Relationship of cytokines to adverse reaction of chimeric antigen receptor T cell immunotherapy and targeted drug intervention / 中国生物制品学杂志

@#Chimeric antigen receptor T cell(CAR-T)immunotherapy is the most potential adoptive immunotherapy for malignant tumors,which needs no antigen presenting cells(APC)and is not limited by major histocompatibiliy complex(MHC). CAR-T immunotherapy not only recognizes and kills tumor cells directly,but also forms memory T cells and establishs long-term anti-tumor mechanism,of which the effect in leukemia,multiple myeloma and other non-solid tumors as well as the great potential in solid tumors have been widely verified. However,a variety of adverse reactions such as cytokine release syndrome(CRS),neurotoxicity(NT)and miss target effect are produced during CAR-T immunotherapy,of which the occurrence of CRS and NT may be related to the abnormal level of cytokines. Remarkable increase of cytokine level is a major characteristics of CRS. However,the increase of cytokines is neither the root cause nor the only result of CAR-T adverse reaction. CAR-T immunotherapy has a high incidence of adverse reaction which may even endanger the life of patients. Cytokine targeted drugs such as Anakinra and Tocilizumab may decrease the incidence of adverse reaction and improve the prognosis of patients. This paper reviews the correlation of cytokines with CRS and NT in CAR-T immunotherapy and the effect of cytokine targeting drugs,so as to provide a reference for the basic research,quality control and clinical application of CAR-T immunotherapy.

Universal chimeric Fcγ receptor T cells with appropriate affinity for IgG1 antibody exhibit optimal antitumor efficacy

Developing universal CARs with improved flexible targeting and controllable activities is urgently needed. While several studies have suggested the potential of CD16a in tandem with monoclonal antibodies to construct universal CAR-T cells, the weak affinity between them is one of the limiting factors for efficacy. Herein, we systematically investigated the impact of Fcγ receptor (FcγR) affinity on CAR-T cells properties by constructing universal CARs using Fcγ receptors with different affinities for IgG1 antibodies, namely CD16a, CD32a, and CD64. We demonstrated that the activities of these universal CAR-T cells on tumor cells could be redirected and regulated by IgG1 antibodies. In xenografted mice, 64CAR chimeric Jurkat cells with the highest affinity showed significant antitumor effects in combination with herceptin in the HER2 low expression U251 MG model. However, in the CD20 high expression Raji model, 64CAR caused excessive activation of CAR-T cells, which resulted in cytokine release syndrome (CRS) and the decline of antitumor activity, and 32CAR with a moderate affinity brought the best efficacy. Our work extended the knowledge about FcγR-based universal CAR-T cells and suggested that only the FcγRCAR with an appropriate affinity can offer the optimal antitumor advantages of CAR-T cells.

Efficacy and safety in the use of intraperitoneal hyperthermia chemotherapy and peritoneal cytoreductive surgery for pseudomyxoma peritonei from appendiceal neoplasm: A systematic review

Abstract The objective of this systematic review is to provide efficacy and safety data in the application of Intra-Abdominal Hyperthermia Chemotherapy (HIPEC) and Cytoreductive Surgery (CRS) in patients with Peritoneal Pseudomyxoma (PMP) of origin in the cecal appendix. The databases Medline and Central Cochrane were consulted. Patients with PMP of origin in the cecal appendix, classified as low grade, high or indeterminate, submitted to HIPEC and CRS. The results were meta-analyzed using the Comprehensive Metanalysis software. Twenty-six studies were selected to support this review. For low-grade PMP outcome, 60-month risk of mortality, Disease-Free Survival (DFS), and adverse events was 28.8% (95% CI 25.9 to 32), 43% (95% CI 36.4 and 49.8), and 46.7% (95% CI 40.7 to 52.8); for high-grade PMP, 60-month risk of mortality, Disease-Free Survival (DFS) and adverse events was 55.9% (95% CI 51.9 to 59.6), 20.1% (95% CI 15.5 to 25.7) and 30% (95% CI 25.2 to 35.3); PMP indeterminate degree, 60-month risk of mortality, Disease-Free Survival (DFS) and adverse events was 32.6% (95% CI 30.5 to 34.7), 61.8% (95% CI 58.8 to 64.7) and 32.9% (95% CI 30.5 to 35.4). The authors conclude that the HIPEC technique and cytoreductive surgery can be applied to selected cases of patients with PMP of peritoneal origin with satisfactory results.

