, 1-6), and median dose was 10 KE (range, 5-55 KE). The success rate was 63% (29/46) and recurrence rate was 17.4% (8/46). Grade 5 adverse events were observed in eight patients, including two patients who developed acute exacerbation of IP. Patients in whom the first OK-432 pleurodesis was successful had a significantly longer median survival time than patients in whom it was unsuccessful (322 days vs. 70 days, p = 0.036). CONCLUSIONS: Our results show that OK-432 pleurodesis is an effective treatment for pneumothorax associated with IP; however, clinicians should be aware of the possibility of adverse events, especially in patients who are critically ill.

Communication Site Ligation and Polyglycolic Acid Sheet Use for the Treatment of Hydrothorax in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis.

INTRODUCTION: Hydrothorax due to pleuroperitoneal communication (PPC) can occur in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). We report our experiences of the safety and efficacy of the treatment of four patients with a novel video-assisted thoracoscopy method. METHODS: Single-port video-assisted thoracoscopic surgery (VATS) was performed with a mini-thoracotomy of 5 cm in length. The PPC site was identified on the diaphragm and ligated using an endoscopic loop. The diaphragm was then covered using a polyglycolic acid (PGA) sheet, over which adhesive chemicals (OK432 and tetracycline) were sprayed. RESULTS: We assessed the efficacy of our approach in four patients (one female and three males) aged 42-74 years (mean: 62.0 years). The hydrothoraxes were right sided in all the patients. The mean operation and postoperative drainage times were 92.5 min and 3.0 days, respectively. The hydrothoraxes did not recur in any patient during follow-up periods of 8-46 months. CONCLUSION: Our suture- and staple-free technique is not only easy to perform but also appears to be safe and effective for the management of hydrothorax in patients receiving CAPD. Larger scale studies are now indicated.

Feasibility and Immune Response of WT1 Peptide Vaccination in Combination with OK-432 for Paediatric Solid Tumors.

BACKGROUND/AIM: Wilms' tumor 1 (WT1) peptide-based vaccination has been reported for its potential usefulness in targeting several cancers. The adjuvant drug OK-432 is known to have potent immunomodulation and therapeutic properties when applied in cancer treatment and may, thus, be important to trigger the appropriate immunological response in paediatric patients with a solid tumor that are vaccinated with a WT1 peptide. PATIENTS AND METHODS: Paediatric patients with a solid tumor were vaccinated with a WT1 peptide and OK-432 once every 2 weeks, for a total of seven times. RESULTS: Of the 24 patients, 18 completed the scheduled vaccinations. Sixteen patients had local skin symptoms and/or fever. In 1 patient, anaphylactic symptoms emerged at the time of the final injection, but these quickly subsided after the treatment. WT1-specific immunological responses were observed in 4 patients (22.2%). WT1 and HLA class I expression were confirmed in 100% and 85% of primary tumors, respectively. CONCLUSION: WT1 peptide vaccine therapy combined with OK-432 appears to be relatively safe for children. However further studies in a larger number of patients are necessary to confirm its safety and efficacy.

Microwave ablation combined with OK-432 induces Th1-type response and specific antitumor immunity in a murine model of breast cancer.

BACKGROUND: Minimally invasive therapies, such as microwave ablation (MWA), are widely used for the treatment of solid tumors. Previous studies suggest that MWA is feasible for the treatment of small breast cancer, and thermal ablation may induce adaptive antitumor immunity. However, the induced immune responses are mostly weak, and the immunomodulation effects of MWA in breast cancer are unclear. Immunostimulant OK-432 can induce tumor-specific T-cell responses and may augment the immunity induced by MWA. METHODS: We treated 4T1 breast cancer bearing BALB/c mice with MWA, OK-432, MWA plus OK-432, or left without treatment. Survival time was evaluated with the Kaplan-Meyer method comparing survival curves by log-rank test. On day 25 after ablation, surviving mice received tumor rechallenge, and the rechallenged tumor volumes were calculated every 5 days. Immunohistochemistry and flow cytometry were used to evaluate the T-cell immune responses in ablated tissues and spleens. The tumor-specific immunity was assessed by enzyme-linked immunospot assays. Besides, the cytokine patterns were identified from enzyme-linked immunosorbent assay. RESULTS: Microwave ablation plus OK-432 resulted in longer survival than single treatment and protect most surviving mice from tumor rechallenge. Both local and systemic T-cell responses were induced by MWA and were further enhanced by subsequent administration of OK-432. Moreover, the combination of MWA and OK-432 induced stronger tumor-specific immune responses than MWA alone. In addition, OK-432 and MWA synergistically promoted the production of Th1-type but not Th2-type cytokines, and polarized T-cell responses to Th1-dominant state. CONCLUSIONS: The T-cell immune responses were activated by MWA in breast cancer. Furthermore, the combination of MWA and OK-432 induced Th1-type response and elicited specific antitumor immunity.

