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Journal of Nanobiotechnology Nov 2023To investigate the efficacy of an injectable hydrogel loaded with lysed OK-432 (lyOK-432) and doxorubicin (DOX) for residual liver cancer after incomplete radiofrequency...
OBJECTIVE
To investigate the efficacy of an injectable hydrogel loaded with lysed OK-432 (lyOK-432) and doxorubicin (DOX) for residual liver cancer after incomplete radiofrequency ablation (iRFA) of hepatocellular carcinoma (HCC), and explore the underlying mechanism.
MATERIALS AND METHODS
The effect of OK-432 and lyOK-432 was compared in activating dendritic cells (DCs). RADA16-I (R) peptide was dissolved in a mixture of lyOK-432 (O) and DOX (D) to develop an ROD hydrogel. The characteristics of ROD hydrogel were evaluated. Tumor response and mice survival were measured after different treatments. The number of immune cells and cytokine levels were measured, and the activation of cGAS/STING/IFN-I signaling pathway in DC was evaluated both in vitro and in vivo.
RESULTS
LyOK-432 was more effective than OK-432 in promoting DC maturation and activating the IFN-I pathway. ROD was an injectable hydrogel for effectively loading lyOK-432 and DOX, and presented the controlled-release property. ROD treatment achieved the highest tumor necrosis rate (p < 0.001) and the longest survival time (p < 0.001) compared with the other therapies. The ROD group also displayed the highest percentages of DCs, CD4 T cells and CD8 T cells (p < 0.001), the lowest level of Treg cells (p < 0.001), and the highest expression levels of IFN-γ and TNF-α (p < 0.001) compared with the other groups. The expression levels of pSTING, pIRF3, and IFN-β in DCs were obviously higher after treatment of lyOK-432 in combination with DOX than the other therapies. The surviving mice in the ROD group showed a growth inhibition of rechallenged subcutaneous tumor.
CONCLUSION
The novel ROD peptide hydrogel induced an antitumor immunity by activating the STING pathway, which was effective for treating residual liver cancer after iRFA of HCC.
Topics: Animals; Mice; Picibanil; Liver Neoplasms; Carcinoma, Hepatocellular; Hydrogels; CD8-Positive T-Lymphocytes; Doxorubicin; Cytokines; Radiofrequency Ablation
PubMed: 37919724
DOI: 10.1186/s12951-023-02170-0 -
Gynecology and Minimally Invasive... 2021This is a case report of a uterine cancer with the International Federation of Gynecology and Obstetrics staging 3c2 with the initial clinical presentation of...
This is a case report of a uterine cancer with the International Federation of Gynecology and Obstetrics staging 3c2 with the initial clinical presentation of postmenopausal vaginal bleeding in August 2015. Endometrium biopsy showed invasive nests of poorly differentiated grade 3 endometrioid adenocarcinoma. The patient received robotic surgery including total hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissection, para-aortic lymph node dissection, and washing cytology. The final pathology showed an endometrioid carcinoma with myometrium invasion up to 85% and para-aortic and pelvic lymph nodes invasion. The patient received six courses of adjuvant chemotherapy (paclitaxel and carboplatin) with concurrent chemoradiotherapy after the surgery. Later, immunotherapy with Picibanil (OK-432) and interleukin-2 (IL-2) was given, and cancer did not recur for 34 months until tumor recurrence at the liver dome and bilateral lung was noted by positron-emission tomography scan in July 2018. The patient received laparoscopic surgery for intra-abdominal tumor excision in December 2018, and the tumor found extended to the right diaphragm, liver surface, omentum, bilateral flank to pelvic peritoneum, Douglas pouch, and upper rectum. We continued the immunotherapy with OK-432, IL-2, Aldara cream (imiquimod), and later on, virotherapy (human papillomavirus vaccine). The immune risk profiles showed T-cells' proliferation and alteration of the Th1/Th2 activation after immunotherapy and virotherapy. Proctectomy with colon-anal anastomosis and cytoreduction surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) (doxorubicin and paclitaxel) was performed in January 2019. After the surgery, the patient received chemotherapy (topotecan, paclitaxel, lipodox, and carboplatin) and continued the immunotherapy. The immune risk profiles showed CD4, CD4/CD8 increase after HIPEC and immunotherapy. The patient continued the therapy until May 2020.
PubMed: 34485069
DOI: 10.4103/GMIT.GMIT_153_20 -
Annals of Medicine and Surgery (2012) Sep 2022Congenital cystic lymphangiomas (CCL) or lymphatic malformations (LMs) are benign malformations due to a developmental disorder of lymphatic vessels. Besides surgical...
