MB Patients Research Articles

Supplementation of Zinc Sulphate Decrease for Cytokine Levels TNF-Α, IL-1β and IL-6 in Multi Basiler Leprosy Patients

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LC‐MS‐based urine metabolomics analyses for early diagnosis of medulloblastoma

(MB) is the most common type of brain cancer in pediatric patients. In present study, we applied liquid chromatography ‐ mass spectrometry (LC‐MS) based metabolomics to analyze a cohort including 425 urine samples (118 healthy controls, 112 medulloblastoma patients, 33 patients with brain malignant cancers and 53 patients with brain benign diseases, 29 MB patients with surgery after a week and 80 MB patients with surgery after a month). Differential metabolites were analyzed to investigate if urine metabolites could differentiate MB from non‐MB. Apparent separation was observed between MB urine samples and healthy controls, brain benign diseases, other brain malignant tumor. The AUC in discovery group respectively were 0.94, 0.938, 0.808, and the AUC of external validation dataset were 0.913, 0.889, 0.822. According to the comparisons, 14 metabolites were found to be the specific metabolites of MB. Among 14 metabolites, two metabolites were validated in postoperative samples and with high AUC values (0.858 compare to non‐MB). Our data showed that urine metabolomics could be used for MB diagnosis and would provide candidates for the potential biomarkers of MB.Support or Funding InformationNational Basic Research Program of China (No. 2013CB530805, 2014CBA02005)

Comparison of Quantitative light-induced fluorescence-digital (QLF-D) images and images of disclosed plaque for planimetric quantification of dental plaque in multibracket appliance patients

The purpose of the present cross-sectional clinical study was to check the ability of plaque detection and quantification by QLF-D against conventional digital photographs of disclosed plaque in multibracket appliance (MB) patients. 20 patients were included according to the following criteria: (1) upper and lower jaw treated by MB appliance, (2) patients being 16 years of age or older, (3) all central and lateral incisors as well as canines in situ, (4) absence of developmental defects, carious lesions, surface fillings, prosthetic restorations or recessions greater than 1/3 of root length in central/lateral incisors and canines as well as (5) declaration of consent. QLF-D and conventional photographs were analyzed planimetrically regarding plaque coverage on buccal and oral surfaces of central/lateral incisors and canines. The conventional photographs of stained plaque served as gold standard. On average, in QLF-D pictures 20.7% ± 17.4 of the tooth surfaces were covered with plaque, while the conventional photographs of disclosed plaque presented a mean plaque-covered area of 36.2% ± 23.5. The Bland-Altman plot for both imaging modalities showed a very large inconsistent scattering with both negative and positive deviations. The method discrepancy increased with increasing plaque coverage, thus indicating a systematic method error. On average, the deviation of the methods from the optimal line of accordance was −15.5%. In patients wearing MB appliances, there was no clinical significant agreement regarding the plaque-covered tooth surface depicted by QLF-D respectively conventional images of disclosed plaque. Due to the large method discrepancy, QLF-D is currently not reliable for precise plaque quantification in MB patients.

Comparison of interleukin 4 levels in leprosy and non-leprosy patients at Dr. Muhammad Hoesen Palembang General Hospital

Leprosy is a chronic granulomatous infectious disease caused by the mycobacterium leprae which injure the skin and peripheral nervous system. The spectrum and clinical type of leprosy are based on cellular immunity responses namely T-helper 1 (Th1) and T-helper 2 (Th2). This study aims to compare serum IL-4 levels between lepers and non-lepers in Dr. Mohammad Hoesin Palembang General Hospital. This research is an observational analytic study with a case-control design conducted at Dr. Mohammad Hoesin Palembang General Hospital. IL-4 examination is carried out using the ELISA method at the Molecular Biology Laboratory, Faculty of Medicine, Sriwijaya University in January to February 2019. The case and control groups were 40 lepers and 40 medical personnel and paramedics working in Dr. Mohammad Hoesin Palembang General Hospital and family patients. The study included IL-4 levels, respondent status, clinical type of leprosy, and characteristics of respondents. In the leprosy group, the average age is 35 years, and most of them are male (27). In the non-leprosy group, the average age is 36.5 years, and most of them are female (24). There are more MB patients (36) than PB type (4) while type BL (19), type LL (10) type BB (7) and type BT and BB (2). The median value of IL-4 levels in leprosy patients is 209.63 pg/ml range from 103-243 pg/ml while the median value of IL-4 levels in non-leprosy patients is 63.38 pg/ml range from 32-125 pg/ml. Mann-Whitney analysis results show a p-value of 0.000. There is a significant difference between Interleukin 4 levels in lepers and non-lepers where IL-4 levels are higher in lepers than non-lepers.