Effect of Shenwei Ningyu Pills on Immunoinflammatory Response Mediated by TLR4/MyD88 Signaling Pathway in Hippocampus of Rats Exposed to Chronic Restraint Stress / 中国实验方剂学杂志

Objective:To explore the effects of Shenwei Ningyu pills （SNP）， a new Chinese medicine for depression， on the immunoinflammatory response mediated by Toll-like receptor 4 （TLR4）/myeloid differentiation factor 88 （MyD88） signaling pathway in the hippocampus of rats exposed to chronic restraint stress （CRS）. Method:Forty-four male Sprague Dawley rats were randomly enrolled into a normal group， a model group， an escitalopram group， and an SNP group. Except for the rats in the normal group， all rats were exposed to CRS and isolated rearing for 21 days continuously. Rats in the escitalopram group and the SNP group were administered with escitalopram （30 mg·kg^-1） and SNP （18 mg·kg^-1） one hour prior to CRS， respectively. The changes in body weight， sucrose preference index， horizontal movement scores， and vertical movement scores were observed by body weight assessment， sucrose preference test， and open field test. The expression of hippocampal TLR4 and MyD88 was detected by Western blot. The content of serum interleukin-1<italic>β</italic> （IL-1<italic>β</italic>）， IL-10， and tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>） was detected by enzyme-linked immunosorbent assay （ELISA）. Result:The results of the behavioral assessment showed that there was no significant difference in the changes of behavioral baselines among the groups before intervention. However， significant differences were found among the groups following different interventions. The body weight， sugar preference index， horizontal movement score， and vertical movement score of rats in the model group decreased after CRS for 21 days as compared with those in the normal group （<italic>P</italic><0.01）. The above indicators in the SNP<italic> </italic>group and the escitalopram group were higher than those in the model group （<italic>P</italic><0.01）， which indicated that SNP<italic> </italic>exerted an obvious antidepressant effect. The results of Western blot and ELISA showed that compared with the normal group， the model group showed elevated levels of hippocampal TLR4 and MyD88 and serum IL-1<italic>β</italic> and TNF-<italic>α </italic>（<italic>P</italic>˂0.01） and dwindled serum IL-10 （<italic>P</italic>˂0.01）， while SNP<italic> </italic>and escitalopram reversed the conditions in the model group （<italic>P</italic>˂0.01） except for TNF-<italic>α</italic>. Conclusion:The present study indicated that the antidepressant effect of SNP was presumedly achieved by inhibiting the immunoinflammatory response mediated by the TLR4/Myd88 signaling pathway in CRS rats.

Research progress on the diagnosis and treatment of CAR-T immunotherapy-induced cytokine release and neurotoxic syndrome / 中国肿瘤生物治疗杂志

@#[摘 要] 嵌合抗原受体基因修饰T淋巴细胞（CAR-T）免疫治疗尤其在复发/难治性恶性血液病的临床应用中显示出卓越的疗效，被认为是最有前景的肿瘤治疗方法之一，但是CAR-T免疫治疗中可引发独特的毒性作用，其中细胞因子释放综合征（cytokine release syndrome，CRS）和免疫效应细胞相关神经毒性综合征（immune effector cell-associated neurotoxicity syndrome，ICANS）在临床应用中最为常见，并具有潜在的致死性，使得CRA-T疗法的广泛应用受到一定的限制，因此如何最大程度地利用CAR-T免疫治疗的同时努力减少或预防CRS和ICANS的发生是目前临床研究的重点，深入了解CRS和ICANS的发生机制能为新的预防措施提供思路。早期识别相关危险因素及鉴定生物预测标志物，熟悉其分级与治疗措施，有利于规范CAR-T免疫疗法的临床应用和患者安全管理。本文就CRS和ICANS的危险因素、发生机制、临床表现、分级与治疗和预防措施等方面进行综述，旨在为CAR-T疗法常见毒性作用的规范管理提供帮助。

