Febrifugine is an alkaloid isolated from Dichroa febrifuga as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. As part of an ongoing malaria chemotherapy project, novel febrifugine analogues were designed and synthesized. Lower toxicity of these newly designed compounds was achieved by reducing or eliminating the tendency to form chemically reactive and toxic intermediates. New compounds possess excellent in vivo antimalarial activity and most of them become less toxic than the natural product febrifugine. Some of the compounds possess a therapeutic index over ten times superior to that of febrifugine and the commonly used antimalarial drug chloroquine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.

The purpose of this study was to investigate the expression of autophagy-related proteins Beclin 1 and LC3 in cervical normal epithelial cells and squamous cancer cells, and to evaluate the prognostic significance of Beclin 1 and LC3 expression in FIGO stage I-II cervical squamous cell carcinoma. The immunohistochemical expression of Beclin 1 and LC3 were evaluated in 26 formalin-fixed paraffin-embedded cervical normal tissue samples and 50 tumor samples of FIGO stage I-II cervical squamous cell carcinoma, respectively. Correlations with clinicopathologic characteristics were determined by Chi-square test. The prognostic impact of Beclin 1 and LC3 expression in regard to overall survival was determined by Kaplan-Meier method. Cervical normal squamous epithelial cells and cancer cells expressed high Beclin 1 immunoreactivity in 96.2 % (25/26) and 28.0 % (14/50) of patients (p = 0.000), and expressed high LC3 immunoreactivity in 76.9 % (20/26) and 26.0 % (13/50) of patients, respectively (p = 0.000). The expression of both Beclin 1 and LC3 were not associated with age, FIGO stage, pathologic differentiation, and lymph node metastasis. The 3-year overall survival (OS) rates with low and high expressions of Beclin 1 were 72.2 and 100.0 %, respectively (p = 0.034). The 3-year OS rates with low and high expressions of LC3 were 75.7 and 92.3 %, respectively (p = 0.224). These results show that expression level of both Beclin-1 and LC3 were significantly lower in cervical squamous cancer cells than normal squamous epithelial cells. The expression of Beclin 1 and LC3 may have prognostic significance in early stage cervical squamous cell carcinoma.

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e18567 Background: Immune checkpoint inhibitors (ICI) have now become the mainstay treatment in patients with many kinds of cancers. Thyroid dysfunction as the most common endocrine toxicity is poorly understood. This study aimed to report hypothyroidism and exam its changing dynamtic in our first series of patients treated with ICI. Methods: This is a retrospective study. Patients received nivolumab or pembrolizumab between July 2018 and December 2019 were considered. Patient must have euthyroidism within the 3 months before immunotherapy and those had previous use of levothyroxine were excluded. They were monitored by thyroid function tests every cycle until stopping ICI. Patients must have received at least 3 cycles of antibody treatment. Results: Among 89 patients treated, 59 met the inclusion criteria. There were 33 males, 26 females, including 26 (44.1%) nivolumab, and 33 (55.9%) pembrolizumab. Median age was 62 years [range: 27-88]). Cancer diagnoses observed were non small cell lung cancer 17(28.8%), small cell lung cancer 4 (6.8%),liver cancer 9 (15.3%), head and neck cancer 5 (8.5%), esophageal cancer4 (6.8%) colon cancer 3 (5.1%), nasopharygeal carcinoma 3 (5.1%) melanoma 3 (5.1%) and other cancers 11(18.6%). There were 9 patients (15.3%) developed a thyroid dysfunction, including 5 females. Four patients had thyrotoxicosis (median onset: 8 weeks) followed by hypothyroidism. There were three types of thyroid dysfunctions: the first type patients 3 (33.3%) had a brief time period of TSH flair (peak 17.4-57.8) after the first cycle of ICI, followed by TSH dramatic drop companied with rising fT4, which usually returned to normal level during 3-4 cycles of . The other 4 patients (44.4%) with thyroid dysfunction presented with remarkably elevated TSH (15.43-125.2) after 3.5-10 months’ treatment, followed by hypothyroidism development with a need of levothyroxine. The remaining 1 patient had a third type of thyroid dysfunction with elevated TSH, elavated more while the treatment continue, the patient should be given levothyroxine as soon as possible. Additionally, 1 patient developed hypopituitarism presented with both low level of TSH and fT4 after 10 month treatment. There was no significant difference in patient characteristics between patients with hypothyroidism and those without. Conclusions: There are heterogeneity in thyroid function and hypothyroidism after ICI. Before more experience is gained, frequent monitoring of thyroid function during ICI is warranted for prompt management of the hypothyroidism.

e21043 Background: Homologous recombination (HR) is an important repair method for DNA double-strand damage. HR is involved with complex signaling pathways and multiple steps, including BRCA1/2. Homologous Recombination Deficiency (HRD) can be caused by the loss of function of BRCA1/2 proteins due to gene mutation. Tumor mutational burden (TMB) was indicated to involved with HRD, which is critical to the guidance of immunotherapy. Methods: Patients available with tumor specimen genomic testing for lung cancer were enrolled in this study. The sequencing library was captured using a 605-gene panel. Homologous recombination (HR)-related gene list included 102 genes. Genomic alterations of HR-related genes were assessed by next-generation sequencing assay, including nonsense, nonstop, frameshift, splice site, damaging missense mutations in somatic variants and pathogenic germline variants. Then, TMB was calculated by dividing the total number of mutations counted by the size of the coding region. Results: A total of 741 patients was enrolled and 182 of them (25.6%) had at least one genomic alteration of the HR genes. The top mutant HR genes included ATM (4.1%), DNMT3A (2.8%), ATR (1.8%), CHEK2 (1.5%), BRCA2 (1.5%), ABL1 (1.4%), FANCA (1.2%), RIF1 (1.1%), FANCI (1.1%), RAD50 (0.9%), BRCA1 (0.9%), and MRE11A (0.9%). The most common mutational type was missense mutation (69.2%), followed by frameshift (15.6%), and nonsense mutation (15.2%). The median age was 62 in the HRD group (age < 45:5.4%, 45-65:59.6%, > 65:34.9%) compared to 60 in the rest of the patients (age < 45:11.3%, 45-65:61.3%, > 65:27.4%). There were overall 57.5% males and 42.5% females in terms of gender. HRD group had a significantly higher rate than Non-HRD group in males (72.1% vs 52.8%, p < 0.01). The occurrence of HRD mutations was significantly correlated with a high level of TMB (p < 0.01). The median TMB of HRD group (7.9 muts/Mb, 95%CI:7.1-9.2 muts/Mb) was significantly higher than that of Non-HRD group (3.8 muts/Mb, 95%CI:3.3-4.2 muts/Mb). In addition, the upper quantile value (7.5 muts/Mb) was used to identify patients with high TMB. HRD group had a significantly higher rate of TMB-high patients than Non-HRD group (51.1% vs 17.0%, p < 0.01). Conclusions: Our study demonstrated genomic alterations of the HR genes in about one fourth’s lung cancer. Besides, there was a significant positive correlation between HRD mutations and TMB level. The significance of HRD genomic mutation on predicting the efficacy of immunotherapy deserves further study.