INTRODUCTION
Congenital cystic lymphangiomas (CCL) or lymphatic malformations (LMs) are benign malformations due to a developmental disorder of lymphatic vessels. Besides surgical excision, sclerosant therapy of these lesions by intracavitary injection of OK-432 (Picibanil®), a lyophilized mixture of group A Streptococcus pyogenes, is a common therapeutical option.
METHODS
In a single center retrospective study we analyzed 37 consecutive patients (30 children, 3 adolescents and 4 adults) who were diagnosed with lymphangioma and subsequently treated with OK-432 (Picibanil®) in a general hospital between October 2000 and November 2021.
RESULTS
The median follow-up period was 2.5 months (range 0.7-56.7 months). The lymphangiomas were localized in the head and neck region (n = 25), the thorax/abdomen (n = 6) and extremities (n = 6). The majority of patients had 1 injection with OK-432 (n = 28), five patients had 2 injections, three patients had 3 injections and one patient had more than 3 injections. The most common complications were swelling (89%), fever (81%), redness at the injection site (81%) and pain (73%). The response to therapy was excellent or good in 32 patients (86.4%), 2 patients had a medium response and 3 patients did not show any response. The clinical reaction after the instillation of OK-432 is not predictive for the quality of outcome.
CONCLUSION
The application of Picibanil is safe and without serious side effects. Parents and patients prefer local sclerotherapy versus surgery as it has less complications. We therefore suggest that Picibanil sclerotherapy should be the first-line treatment for macrocystic and mixed type lymphangiomas.
PubMed: 36147081
DOI: 10.1016/j.amsu.2022.104531 -
Clinical Case Reports Oct 2023Proteus syndrome is a rare genetic disease characterized by an asymmetrical growth of individual parts of the body and has only been described in single cases. This...
Proteus syndrome is a rare genetic disease characterized by an asymmetrical growth of individual parts of the body and has only been described in single cases. This patient presented with recurrent manifestations of a laryngeal and hypopharyngeal lymphangioma, which were treated with laser surgery, systemic therapy, and sclerotherapy. The reported data depict the diagnosis and treatment in the department of otorhinolaryngology, head and neck surgery of the university hospital Heidelberg from 2019 until May 2023. The recurrent endoscopy of the upper airway was performed using a flexible HD-endoscope and the Visera Elite video tower from Olympus, Hamburg. The 29-year old female patient initially presented in February 2019 with stridor and exertional dyspnea due to a lymphatic malformation of the left larynx and hypopharynx. In April 2019 there was no improvement by sclerotherapy with Picibanil, so that systemic therapy with the PIK3CA inhibitor alpelisib was initiated (03-07/2020) and discontinued due to a high side effect profile. In the course of 2021-2023, three microlaryngoscopies with laser surgical resection and renewed sclerotherapy of the lymphangioma with Picibanil were carried out due to fluctuating findings. After these interventions a stable disease could be established until May 2023. Laser surgical therapy is currently described as the therapy of choice in lymphangiomas in the head and neck region and also showed the highest effectiveness in our patient. In case of airway obstruction in particular, it can bring rapid symptom relief. Alternatively, and with a lower surgical risk, local improvements have been reported by sclerotherapy, which was less effective in the presented case. Rare syndromic diseases require multidisciplinary collaboration. In the case of laryngeal lymphangiomatosis, other treatment options should be considered in addition to surgical excision, especially in the case of recurrence.
PubMed: 37854262
DOI: 10.1002/ccr3.8073 -
Journal of Cardiothoracic Surgery Jun 2019Postoperative pericardial adhesions are considered a risk factor for redo cardiac surgery. Several large- and medium-size animal models of pericardial adhesions have...
BACKGROUND
Postoperative pericardial adhesions are considered a risk factor for redo cardiac surgery. Several large- and medium-size animal models of pericardial adhesions have been reported, but small animal models for investigating the development of anti-adhesion materials and molecular mechanisms of this condition are lacking. In this study, we aimed to establish a simple mouse model of pericardial adhesions to address this gap.
METHODS
We administered blood, minocycline, picibanil, and talc into the murine pericardial cavity via one-shot injection. Micro-computed tomography analyses of contrast agent-injected mice were carried out for methodological evaluation. We investigated various dosages and treatment durations for molecules identified to be inducers of pericardial adhesion. The adhesive grade was quantified by scoring the strength and volume of adhesion tissues at sacrificed time points. Histological staining with hematoxylin and eosin and Masson's trichrome, and immunostaining for F4/80 or αSMA was performed to investigate the structural features of pericardial adhesions, and pathological features of the pericardial adhesion tissue were compared with human clinical specimens.
RESULTS
Administration of talc resulted in the most extensive pericardial adhesions. Micro-computed tomography imaging data confirmed that accurate injection into the pericardial cavity was achieved. We found the optimal condition for the formation of strong pericardial adhesions to be injection of 2.5 mg/g talc for 2 weeks. Furthermore, histological analysis showed that talc administration led to an invasion of myofibroblasts and macrophages in the pericardial cavity and epicardium, consistent with pathological findings in patients with left ventricular assistive devices.