OK-432 (Sapylin) Reduces Seroma Formation After Axillary Lymphadenectomy in Breast Cancer.

Purpose/aim: Modified radical mastectomy is the standard surgery for breast cancer in developing countries. However, seroma formation regarded as the most frequent postoperative complication limits the therapeutic benefit of mastectomy and axillary surgery. The purpose of this study was to evaluate the efficacy of OK-432 in reducing seroma formation after axillary dissection. METHODS: This prospective cohort study included 80 patients with advanced breast cancer who underwent modified radical mastectomy. Patients were randomized into two groups, which differed with the OK-432 administration. N = 40 patients per group were treated with either OK-432 plus closed suction drainage or drainage-only. RESULT: In comparison with the drainage-only group, we found that patients in the OK-432 group had a lower drainage volume (p = .030) and a shorter duration of axillary drainage (p < .01). Besides, the use of OK-432 could reduce the incidence of seroma formation (p < .01) and the volume of seroma (p = .040). There were also significant differences in reducing the chance of evacuative punctures (p = .036) and the healing time (p < .01) between control and OK-432 group. CONCLUSION: OK-432 not only shortened the suction drainage duration, but also significantly reduced seroma formation as well as the needs for aspiration punctures after modified radical mastectomy.

Evaluation of OK-432 Injection Therapy as Possible Primary Treatment of Intraoral Ranula.

PURPOSE: A ranula is a pseudocyst caused by mucous extravasation from the sublingual gland. Recently, a sclerosing agent, OK-432 (picibanil), has been reported to be highly effective for treating lymphangioma and cervical cystic lesions. The present study assessed the effectiveness of OK-432 injection therapy for intraoral ranula to clarify whether it can be used as the primary treatment. PATIENTS AND METHODS: The present study was a retrospective clinical study of patients with intraoral ranula who received OK-432 injection therapy from 2005 to 2015. The ranula size was measured on computed tomography or magnetic resonance imaging studies. We dissolved 1 Klinische Einheit (KE) unit of OK-432 powder in normal saline equal to the aspiration volume. The primary endpoint was the treatment results. The secondary endpoints were the relation between the treatment results and the lesion length and aspiration volume. RESULTS: A total of 23 patients received OK-432 injection therapy for an intraoral ranula. The mean lesion size was 19.96 mm. The mean aspiration volume was 2.14 mL. The number of injections was 1 to 4 (mean 1.70). The treatment results were complete regression (CR) in 18 (78.2%), partial regression (PR) in 3 (13.0%), and no response (NR) in 2 (8%) patients after the last injection. The overall efficacy rate was 91.2% (21 of 23). No serious complications were observed. The lesion length and aspiration volume of the CR group was 17.38 mm and 1.40 mL, respectively. The lesion length and aspiration volume of the PR/NR group was 29.20 mm and 4.80 mL, respectively. The PR/NR group lesions were significantly larger than the CR group lesions. CONCLUSIONS: OK-432 injection therapy for intraoral ranula is safe and effective compared with other surgical therapies. This therapy could potentially become a primary treatment of intraoral ranula.

Excellent Result With the Use of Single-Dose OK-432 in Cervical Macrocystic Lymphangioma.

Though the lymphangioma is a benign neoplasm, it may make an invasion to vital structures by progressively growing. For lymphangioma, which progressed in such a way, surgical treatment has high morbidity and recurrence risk. On these cases, OK-432 is a frequently used sclerotherapy agent. The authors report the result they obtained by the use of single-dose OK-432 on an inoperable pediatric cervical macrocystic lymphangioma case and also their experiences.

Life-Threatening Hemolytic Anemia after Intrapleural Instillation of OK-432 for Treatment of Congenital Chylothorax.

Recent reports have advocated treatment of congenital chylothorax with chemical pleurodesis via intrapleural administration of OK-432. Severe complications have not been reported, but recently we have encountered a life-threatening case of massive hemolysis after the procedure. The hemoglobin of the infant decreased from 8.7 to 3.1 g/dl within 48 h, with concomitant severe hyperbilirubinemia (472 µmol/l) requiring exchange transfusion. Frontline neonatologists should be aware of this rare but potentially life-threatening adverse reaction. In addition, it is possible that a longer indwelling time (3.5 vs. 0.5 h) for OK-432 pleurodesis may alter the therapeutic response.

A propensity score-matched comparison of the efficacies of OK-432 and talc slurry for pleurodesis for malignant pleural effusion induced by lung adenocarcinoma.