Clinical and molecular characteristics of WNT medulloblastomas

WNTMBaccounts for about 10% of all medulloblastomas and have a favorable outcome in patients under 16 years according international data. We analyzed clinical and molecular characteristics of 20 patients with WNTMBpatients. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The molecular group verification was performed by Nanostring gene expression profiling. The detection ofCTNNB1andTP53gene mutations was carried out with Sanger sequencing. WNT Medulloblastoma are mainly classic (18/20 patients), non-metastatic (19/20 patients). Gross total resection was performed in 18 patients. SomaticCTNNB1mutations were found in 17 patients, somaticTP53were identified in 2 patients. 19/20 assessable patients are disease-free with a median follow-up of 23 months. One patient died from the progression of the disease. WNT MB patients have an overall favorable outcome, even for metastatic andTP53positive tumors. The reduction in the intensity of therapy is indicated forWNTMB in case of reliable identification ofWNTMB.

Desempenho dos antígenos PGL-1, LID-1 e NDO-LID para diagnóstico sorológico de hanseníase em pacientes e contatos domiciliares


 A hanseníase afeta os nervos periféricos e a pele levando a ocorrência de incapacidades na ausência de tratamento específico oportuno. Portanto, parâmetros sorológicos são necessários para intervenções terapêuticas precoces. A detecção de anticorpos contra o glicolipídio fenólico I (PGL-I) é amplamente empregada no diagnóstico e classificação clínica, enquanto a proteína Leprosy IDRI Diagnostic (LID)-1 foi desenhada com a intenção de melhorar o diagnóstico de pacientes paucibacilares. Posteriormente, este antígeno foi conjugado com o natural dissacarídeo ligado ao radical octil (ND-O) do PGL-I, originando o NDO-LID, para aumentar sua sensibilidade. Nesta revisão, avaliamos 16 estudos, comparando a performance desses três antígenos (PGL-I, LID-1 e NDO-LID) para diagnóstico da hanseníase e avaliação de contatos domiciliares. Verificamos grande variação quanto às populações envolvidas, tamanho das amostras, classificação clínica dos pacientes e metodologia utilizada, dificultando a comparação. Entre os pacientes multibacilares, a positividade anti-PGL-I variou de 54,0 a 96,0%, enquanto para LID-1 foi de 47,4 a 94,8% e para NDO-LID apresentou níveis de 60,0 a 98,9%. Nos pacientes paucibacilares, a positividade variou de 6,4 a 52,9% quando PGL-I foi utilizado, 4,0 a 60% contra LID-1 e 16,0 a 63,6% frente ao NDO-LID. Para os contatos domiciliares, as respostas anti-PGL-I, LID-1 e NDO-LID foram 13,2%, 21,7% e 22,9%, respectivamente. O antígeno NDO-LID apresentou maior sensibilidade na maioria dos estudos refletindo seu potencial como ferramenta para o diagnóstico da hanseníase, principalmente em pacientes MB, entretanto, o reconhecimento desse antígeno por contatos domiciliares saudáveis reforça o valor da avaliação clínica para o diagnóstico da hanseníase.

PATH-18. CSF-DERIVED CIRCULATING TUMOR DNA REFLECTS DISEASE COURSE AND CLONAL EVOLUTION IN MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in young children. A multi-modal approach comprises standard of care, and recent advances in molecular studies have identified clinically relevant subgroups. Nonetheless, 30% of MB patients relapse or progress, conferring dismal prognosis. Such suboptimal outcome is partly due to a lack of sensitive biomarkers for response-adapted personalization of treatment and relapse prediction. Circulating tumor DNA has been shown to correlate with disease status in a variety of adult cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. Here, we aim to evaluate the utility of profiling cell-free DNA (cfDNA) derived from longitudinally-banked cerebrospinal fluid (CSF) samples collected from children with MB enrolled in two prospective, multi-center trials (SJMB03 and SJMB12, estimated sample size of 100 patients, including 50 with subsequent progression). cfDNA was extracted, quantified, and analyzed for size distribution from pre-centrifuged CSF serially banked during the course of treatment and follow-up. Low-pass whole genome sequencing (LP-WGS) enabled detection of chromosomal and focal copy number alterations (CNAs). CNAs detected in cfDNA were compared against known somatic changes in corresponding primary tumors. Detectability of tumor-specific CNAs in cfDNA was then correlated with tumor burden and patient outcome. Pilot analysis showed presence of arm level and/or focal CNAs in cfDNA from 80% of CSF samples in 20 children with metastatic MB, and longitudinal assessment revealed correlation with clinical course throughout treatment with radiotherapy and chemotherapy. Further comparison of tumor and longitudinal cfDNA derived CNAs revealed divergent genomic alterations implicating potential oncogenic mechanisms underlying treatment failure and recurrence. Our study performed on a large prospective series of MB trial patients substantiates the utility of CSF derived cfDNA as an actionable biomarker in high-risk MB patients while also facilitating understanding of tumor evolution and heterogeneity.