Preclinical study of suicide gene as a safety switch to control CAR-T cell cytotoxicity / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate whether AP1903, a small-molecule chemical inducer, can terminate the cytotoxicity of CD19CAR-T cells over-expressing iCasp9 suicide gene in vivo and in vitro. Methods: CD19CAR-T cells over-expressing iCasp9 (iCasp9-CD19CAR-T) were constructed and co-incubated with AP1903. Then, the cell phenotype and apoptosis were detected by Flow cytometry, and the iCasp9/CID suicide gene system was verified on K562 and T cells, respectively. The cytotoxicity of iCasp9-CD19CAR-T cells was detected in vivo (survival rate of NCG mice bearing Raji cell transplanted xenograft) and in vitro (cell killing function was detected by Flow cytometry) under the administration of AP1903. Results: Compared with CD19CAR-T cells, iCasp9-CD19CAR-T cells showed in significant difference in proliferation, phenotype and cytotoxicity both in vitro and in vivo (all P>0.05). At 2 h after AP1903 administration, the apoptosis rates of K562 and T cells co-expressing iCasp9 and CD19CAR were (33.8±0.9)% and (27.95±0.35)%, respectively; and at 24 h after AP1903 administration, the apoptosis rates reached 100% in both cell lines. The in vitro cytotoxicity of iCasp9-CD19CAR-T cells induced by AP1903 was significantly lower than that without AP1903 treatment (P<0.01); the 60-day survival rate of mice bearing Raji cell transplanted tumor treated with AP1903-induced iCasp9-CD19CAR-T cells was also significantly lower than those treated with iCasp9-CD19CAR-T cells alone (P<0.01). Conclusion: AP1903 can effectively terminate the cytotoxicity of CD19CAR-T cells over-expressing iCasp9 suicide gene in vitro and in vivo.

Clinicalstudy of low dose dexamethasone in preventing severe CRS after CD19 CAR-T therapy / 中国输血杂志

【Objective】 To investigate the clinical application value of low dose dexamethasone in CRS prevention after CD19 CAR-T therapy. 【Methods】 67 cases of acute lymphoblastic leukemia(ALL) patients from January 2018 to March 2021 were selected as the research subjects. According to the admission time, patients were divided into dexamethasone prevention(DDD≤5 mg)group(n=36)and the control(n=31). The incidence of severe CRS and treatment outcome were compared. 【Results】 In the dexamethasone prevention group and the control, the incidence of severe CRS were 8.3%(3/36)vs 38.7%(12/31)(P0.05), the complete remission rate was 91.7%(33/36)vs 87.1%(27/31)(P>0.05), and the infection rate was 33.3%(12/36)vs 35.4%(11/31)(P>0.05). 【Conclusion】 The low dose dexamethasone as a prophylactic could significantly reduce the incidence of severe CRS, but had no influence on CAR-T cell proliferation and treatment outcome.

International guidelines for the treatment of peritoneal cancer: clinical pathways of cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy / 中国肿瘤临床

Peritoneal cancer originates from a wide range of tumor sources and is associated with poor prognosis. Standardized therapy is of great significance in the treatment for patients with peritoneal cancer. The Peritoneal Surface Oncology Group International (PSOGI) instituted guidelines for peritoneal metastases. This article uses the Chinese version, which is divided into four parts: preoperative evaluation, surgery, chemotherapy, and clinical pathway. The preoperative evaluation consists of preoperative computed tomography, prognostic evaluation model, diagnostic laparoscopic exploration, the peritoneal cancer index, and the cytoreduction score. Peritoneal cancer treatment primarily consists of comprehensive treatment with cytoreductive surgery (CRS) and intraperitoneal hyperthermic chemotherapy. However, complete CRS is the key to the long-term survival of patients. Peritoneal cancer chemotherapy generally includes perioperative chemotherapy and regional chemotherapy. Finally, this guide outlines the clinical pathways. The Chinese version of the guidelines was published under the permission of the Secretary-General of the PSOGI Executive Committee.