BACKGROUND: The choice of an optimal sclerosant for pleurodesis for malignant pleural effusion remains controversial. This retrospective clinical study compared the efficacy and safety of two sclerosants; talc slurry (talc-s) and OK-432. METHODS: We compared the characteristics, 30/90-day success rates, and adverse events in patients with lung adenocarcinoma who underwent pleurodesis by using either OK-432 or talc-s. Propensity score matching was used to compare the two scelrosants. RESULTS: Ninety-four patients (mean age=71.6±9.6 years) were included in this retrospective study, of whom 64 received OK-432 and 30 received talc-s. Seventy-three patients (77.6%) were initially diagnosed with clinical stage IV lung cancer, with a 28.7% epidermal growth factor receptor mutation frequency. The propensity score-matched cohort included 26 patients from each group. The 30-day success rates for OK-432 and talc-s were 80.7% and 76.9%, respectively (odds ratio: 1.26, 95% confidence interval: 0.33-4.77, p=0.73). Neither the overall incidence of adverse events nor the 90-day success rates differed significantly. Multivariate logistic regression revealed that the predictors of 30-day success were lower drainage volume on the previous day, particularly <250mL/day, the presence of full lung expansion, and pre-therapy with an epidermal growth factor receptor-tyrosine kinase inhibitor. The median post-pleurodesis survival time was 6.9 months, which was not significantly different between the study groups. CONCLUSIONS: Propensity score-matched analyses showed that pleurodesis using OK-432 and talc-s demonstrated comparable efficacy and safety profiles in patients with lung adenocarcinoma. This indicated that OK-432 could be a viable alternative to talc-s in this procedure.

M1 macrophage infiltrations and histological changes in the liver after portal vein embolization using fibrinogen and OK432 in the rat.

The mechanism of anti-tumor effect of transarterial Immuno-Embolization (TIE) using OK-432 has not been well elucidated. In this study, we aimed to investigate the tissue injury and immune response after portal venous embolization (PVE) with/without OK-432. Embolic materials (L group: lipiodol, LF group: lipiodol+fibrinogen, LO group: lipiodol+OK-432, LFO group: lipiodol+fibrinogen+OK-432) were administered via the right portal vein in Wistar rats. The histological findings in LFO group demonstrated liver damage with severe architectural changes. The concentrations of CD68(+) cells were observed in a time-dependent manner; it was significantly increased in the LO group on day 1 and in the LFO group on day 3. CD68(+)CD163(-) macrophages significantly increased in the LFO group on day 7 (P<0.05). In conclusion, PVE with fibrinogen and OK-432 markedly increased the CD68(+)CD163(-) infiltrating macrophages around the peri-portal area in the liver. This novel technique could be applied as immune-enhanced chemo-embolization of liver tumors.

Role of intratumoral infiltrating macrophages after transarterial immunoembolization for hepatocellular carcinoma.

BACKGROUND: Preoperative transarterial immunoembolization (TIE) for hepatocellular carcinoma (HCC) is effective for preventing recurrence. We aimed to investigate the intratumoral and peritumoral M1 macrophage-induced immune response following TIE treatment. METHODS: We compared 13 patients treated with TIE between 2003 and 2009 (TIE group) and 13 patients treated with surgery alone during the same period of time at our institute (control group) using an immunohistological study with CD68 and CD163 antibodies. RESULTS: No significant differences in clinicopathological characteristics, except for surgical time, were observed between the two groups. The 3-year recurrence-free survival outcome of the TIE group was quite different from that of the control group (100% vs. 38.5%, P = 0.034). In the histological investigation, lytic necrosis and coagulation necrosis of the main tumor along with the presence of multinuclear giant cells were observed in 10 of the 13 patients in the TIE group. The immunohistological study showed that not only the numbers of intratumoral CD68(+) cells, but also the numbers of intratumoral and peritumoral CD8(+) cells were significantly increased in the TIE group. CONCLUSIONS: The suppression of tumor recurrence induced by preoperative TIE might be induced by intratumoral M1 macrophages that are activated by OK-432 and fibrinogen.

TLR4 preconditioning is associated with low success of OK-432 treatment for lymphatic malformations in children.

PURPOSE: We have recently shown that the relative TLR4 expression on monocytes of low responding pediatric patients after OK-432 treatment is significantly reduced after stimulation with lipopolysaccharide (LPS) compared with high responding children. The aim of this study was to perform further analysis to explain this observation. METHODS: Monocytes from children with high (HR, n = 5) and low response (LR, n = 6) after previous OK-432 treatment were stimulated with LPS for 20 h and analyzed with fluorescence-activated cell sorting (mean fluorescence intensity, MFI; level of significance P ≤ 0.05). RESULTS: Mean MFI after LPS stimulation was comparable in both groups (HR 1142 ± 652 units, LR 839 ± 427 units, P = 0.85). Significant changes after LPS stimulation are explained by higher pre-stimulation values in the LR group compared with the HR group (950 ± 718 vs. 477 ± 341, P = 0.25) with considerable differences of the mean expression changes after LPS stimulation (HR 665 ± 683 vs. LR -111 ± 605, P = 0.08). CONCLUSION: The previously shown reduced TLR4 upregulation on monocytes after LPS stimulation in the LR group compared with the HR group can be primarily explained by TLR preconditioning. This observation implies the use of absolute values with definite thresholds.