HOUT-23. ADULT MEDULLOBLASTOMA TREATMENT IMPACT SINCE 2006: A CANADIAN UNIVERSITY CENTER EXPERIENCE

Abstract INTRODUCTION Medulloblastoma (MB) is an aggressive primary brain tumor rare in adults. Prospective studies in adults are limited by the small number of patients. METHODS We retrospectively reviewed all MB patients treated at the CHUM between 2006 and 2017 in our clinical database adult SARDO. We don’t have the children follow up. We divided our cohort in 2 groups, those diagnosed between 2006–2013 and those diagnosed between 2014–2017. RESULTS 49 patients were treated, 23 (47%) were children referred for radiation only from a pediatric center and 26 (53%) were adults. Median follow up of adults was 26 months. At 5 years, the entire cohort OS was 58%, but specifically for adults, the 5yOS was 80%. First line therapy had a 5y PFS 77% for adults, negatively influenced by the absence of adjuvant radiotherapy (83% vs 0%; p < 0.001) and the absence of adjuvant chemotherapy (80% vs 39%; p < 0.008). 96% of adult patients received radiotherapy and 52% of them received concomitant radiosensitizing chemotherapy with no impact on survival. Complete surgical resection was performed on 88% of patients, but the extent of resection did not have an impact on survival and did not change with time. From 2006–2013, the most common chemotherapy treatment (80%) in adults was Vincristine, Cisplatin and Lomustine. From 2014–2017, the chemotherapy was replaced by Cisplatin, Etoposide and Cyclophosphamide in 82% with no impact on survival (specific mortality for this chemo 3yOS 100% for both, 3y PFS 100%). Non Cisplatin based chemotherapy regimens were associated with decrease in PFS (67% at 3y). 78% of the progressive patients received second line chemo. CONCLUSION In our adult MB population, the demographic and tumor factors did’nt have an impact on prognosis but adjuvant radiotherapy and chemotherapy had a favorable impact on survival especially with Cisplatin, Etoposide and Cyclophosphamide regimen.

RTHP-03. FRAME-BASED AND MASKED STEREOTACTIC RADIOSURGERY: A PATIENT EXPERIENCE COMPARISON WITH THE GAMMA KNIFE ICON

Abstract INTRODUCTION Patients undergoing stereotactic radiosurgery (SRS) for intracranial pathology have two treatment options: frame-based (FB) versus masked (MB). There is sparse information on a patient’s experience between the two types and to what extent a patient’s diagnosis will predict their SRS experience. METHODS A retrospective analysis of patients who completed a questionnaire of their experience after SRS using the Gamma Knife Icon was completed. RESULTS Fifty-eight patients completed the questionnaire, 60% were FB and 40% MB. The average age was 63.3 + 15.3 years, 40% were male. Of the patients treated with a FB technique, 51% didn’t find SRS to be uncomfortable. Comparatively, 91% of MB patients didn’t find SRS to be uncomfortable. Patients who underwent FB treatment rated their pain of frame placement on a visual analog scale (VAS) 1–3, 24%, VAS 4–6, 46%, VAS 7–10, 30%. Eight patients answered that they didn’t tolerate the procedure as expected, most of which were treated using a FB method (87%). Compared to previous surgery or SRS, five patients found their experience of SRS wasn’t tolerable, while 93% of patients would consider repeat SRS. All patients treated felt adequately informed about the procedure. The patient experience of discomfort during SRS and their evaluation of pain during frame placement between patients treated for benign versus malignant lesions (discomfort: 59% vs. 22%, respectively and median VAS pain: 6 + 2.67, 4.5 + 1.99, respectively) determined a benign diagnosis had more discomfort during SRS compared to a malignant diagnosis. Pain during frame placement was similar for both diagnoses. CONCLUSION Patients experienced frame-based SRS as more uncomfortable than mask-based treatment. Benign pathologies appeared to have more discomfort compared to malignant pathologies. All patients of both techniques felt adequately informed about their procedure.