CONCLUSIONS
We successfully established a simple mouse model of talc-induced pericardial adhesions, which mimics human pathology and could contribute to solving the clinical issues related to pericardial adhesions.
Topics: Animals; Cardiac Surgical Procedures; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Pericardium; Postoperative Complications; Tissue Adhesions; X-Ray Microtomography
PubMed: 31253183
DOI: 10.1186/s13019-019-0940-9 -
Brazilian Journal of Otorhinolaryngology 2023This study aims to perform a meta-analysis to figure out the efficacy of OK-432 sclerotherapy between Macrocystic (MAC) lymphangiomas and Microcystic (MIC) lymphangiomas. (Meta-Analysis)
Meta-Analysis Review
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 (I=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.
Topics: Humans; Picibanil; Sclerotherapy; Retrospective Studies; Lymphangioma; Cysts; Treatment Outcome
PubMed: 37331237
DOI: 10.1016/j.bjorl.2023.03.007 -
Transfusion Medicine and Hemotherapy :... Feb 2022Myeloid leukaemic blasts can be converted into leukaemia-derived dendritic cells (DC), characterised by the simultaneous expression of dendritic- and...
Interferon Gamma Secretion of Adaptive and Innate Immune Cells as a Parameter to Describe Leukaemia-Derived Dendritic-Cell-Mediated Immune Responses in Acute Myeloid Leukaemia in vitro.
INTRODUCTION
Myeloid leukaemic blasts can be converted into leukaemia-derived dendritic cells (DC), characterised by the simultaneous expression of dendritic- and leukaemia-associated antigens, which have the competence to prime and enhance (leukaemia-specific) immune responses with the whole leukaemic antigen repertoire. To display and further specify dendritic cell (DC)- and DC-mediated immune responses, we analysed the interferon gamma (IFNy) secretion of innate and adaptive immune cells.
METHODS
DC/DC were generated from leukaemic whole blood (WB) with (blast)modulatory Kit-I (granulocyte-macrophage colony-stimulating factor [GM-CSF] + Picibanil [OK-432]) and Kit-M (GM-CSF + prostaglandin E1) and were used to stimulate T cell-enriched immunoreactive cells. Initiated anti-leukaemic cytotoxicity was investigated with a cytotoxicity fluorolysis assay. Initiated IFNy secretion of T, NK, CIK, and iNKT cells was investigated with a cytokine secretion assay (CSA). IFNy positivity was additionally evaluated with an intracellular cytokine assay (ICA). Recent activation of leukaemia-specific cells was verified through addition of leukaemia-associated antigens (LAA; WT-1 and Prame).
RESULTS
We found Kit-I and Kit-M competent to generate mature DC and DC from leukaemic WB without induction of blast proliferation. Stimulation of immunoreactive cells with DC/DC regularly resulted in an increased anti-leukaemic cytotoxicity and increased IFNy secretion of T, NK, and CIK cells, pointing to the significant role of DC/DC in leukaemia-specific alongside anti-leukaemic reactions. Interestingly, an addition of LAA did not further increase IFNy secretion, suggesting an efficient activation of leukaemia-specific cells. Here, both the CSA and ICA yielded comparable frequencies of IFNy-positive cells. Remarkably, the anti-leukaemic cytotoxicity positively correlated with the IFNy secretion in T, T, T, and NK cells.
CONCLUSION
Ultimately, the IFNy secretion of innate and adaptive immune cells appeared to be a suitable parameter to assess and monitor the efficacy of in vitro and potentially in vivo acute myeloid leukaemia immunotherapy. The CSA in this regard proved to be a convenient and reproducible technique to detect and phenotypically characterise IFNy-secreting cells. In respect to our studies on DC-based immunomodulation, we were able to display the potential of DC/DC to induce or improve leukaemia-specific and anti-leukaemic activity.
PubMed: 35221867
DOI: 10.1159/000516886 -
Cancer Cell International Jun 2022Colorectal cancer (CRC) with pulmonary metastasis usually indicates a poor prognosis, whereas patients may benefit from adoptive cell therapy. Tumor-specific cytotoxic T...
BACKGROUND
Colorectal cancer (CRC) with pulmonary metastasis usually indicates a poor prognosis, whereas patients may benefit from adoptive cell therapy. Tumor-specific cytotoxic T lymphocytes (CTLs) have been reported as a promising treatment for CRC. However, the antitumor effect of CTLs remains limited partially due to insufficient production of effector cells via the activation by antigen-presenting dendritic cells (DCs).