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei: a single-center experience with 854 patients / 中国肿瘤临床

Pseudomyxoma peritonei (PMP) is a rare clinical syndrome. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is gradually being accepted as the standard treatment for PMP. At Aerospace Hospital, we have been treating patients with PMP since 2008 and performing total peritoneal resection since 2016. This study summarizes the experience at our center and collates past data. Methods: We performed a retrospective analysis of a prospectively maintained database of all patients who had undergone CRS and HIPEC for PMP at our center. Clinical data, such as the surgical approach, completeness of cytoreduction, and surgical complications, were collected. The results from follow-up were analyzed to simultaneously evaluate the clinical value of CRS+HIPEC and peritonectomy procedures. Results: A total of 854 consecutive patients with PMP were included in the study. Their mean age was 50 years. The median modified peritoneal cancer index (PCI) was 29. Of the patients, 25.5% under-

Selection strategy for complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy among patients with gastric cancer with peritoneal metastasis / 中国肿瘤临床

Objective: To construct a predictive model to assess the completeness of cytoreduction (CC) and help guiding selection for cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) in patients with gastric cancer with peritoneal metastasis (GCPM). Methods: GCPM patients treated with CRS+HIPEC at Beijing Shijitan Hospital were enrolled in this study. The major clinicopathologic and therapeutic characteristics were compared between those with complete CRS (CCRS) and incomplete CRS (ICRS). A nomogram based on a Logistic regression model was constructed for predicting the risk of ICRS. The nomogram was evaluated using area under receiver operating characteristic curve (AUC) and validated using the bootstrap resampling method. The probability of CCRS was predicted using the nomogram. Results: Among the included 125 patients with GCPM, 52 had CC0 cytoreduction and 73 had CC1-3 cytoreduction. The median overall survival (mOS) was 30.0 (95% CI: 16.8-43.3) months in the CC0 group, which was significantly longer than the mOS of 7.3 (95% CI: 5.8-8.8) months in the CC1-3 group (P<0.001). As there were no significant differences in OS among the CC1, CC2, and CC3 groups, CC0 patients were included in the CCRS group and CC1-3 patients were included in the ICRS group. Multivariate Logistic regression demonstrated that the time of peritoneal metastasis development (OR=14, 95% CI: 2.0-97.9, P= 0.008), preoperative tumor markers (TM) (OR=6.5, 95% CI: 2.1-37.8, P=0.037), and peritoneal cancer index (PCI) (OR=1.5, 95% CI: 1.3-1.8, P<0.001) were independent predictive factors for ICRS. The AUC of the nomogram was 0.985. Internal validation displayed good accuracy and consistency between the predictions and the actual observations. The cutoffs of PCI, with the probability of CCRS set at ≥ 50%, were ≤16, ≤12, ≤10, and ≤5 for synchronous GCPM with normal TM, synchronous GCPM with abnormal TM, metachronous GCPM with normal TM, and metachronous GCPM with abnormal TM, respectively. Conclusions: Complete CRS+HIPEC improves the survival of some patients with GCPM. A selection strategy based on PCI combined with the time of peritoneal metastasis development and TM may be a practical way for selecting patients with GCPM eligible for CCRS.

Progress on chemotherapy for peritoneal carcinomatosis / 中国肿瘤临床

Peritoneal carcinomatosis is obtaining extensive attention because of its late detection and poor prognosis. Lately, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are widely used for the treatment of this condition and could be effective in some carefully selected patients. Different chemotherapies are combined with CRS or HIPEC, and different drug administration routes are used, such as intraperitoneal or pressurized intraperitoneal aerosol chemotherapy. Furthermore, the results of many clinical trials differed among patients with different types of cancer. Herein, we reviewed recent studies in patients with gastric, colon, and ovarian cancer to evaluate the progress of chemotherapy for peritoneal carcinomatosis.

A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma / 医学前沿

The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

Non-linear Finite Element Analysis of Trans-Tibial Residual Limb and Prosthetic Socket / 医用生物力学

Objective To study the load transfer mechanics between residual limb and prosthetic socket, as well as stress distributions below the residual limb, so as to provide a theoretical basis for designing and optimizing of prosthetic socket and improving the wearing comfort. Methods Aiming at compression-release stabilization （CRS）, the finite element software ABAQUS was used to analyze the stress distribution at the interface between the residual limb and CRS socket. The soft tissues were defined using the Mooney-Rivlin function. The interface pressures and shear stresses between the residual limb and CRS socket during mid-stance were obtained. A three-dimensional finite element model of the patellar tendon bearing (PTB) socket was established, and the results were compared. Results The interface pressures between the residual limb and CRS socket were mainly distributed at lateral tibia, media tibia and popliteal depression regions, which were similar to the main force regions of PTB socket. The mean interface pressures on the end of stump for CRS socket was increased by 19 kPa over PTB socket. Conclusions CRS socket had better breathability and reasonable stress distributions. The stress distribution of biomechanical interface was different due to the different shapes of socket. Therefore, the optimization of prosthetic socket can help to improve the wearing comfort of prosthetic limbs.