415P - Trends in incidence and survival analyses of adult-onset medulloblastoma

BackgroundMedulloblastoma (MB) is a rare central nervous system malignancy in adult. For its rarity, most previous studies are limited on patient populations and ascertainment bias. We aimed to explore the population-level trends in incidence and assess potential predictors of overall survival (OS). MethodsWe utilized the Surveillance, Epidemiology and End Results Program (SEER) database between 1973 and 2015, to estimate the epidemiological trends of adult MB in the United States. Propensity-score matching was used to balance potential selection biases and Cox proportional hazard modeling was used to determine predictors of OS. ResultsThe age-adjusted incidence was stable in MB patients aged 20 years old and elder in total (annual percent change (APC)=0.15). The age-adjusted incidence rate in males was slightly higher than that in females (0.065 vs. 0.049 per 100,000). Compared to whites, the rate was nearly doubled to blacks (0.063 vs. 0.033 per 100,000). There was obvious differ between the younger group and the elder group (aged 20-39: 0.107 vs. aged≥40: 0.025 per 100,000). According to multivariable Cox analysis, age (P<0.001) and surgical resection (P=0.002) were independently prognostic factors. Moreover, subgroup analysis showed that the benefits of radiotherapy (P=0.048) and chemotherapy (P=0.045) were observed in the patients without gross total resection (GTR). After propensity-score matching (n=582), factors impacting OS were age (P<0.001), surgical resection (P=0.012), histology (P=0.031), insurance status (P=0.014) and marital status(P=0.040). ConclusionsFrom the SEER database, race, gender and age disparities were found in incidence of adult MB patients. The survival analysis demonstrated the benefits of the GTR and younger patients. As for patients without GTR, radiotherapy and chemotherapy may improve the long-term survival. Legal entity responsible for the studyFeifei, Lin. FundingThe Fujian Province Natural Science Foundation (2017J01260), Joint Funds for the Innovation of Science and Technology, Fujian province (2017Y9074), and the Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing (2017 Open Project-9). DisclosureAll authors have declared no conflicts of interest.

Comparison of potential long-term costs for preventive dentistry treatment of post-orthodontic labial versus lingual enamel cavitations and esthetically relevant white-spot lesions: a simulation study with different scenarios

BackgroundPost-orthodontic white-spot lesions (WSL) in esthetically relevant incisor and canine areas impair dentofacial esthetics, and preventive dentistry treatment is definitely required in case of enamel cavitations. The incidence of lingual post-orthodontic WSL and cavitation following lingual MB treatment has been reported to be distinctively decreased compared to labial MB treatment. Moreover, lingual WSL do not impair dentofacial esthetics. It was the objective of this study to calculate consequential costs of preventive dental care necessary to recover labial or lingual post-orthodontic cavitations as well as esthetically relevant WSL following either labial or lingual MB interventions.MethodsMB treatments (labial / lingual) were simulated in 1,000,000 patients between the ages of 12-18Y, with a median residual life time expectancy of 58Y based on local mortality tables. Range of MB Tx duration was 9–45 mo. Frequencies of post-orthodontic (labial / lingual) enamel damages were derived from large-scale WSL incidence studies. Anterior composite survival rates were based on a systematic review on the subject. Within the context of the German dental fee system (GOZ 2.3 and 3.5 fee increments), simulation of costs for enamel damage treatment and re-treatment (maximum: 5x) were based on single-surface composite restorations for lingual or labial cavitations and labial WSL treatment; and lingual WSL fluoridation.ResultsOverall mean total costs for Tx and re-Tx of both WSLs and cavitations may sum up to 1718.91 Eur in the high-cost (GOZ 3.5) scenario for conventional MB cases, versus 19.94 Eur for lingually treated cases, given that renewal of simulated single-surface restorations takes place at 15-year intervals. When focussing on patients diagnosed with least of one WSL, and/or cavitation, these mean costs increase up to 2332.35 Eur for conventionally treated MB patients, or 65.03 Eur for lingual MB patients.ConclusionCosts for repeated treatment of post-orthodontic enamel damages produced by conventional vestibular fixed appliances may easily exceed the initially higher costs associated with lingual orthodontic treatment. Judged economically in the long term, lingual MB Tx may be considered as a more cost-effective solution for a correction of malocclusion.