METHOD
This study showed that a combination of CD40 mAb and Picibanil (OK-432) could significantly enhance the activation of CTLs by DCs, both in vitro and in vivo. Flow cytometry, colon cancer mouse model, and pathological staining were employed to demonstrate the specific functions.
RESULTS
This approach promoted the maturation of DCs, augmented the production of stimulatory cytokines, and suppressed the secretion of inhibitory cytokines. Additionally, it facilitated the killing efficiency of CTLs via stimulating their proliferation while restraining the number of Tregs, concomitantly with the positive regulation of corresponding cytokines. Furthermore, the combined unit could hurdle the expansion of tumor cells on metastatic lungs in the colon cancer mouse model.
CONCLUSION
Collectively, the combination of CD40-mAb and OK-432 facilitated the maturation of DCs and enhanced the cytotoxicity of T cells, promising therapeutic approach against CRC.
PubMed: 35715855
DOI: 10.1186/s12935-022-02630-x -
Biomedicine & Pharmacotherapy =... Oct 2023Radiofrequency ablation (RFA) often results in incomplete ablation for medium-to-large and irregular tumors. To solve this clinical problem, we proposed a new treatment...
BACKGROUND AND AIMS
Radiofrequency ablation (RFA) often results in incomplete ablation for medium-to-large and irregular tumors. To solve this clinical problem, we proposed a new treatment strategy of OK-432 in combination with an anti-programmed cell death protein 1 (αPD-1) antibody for residual tumors after incomplete RFA (iRFA) of hepatocellular carcinoma (HCC).
APPROACH AND RESULTS
The effect of OK-432 on immature dendritic cells (iDCs) was evaluated in vitro. A CCK-8 kit and ELISPOT were used to assess the killing effect of OK-432-induced CD8 T cells in combination with an αPD-1 antibody on Hepa1-6 cells. We found that OK-432 significantly increased the maturation level of DCs, and OK-432-induced CD8 T cells in combination with αPD-1 antibody significantly enhanced the function of CD8 T cells. In the in vivo experiment, HCC model mice were treated with (1) pseudo iRFA + phosphate-buffered saline (PBS); (2) iRFA + PBS; (3) iRFA + OK-432; (4) iRFA + αPD-1; or (5) iRFA + OK-432 + αPD-1. We found that the combined therapy of OK-432 with αPD-1 antibody significantly increased the infiltration and function of CD8 T cells and significantly decreased the number of FoxP3 regulatory T cells in residual tumors after iRFA of HCC. Moreover, the smallest tumor volumes and the longest survival were observed in the triple combination treatment (iRFA+OK-432 +αPD-1 antibody) group compared with the other four groups.
CONCLUSIONS
The combined therapy of OK-432 with αPD-1 antibody induced a strong antitumor immune response, which significantly inhibited the residual tumors after iRFA of HCC. This concept may provide a new treatment strategy to increase the curative efficacy of RFA for medium-to-large and irregular HCCs.
AVAILABILITY OF DATA AND MATERIAL
The data of this study are available from the corresponding author on reasonable request.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Neoplasm, Residual; Picibanil; CD8-Positive T-Lymphocytes; Liver Neoplasms; Mice, Inbred Strains; Antibodies; Radiofrequency Ablation
PubMed: 37625323
DOI: 10.1016/j.biopha.2023.115351 -
Otolaryngologia Polska = the Polish... Jun 2021<b>Introduction:</b> Recurrent thyroglossal duct cyst after surgery is not a rare condition and first-line treatment has not been established...
<b>Introduction:</b> Recurrent thyroglossal duct cyst after surgery is not a rare condition and first-line treatment has not been established yet.<br/><br/> <b>Aim:</b> Evaluation of outcomes and complications of OK-432 treatment in patients with recurrent thyroglossal duct cyst after surgery. <br/><br/> <b>Material and methods:</b> This study is designed as a case series with planned data collection at Tohoku Medical and Pharmaceutical University and Fukase Clinic. Five patients with recurrent thyroglossal duct cyst after surgery received this therapy between January 2014 and February 2020 on an outpatient basis, without hospitalization. OK-432 solution was injected into the lesion using an 18- or 27-gauge needle, depending on the location and size of the lesion, as well as on possible complications.<br/> <br/> <b>Results:</b> Lesions showed marked reduction or total shrinkage in all patients, with no local scarring or deformity at the injection site. Side effects manifested as local pain at the site of injection and fever (37.5-38.5°C) observed in three patients, but the symptoms resolved within a few days.<br/> <br/> <b>Conclusions:</b> Since OK-432 therapy is simple, easy, safe and effective, it can be used as an alternative to surgery in the treatment of recurrent thyroglossal duct cyst after surgery.
Topics: Child; Humans; Picibanil; Thyroglossal Cyst
PubMed: 35175217
DOI: 10.5604/01.3001.0014.9073