The Association of Patient-Reported Local Allergic Symptoms with Postoperative Outcomes of Chronic Rhinosinusitis

Diagnosis and treatment of pseudomyxoma peritonei of extra-appendiceal origin:analysis of 34 cases / 中国肿瘤临床

Objective: To investigate the clinicopathological features and treatment strategy of pseudomyxoma peritonei (PMP) of ex-tra-appendiceal origin. Methods: Clinical data of 34 patients diagnosed with PMP of extra-appendiceal origin who were treated by cy-toreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the Aerospace Center Hospital from September 2011 to February 2019 were retrospectively analyzed. Clinical and imaging features were summarized and the Log-rank test was used for survival analysis. Results: The clinical manifestations of the 34 patients with PMP of extra-appendiceal origin were mainly abdomi-nal distension (58.8%) and abdominal pelvic mass (52.9%), which are very similar to those of appendiceal PMP. The incidence of main complications after CRS and HIPEC was 14.7%. During the follow-up period of a median of 12 months (range 1-46 months), 9 patients died, and the 1-and 3-year overall survival rates were 69.6% and 53.5%, respectively. In the univariate analysis, peritoneal cancer in-dex (PCI)>20, no HIPEC, and non-radical surgery were significant risk factors for poor prognosis, while gender, age, origin, and patho-logical type did not show significant correlations. Conclusions: The clinical features of PMP of extra-appendiceal origin are not differ-ent to those of PMP originating from the appendix. It is difficult to ascertain the primary lesion before the operation; however, regard-less of the origin, CRS combined with HIPEC is always a safe and effective treatment choice.

Hygroscopicity Study of Vitamin B12 Chemical Reference Substance / 中国药学杂志

OBJECTIVE: To investigate the hygroscopicity of vitamin B12 and the related problems of its chemical reference substance (CRS) that should be paid attention to. METHODS: UV absorption coefficient was determined at 361 nm, using water as solvent. Dynamic vapor absorption analysis (DVS) was applied to evaluate the moisture sorption trend and capacities of vitamin B12 under different humilities. RESULTS: Owing to the strong hygroscopicity of vitamin B12, deviation in the process of weighing might result in smaller UV absorption coefficient compared with the actual value, especially for dried and low moisture content raw materials in high-humidity environment. CONCLUSION: In the study of drug quality control for vitamin B12, the strong hygroscopicity of the raw material should be paid attention to, particularly in the research and application of vitamin B12 CRS.

Quality of Life after Functional Endoscopic Sinus Surgery in Patients with Chronic Rhinosinusitis at Tertiary Care Hospital

Background: Chronic rhinosinusitis (CRS) is a pathogenic disease of infection commonly affected the ear, nose and throat. Chronic Rhinosinusitis (CRS) has a serious negatively impact over quality of life of patients. Quality of life, nature of job and environmental conditions are the primary reasons of spread of rhinosinusitis. Most of the symptoms of CRS are not life threatening but generally these leads to poor quality of life by affecting the efficiency of individuals. Methods: This prospective study was conducted in the department of ENT in tertiary care hospital among the 50 patients with clinical presentation, endoscopy examination and CT-scan changes of chronic rhinosinusitis (CRS) without a polyp. The history of the patients were taken and then the different ENT examinations were done like endoscopic examination of the nose and CT-scan imaging. All the surgeries like uncinectomy, middle meatal antrostomy, anterior and posterior ethmoidectomy, or opening of the sphenoid sinus were performed under general anesthesia with orotracheal intubation and hypotensive technique. All the patients were regularly given the postoperative antibiotic and nasal steroid treatments and reviewed regularly. Sinonasal Assessment Questionnaire - 11 (SNAQ-11) were used for the collection of data because this questionnaire contains 11 questions covering most of the symptoms of sinonasal diseases. Results: ‘Total 50 patients were included in this study among them 32 (64%) were male and 18 (36%) were females. All the patients was between 18-60 years among them 16 (32%) were the age group 25-35 years, followed by age group 35-45 years 14 (28%). The most common preoperative complaint of the patients was nasal obstruction (100%) patients, followed by nasal congestion (96%), facial pain (94%), running nose (90%), anterior nasal discharge (76%), and least complaint was sneezing (28%) and earache (28%). Conclusion: The study concludes, this study shows the significant outcome of improvement in the quality of life of patients in all the three subgroups of chronic rhinosinusitis which can be assessed by using SNOT-11 questionnaire. The Functional endoscopic sinus surgery performed in patients with chronic rhinosinusitis has statistically significant with the association of improvement in the QoL after twenty 24 month follow up. There is paucity of data so more studies are required to the scientific evidence gathered on the effectiveness of surgery offered to our population, as seen in studies performed in other countries.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gastrointestinal cancers: fad or standard of care?