Abstract 1122: CD44 as potential therapeutic target for medulloblastoma metastasis

Abstract Medulloblastoma (MB) is a commonly diagnosed pediatric brain tumor that shows highly variable rates of morbidity and mortality. Metastasis is the leading cause of death in patients with MB, approximately 30% of MB patients have metastatic tumors right at diagnosis. Therefore, there is a critical need to dissect the molecular mechanisms that govern MB progression and metastasis. In our previous work, we found that DHA and VP16 synergistically inhibit MB cell proliferation and induce cell death accompanied with a marked reduction in the expression of CD44 standard form (CD44s). In this study, we show that MB cells express CD44s mainly and the elevated level of CD44s enhances MB cell invasion, suggesting that CD44s may play a crucial role in MB metastasis. In addition, we observed CD44s expression only in MB patients with metastasis using a small cohort of samples. Large database analysis show that MB patients with elevated levels of CD44 have poorer outcomes. Moreover, CD44 knockdown markedly reduces the expressions of transcription factor c-Myc and the platelet derived growth factor receptor (PDGFR) β, both are therapeutic targets for MB. Interestingly, PDGFRβ knockdown abolishes CD44s expression and downregulates the level of c-Myc. However, there is no expression change of CD44s and PDGFR β after the knockdown of c-Myc. These results indicate that the expression and function of CD44s could be critical to MB progression and metastasis, highlighting the potential therapeutic targets for MBs with metastasis. Citation Format: Dan Qi, Fengfei Wang, Ekokobe Fonkem, Jason H. Huang, Erxi Wu. CD44 as potential therapeutic target for medulloblastoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1122.

Pengaruh Suplementasi Seng Sulfat 40 mg/hr Selama 12 Minggu terhadap Kadar Sitokin proinflamasi TNF-α, IL-1β dan IL-6 Pada Penderita Kusta Multi Basiler

The role of zinc as an anti-oxidant and anti-inflammatory has been widely proven, this substance is relatively inexpensive and easily available to the public. Serum zinc levels of leprosy patients and patients with leprosy reactions are lower compared to healthy people, and proinflammatory cytokines including TNF-α, IL-1β and IL-6 play a role in the mechanism of leprosy reactions. Research on the effect of zinc supplementation on leprosy sufferers who have not experienced a reaction has not been done. Objective: To analyze the effect of 40 mg / day dose of zinc sulphate supplementation for 12 weeks on the levels of proinflammatory cytokines and the incidence of reactions in type MB leprosy patients. An experimental study with a randomized control group pre and post test design approach, the subjects of this study were MB patients with 121 patients who did not experience a leprosy reaction, the sample was taken randomly as many as 31 patients as a supplementation group (treatment), and 31 patients as Control group. BMI measurements, food intake by re-call method, Hb level using Hematology Analyzer, serum zinc levels using Atomic Absorption Spectrophotometry (AAS) method, TNF-α, IFN-γ, and IL-1β levels used the ELISA method. Data analysis using chi-square correlation statistical test and mean (mean) test. Zinc sulfate supplementation dose of 40 mg / day for 12 weeks in type MB leprosy patients was able to maintain a decrease in zinc levels of 1.22 pg / dL higher than leprosy patients who did not receive zinc supplementation, reduce levels of IL-1β (p: 0.032 ) However, statistically there is insufficient evidence to reduce levels of TNF-α (p: 0.063) and IL-6 (p: 0.389) and risk factors. Food intake is associated with the incidence of leprosy reactions (p <0.05). Keywords:Supplementation, cytokines, leprosy type MB. Conclusion: The most recent findings in this study were 40 mg / day supplementation of zinc sulfate for 12 weeks in MB type leprosy patients able to maintain a decrease in serum zinc levels, reduce IL-1β levels, and risk factors. Food intake correlated with the incidence of leprosy reactions

Analysis of the rs2476601 polymorphism of PTPN22 in Mexican mestizo patients with leprosy.

Leprosy, a human chronic granulomatous disease caused by Mycobacterium leprae (M. leprae), remains endemic in certain countries despite the use of multidrug therapy. Recently, several host genes modulating the immune responses to M. leprae infection have been suggested to influence the acquisition and clinical course of leprosy. Lymphoid protein tyrosine phosphatase, encoded by the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, serves a negative regulatory role in T cell activation. The non-synonymous single-nucleotide polymorphism (SNP) rs2476601 (1858C>T) has been associated with autoimmune diseases. Here, the present study investigated if rs2476601 polymorphism was associated with leprosy in a Mexican mestizo population. Genotyping was performed in patients with leprosy (n=189) and control subjects (n=231) from regions with higher incidence of leprosy. Genotypic (P=0.44) and allelic frequencies (P=0.45) of the rs2476601 polymorphism were similar between patients and controls; genotypic frequencies were 91 vs. 94% for CC and 9 vs. 6% for CT, and the TT genotype was absent in both groups. Allelic frequencies were 96 vs. 97% for C, and 4 vs. 3% for T. In the same way, the genotypic (P=0.46) and allelic frequencies (P=0.47) from MB patients and controls were similar. In conclusion, there was a lack of association of the PTPN22 rs2476601 polymorphism with the development of leprosy, which suggests that this SNP was not a genetic risk factor for leprosy in the Mexican mestizo population studied.

DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas.

Wingless-activated medulloblastoma (WNT MB) represents a well-characterized molecular variant accounting for 10-15% of all MB and is associated with a favorable clinical outcome. Patients with localized WNT MBs could benefit from de-intensification of combined treatment, which would require an accurate diagnosis of these tumors. However, despite the presence of molecular features related with a WNT MB signature (nuclear ß-catenin immunoexpression, CTNNB1 mutation, and monosomy 6), a prompt and reliable diagnostic verification of these tumors is not yet feasible. In the current study, we analyzed 78 samples of WNT MB treated in a single institute through genome-wide DNA methylation and targeted next generation sequencing to elaborate an optimal method for WNT MB molecular verification. We found that DNA methylation profiling discloses significant advantages for molecular diagnostic of WNT MB. All other "routine" methods applied, such as ß-catenin immunohistochemistry, CTNNB1 mutation analysis, and detection of monosomy 6, failed to identify all WNT MB cases. Survival analysis revealed that application of a reduced radiotherapy protocol for WNT MB treatment had no influence on patients' survival. Only one patient died due to local relapse but recurrent tumor was pathologically and molecularly diagnosed as a secondary glioblastoma. DNA methylation analysis should be considered as a method of choice for further clinically relevant stratification of WNT MB and for correct diagnosis of the recurrent tumors. WNT MB patients with localized disease could benefit from treatment de-intensification.

Profile of Person Affected by Leprosy with Clinical Relapse among in High Endemic State of India

Objective: Relapse is not an unusual phenomenon in leprosy, there are many predisposing factors which may lead to occurrence of relapse; some of these include the presence of persistent bacilli, drug monotherapy, inadequate or irregular therapy. Patients usually presents with presence of multiple skin lesions and/or thickened nerves, reason for early relapse is probably bacillary persistence due to inadequate treatment and for late relapse due to or re-infection. The objectives of this study are to assess various clinico-epidemiological factors associated with the occurrence of relapses in leprosy patients. Methods: A hospital record based retrospective follow-up study has been performed and 117 relapse cases of leprosy were included. Leprosy relapse cases presented in the study hospital were interviewed using a predesigned and pretested preformed. Each patient was subjected to clinical, bacteriological and disability assessments for diagnosis of relapse and followed until the completion of multi drug therapy. Results: During a study period, relapse was seen more in male as compared to female. The duration between cessation of treatment and re-appearance of new lesions varied from 1 to 33 years. Disability proportion was high among MB patients. Conclusion: Relapse in leprosy should be thoroughly examined and looked for drug resistance. J Microbiol Infect Dis 2018; 8(3):103-107

Abstract 5859: Enhanced therapy for MYC-driven medulloblastoma by targeting protein translation pathway

Abstract Medulloblastoma is the most frequent pediatric brain tumor of neuroectodermal cerebellar origin. High-risk MB patients with MYC overexpression and amplification usually show an extremely poor clinical outcome responding poorly to current therapies. Recent preclinical studies have revealed that the aberrant activation and interactions of PI3K/AKT/mTOR signaling is frequently associated with MYC-driven MB therapy-resistance. In addition, it is evident that both MYC and mTOR components of the PI3K/AKT/mTOR signaling axis can directly control and share a common translation pathway in increasing protein synthesis by regulating the expression of multiple components of the protein synthesis machinery, including ribosomal proteins and initiation factors of translation. Thus, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of MYC-driven MB. Therefore, in this study, we investigated the single agents and combined anti-MB efficacies of a recently well-established BRD4 (bromodomain-containing protein 4)/MYC inhibitor JQ1 and PI3K-mTOR dual inhibitor BEZ235. Using four MB cell lines including three MYC amplified cell lines, the in vitro efficacy of this combined approach on cell growth/apoptosis and cell cycle along with associated molecular mechanism(s) were investigated. We used an MTT assay to measure survival and proliferation, flow-cytometric-based propidium-iodide staining to determine the effects of these inhibitors on cell-cycle, Annexin-V analyses to examine the cells undergoing apoptosis following treatments and western blot analyses to determine the expression levels of target molecules. Our results showed that both inhibitors as single agents, significantly decreased MB cell growth and induced apoptosis by targeting the key molecules of the associated pathways. Combined treatment of JQ1 and BEZ235 significantly decreased MB cell growth/survival in a dose-dependent fashion compared to single agent activity. Moreover, JQ1 and BEZ235 alone or combined significantly induced G1 cell-cycle arrest which coincided with decreased expression of cyclin-D1 and increased expression of p21 proteins in MYC-driven MB cells. Mechanistically, the co-treatment of JQ1 and BEZ235 significantly downregulated the expression levels of phosphorylated 4EBP1/p70-S6K (mTOR components) and BRD4/MYC proteins. Together, our findings demonstrate that the combination of JQ1 and BEZ235 showed significant synergistic efficacy against MYC-driven MB, by enhancing the inhibition of protein synthesis (translation) pathway. Initial evidence from this targeted approach, suggests that additional preclinical evaluation is warranted to determine likely clinical utility of targeted therapy for high-risk MB patients. Citation Format: Nagendra K. Chaturvedi, Don W. Coulter, Matthew J. Kling, Sutapa Ray, Timothy R. McGuire, Shantaram S. Joshi, J. Graham Sharp. Enhanced therapy for MYC-driven medulloblastoma by targeting protein translation pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5859.