Peritoneal metastases (PM) are the common endpoint for patients with advanced gastrointestinal cancers. PM from these cancers are often managed in a similar fashion to other sites of systemic metastases, but the following must be taken into consideration. (a) PM do not respond to systemic chemotherapy in the same fashion as liver and lung metastases. (b) PM cause local problems, resulting in disruption of chemotherapy. (c) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) actually work for PM. (d) PM are not easily detected on imaging modalities. There has been mounting evidence of the effectiveness of CRS-HIPEC at prolonging survival in selected patients with colorectal and gastric PM, but there remains a reluctance to explore this treatment modality. This is likely because of the perceived morbidity and mortality. An effective management strategy employing CRS-HIPEC for selected patients with gastrointestinal PM can only be achieved if a concerted effort is made to understand this disease and address the concerns regarding this treatment.

Meningococcal disease outbreak related to the World Scout Jamboree in Japan, 2015

Problem: Six invasive meningococcal disease cases occurred among Scottish and Swedish nationals associated with the World Scout Jamboree (WSJ), an international mass gathering, held in Japan. The index case developed symptoms while returning home. The strains from all six cases were identical and seldom seen in Japan. Context: Over 33 000 participants from 155 countries attended WSJ. At the Jamboree site, participants of the North of Scotland’s and Sweden’s units camped within the same subcamp and kept the same schedule of events. No information was available about the Swedish and Scottish cases’ close personal contact history. Action: Health Protection Scotland investigated Scottish cases, conducted active case finding, provided chemoprophylaxis, vaccinated close contacts and advised Scottish WSJ participants and contacts to seek medical care if they developed symptoms. The Public Health Agency of Sweden recommended chemoprophylaxis to all participants in Sweden. In Japan, the Ministry of Health, Labour and Welfare (MHLW) requested the Scout Association of Japan advise all participants to seek medical attention if they developed symptoms. MHLW shared information about the event with local authorities, medical associations, and the Ministry of Education, Culture, Sports, Science and Technology. Outcome: No additional case related to WSJ has been reported. This outbreak highlighted the risk for international spread of invasive meningococcal disease at international mass gatherings. Discussion: Assessing risk, educating participants, enhancing surveillance and sharing timely information among related countries are significant for prevention and response against invasive meningococcal disease outbreaks at mass gatherings.

The burden of congenital rubella syndrome in the Philippines: results from a retrospective assessment

Introduction: In line with the regional aim of eliminating rubella and congenital rubella syndrome (CRS), phased introduction of rubella-containing vaccines (RCV) in the Philippines’ routine immunization programme began in 2010. We estimated the burden of CRS in the country before widespread nationwide programmatic RCV use. Methods: We performed a retrospective chart review in four tertiary hospitals. Children born between 1 January 2009 and 31 December 2014 and identified as possible CRS cases based on the presence of one or more potential manifestations of CRS documented in hospital or clinic charts were reviewed. Cases that met the clinical case definition of CRS were classified as either confirmed (with laboratory confirmation) or probable (without laboratory confirmation). Cases that did not fulfil the criteria for either confirmed or probable CRS were excluded from the analysis. Results: We identified 18 confirmed and 201 probable cases in this review. Depending on the hospital, the estimated incidence of CRS ranged from 30 to 233 cases per 100 000 live births. The estimated national burden of CRS was 20 to 31 cases per 100 000 annually. Discussion: This is the first attempt to assess the national CRS burden using in-country hospital data in the Philippines. Prospective surveillance for CRS and further strengthening of the ongoing measles-rubella surveillance are necessary to establish accurate estimates of the burden of CRS and the impact of programmatic RCV use in the future.