Abstract 2819: Targeting histone chaperone FACT complex sensitizes medulloblastoma cells to chemo and radiation therapy

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. Post-surgical radiotherapy in combination with adjuvant chemotherapy are considered as standard treatment of care for MB. However, this long-term treatment often leads to harmful neurologic effects to the developing brain in children. Therefore, identification of novel therapeutic target to increase efficacy and reduce toxicity in MB represent an unmet clinical need. Apurinic/apyrimidinic (AP)-endonuclease (APE1) plays a central role in the base excision repair (BER) pathway by repairing AP sites and single-strand breaks, the downstream cytotoxic BER intermediate that occurs following radiation and chemotherapy. Elevated levels of APE1 or its activity has been shown to be associated with response to radiation and chemotherapy in MB. However, how APE1 repairs AP sites in the context of nucleosome in cells and how APE1-dependnt BER pathway can be manipulated to increase the therapeutic efficacy of chemo and radiation therapy remain an open question. We have recently shown that APE1 is acetylated (AcAPE1) at AP site damage in chromatin by p300 and that acetylation enhances AP-endonuclease activity of APE1. Here, we show that APE1 interacts with the nucleosome remodeling histone chaperone Facilitates of Chromatin Transcription (FACT) complex (a heterodimer of SSRP1 and SPT16 proteins) and that FACT complex is required for binding and acetylation of APE1 at AP site damages in highly aggressive MB cell lines HD-MB03 and ONS-76. Furthermore, we have mapped genome-wide binding of AcAPE1 in HDMB cells and our ChIP-seq data analysis revealed ~68154 (p&amp;lt;.001) AcAPE1 binding predominantly located in the transcribed gene regions corresponding to 16370 genes. We aligned ChIP-Seq with RNA-Seq of HD-MB03 cells and found a significant (p&amp;lt;0.0001) correlation of AcAPE1 binding with gene expression. Furthermore, our data show that inhibition of FACT with small molecule inhibitor CBL0137/curaxin, reduces SSRP1 and SPT16 levels from soluble fraction and trap them in chromatin. We found that CBL0137/curaxin treatment results in inhibition of APE1 acetylation, and that MB cells cannot repair DNA damages in the presence of FACT inhibitor. FACT has been shown to play an important role in removal of cisplatin-induced DNA adducts via nucleotide excision repair pathway (NER). Of importance, downregulation of APE1 levels or inhibition of FACT with CBL0137/curaxin sensitizes a panel of highly aggressive MB cell lines to cisplatin and alkylating drug temozolomide. Together, our study suggest that co-suppression of both BER and NER pathways via targeting FACT complex can greatly sensitize MB tumors to chemo and radiation therapy. A major implication of our studies is that combination of curaxin with low dose of cisplatin may have considerable therapeutic potential to improve efficacy and reduce cytotoxic side effects of cisplatin to MB patients. Citation Format: Sutapa Ray, Heyu Song, Shrabasti Roychoudhury, Pranjal Biswas, Sutapa Ray, Kishor Bhakat. Targeting histone chaperone FACT complex sensitizes medulloblastoma cells to chemo and radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2819.

Abstract 1309: Network as a biomarker to predict drug candidates: Mapping driver dysregulated target networks onto pharmacologic data-derived drug networks identifies cardiac glycosides as the potential treatment of Group 3 medulloblastomas

Abstract Background: Medulloblastoma is a heterogeneous group of tumors that consists of four subtypes with distinct genomic signatures. Two of these subgroups are defined by a single dysfunctional signaling pathway, WNT and SHH respectively, which has raised the prospect of taking a rational target based approach to the development of new therapies. Conversely, the other 2 sub-types, Groups 3 and 4, which compose 60-65% of total medulloblastoma cases, are associated with much more complicated genetic, epigenetic and genomic contents and display significant intragroup heterogeneity. In addition, Group 3 are associated with the worst prognosis among all the subgroups and are frequently metastatic at presentation which makes the need for novel approaches to drug discovery for these tumors particularly acute. Results: We developed a computational systems biology method that incorporates novel algorithms for driver signaling network identification (DSNI) and drug functional network-(DFN) based drug repositioning to integrate multiple types of genomics profiles for Group 3 MB patients with human cancer signaling pathways resources and gene expression profiles of 1,309 drugs in CMAP with drug structure information and effects. By applying the DSNI-DFN method on Groups 3 MB data we identified five members of the cardiac glycoside family, a group of Na/K pump inhibitors best known for their role in the treatment of heart failure, as potential inhibitors of driver dysregulated network of the Groups 3 MB. We were subsequently able to validate this finding in cell culture where all 5 compounds lead to significant growth inhibition of Group 3 derived medulloblastoma cell lines. Members of the cardiac glycoside family showed efficacy in vivo in animal models inhibiting proliferation. Digoxin significantly prolonged survival in both PDOX models of Group 3 medulloblastoma (ICb-2055) at a dose which resulted in plasma trough levels similar to those targeted in cardiac patients receiving digoxin. Digoxin-treated mice (n=10) had a median survival of 180 days compared to a median survival of 102 in untreated controls (n=8) (P&amp;lt;0.0001). Furthermore, in the Group 3 model digoxin showed survival extension comparable to ionizing radiation which represents a major component of the current standard care for medulloblastoma. Taken together, these data demonstrate that digoxin has a strong in vivo anti-tumor effect against preformed PDOX tumors derived from Groups 3 medulloblastoma. Conclusions: Our findings represent both an exciting potential new therapy for Group 3 medulloblastoma and validation of an approach that can be applied to identify driver dysregulated networks and predict drugs for a wide variety of genomically complex tumors. Citation Format: Lei Huang, Sarah Garrett Injac, Xiaonan Li, Adesina Adekunle, Hong Zhao, Ching Lau, Stephen Wong. Network as a biomarker to predict drug candidates: Mapping driver dysregulated target networks onto pharmacologic data-derived drug networks identifies cardiac glycosides as the potential treatment of Group 3 medulloblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1309.

Abstract 1140: Genes preserving stem cell state in group 3 medulloblastoma brain tumor initiating cells contribute to therapy evasion and relapse

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of current molecular subgroups, Group 3 patients face the highest incidence of metastatic spread and overall patient survival of less than 50%. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors provide limited clinical benefit, since recurrent metastatic MBs are highly genetically divergent from their primary tumors. By adapting the existing COG (Children's Oncology Group) protocol for children with newly diagnosed high-risk MB to the treatment of immuno-deficient mice intracranially engrafted with human MB brain tumor initiating cells (BTICs), we have characterized the rare treatment-refractory cell population in Group 3 MBs. MB cell populations recovered separately from brains and spines during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy to relapse. One of the most intriguing observations from our gene expression data was consistent over-expression in the treatment-refractory cell population of proteins belonging to the Inhibitor of DNA-binding/differentiation (ID) family (transcription factors with a basic helix-loop-helix motif that act as suppressors cellular differentiation), and a longevity-associated protein known as bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4). This persistent upregulation of genes preserving undifferentiated state and cellular longevity further strengthens the hypothesis of stem-cell like cells driving tumor relapse in MB. Targeting ID1 and BPIFB4 using both knockdown (KD) and knockout (KO) strategies has resulted in decreased self-renewal and tumorigenicity of both primary and recurrent MB cells, further highlighting their potential as novel therapeutic targets in MB. Our differential genomic and gene expression profiles of the “treatment-responsive” tumors against those that fail therapy have successfully contributed to discovery and characterization of novel therapeutic targets for the most aggressive subgroup of MB. Citation Format: Sheila Kumari Singh, David Bakhshinyan, Chitra Venugopal, Ashley Adile, Mohini Singh, Maleeha Qazi, Branavan Manoranjan, Michelle Kameda-Smith. Genes preserving stem cell state in group 3 medulloblastoma brain tumor initiating cells contribute to therapy evasion and relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1140.