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Purpose: RABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.Methods: Through GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped.Results: We report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly.Conclusion: Collectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.

Summary Serotonin (5-HT) neurons, the major components of the raphe nuclei, arise from ventral hindbrain progenitors. Based on anatomical location and axonal projection, 5-HT neurons are coarsely divided into rostral and caudal groups. Here, we propose a novel strategy to generate hindbrain 5-HT neurons from human pluripotent stem cells (hPSCs), which involves the formation of ventral-type neural progenitor cells and stimulation of the hindbrain 5-HT neural development. A caudalizing agent, retinoid acid, was used to direct the cells into the hindbrain cell fate. Approximately 30%–40% of hPSCs successfully developed into 5-HT-expressing neurons using our protocol, with the majority acquiring a caudal rhombomere identity (r5–8). We further modified our monolayer differentiation system to generate 5-HT neuron-enriched hindbrain-like organoids. We also suggest downstream applications of our 5-HT monolayer and organoid cultures to study neuronal response to gut microbiota. Our methodology could become a powerful tool for future studies related to 5-HT neurotransmission., Graphical abstract, Highlights • Activation of SHH and RA signaling induces 5-HT neuronal fate from hPSCs • The generated 5-HT neurons have caudal hindbrain characteristics • Hindbrain-like organoids may form from hPSCs by activation of SHH and RA signaling • 5-HT neurons in monolayer and organoid culture can be used as a screening platform, In this article, Shim and colleagues show that the generation of caudal hindbrain-type 5-HT neurons as well as 5-HT-neuron-enriched hindbrain-like organoids can be achieved through the modulation of SHH and RA signaling in differentiating hPSCs. The authors further propose that these 5-HT neurons in a monolayer and organoid culture system could be utilized as a screening platform for small molecules that trigger the release of 5-HT.

Introduction: Dual checkpoint inhibitor therapy with nivolumab and ipilimumab has been FDA-approved for a number of different cancers including melanoma, recurrent NSCLC, and hepatocellular carcinoma. However, their role in the treatment of ACC and other salivary gland carcinomas is not well established. Methods: We performed a Simon’s two-stage prospective single-institution phase II clinical trial of nivolumab (240 mg intravenously every 2 weeks for 16 weeks, then 480 mg every 4 weeks) with ipilimumab (1 mg/kg intravenously every 6 weeks), both of which were provided until intolerable toxicity or disease progression. Two cohorts were analyzed: patients with metastatic/recurrent ACC and patients with other salivary gland cancers. The primary endpoint was median progression-free survival (PFS) based on RECIST and immune-related RECIST (irRECIST) criteria; secondary endpoints were overall response rate (ORR), overall survival (OS), and toxicity. Results: Patients with ACC (n=19) and other salivary gland carcinomas (total n=5; parotid gland adenocarcinoma (n=3), salivary duct carcinoma (n=1), and myoepithelial carcinoma (n=1)) were enrolled between May 2017 and July 2019. Among the patients with ACC, the median OS was 30.0 months (95% confidence interval (CI) 15.3 months to not reached), the median PFS was 8.3 months (95% CI 5.5 - 30.0 months), and the disease control rate (DCR) was 53% (10/19). The ORR in the ACC group was 5% (CR 0%, n=0; confirmed PR 5%, n=1) using both RECIST and irRECIST criteria, with one patient having continued stable disease at the time of trial conclusion. In the salivary gland tumor cohort, the median OS was 10.4 months (95% CI 6.21 months to not reached), the median PFS time was 6.21 months (95% CI 2.83 months to not reached), and the DCR was 40% (2/5). The ORR in this cohort was 0% using both RECIST and irRECIST criteria. Across both cohorts, platelet counts above the joint cohort’s median were significantly associated with better OS (p=0.032) and PFS (p=0.046). Additionally, although not significant, there was a trend for improved OS and PFS among patients with neutrophil-to-lymphocyte ratios >5 (OS p=0.42, PFS p=0.25) and above median neutrophil counts (OS p=0.24, PFS p=0.18). Four patients with ACC underwent circulating tumor DNA sequencing, resulting in the identification of two MYB-NFIB translocations, one NOTCH1 Cys1383 frameshift mutation, one MTOR N1760K mutation, and one PDGFRA copy number gain. Common immune-related toxicities include fatigue (54%), lymphocytopenia (46%), and anemia (42%) with lymphocytopenia being the most common grade III/IV adverse event. Conclusion: In patients with recurrent or metastatic ACC and other salivary gland neoplasms, combination nivolumab with ipilimumab resulted in moderate disease control. Further studies are warranted to validate our findings. Citation Format: Young Kwang Chae, Richard Duan, Liam Il-Young Chung, Youjin Oh, Maria Matsangou, Mark Agulnik, Victoria Villaflor, Devalingam Mahalingam. Phase II study of nivolumab and ipilimumab for treatment of metastatic/recurrent adenoid cystic carcinoma (ACC) of all anatomic sites of origin and other malignant salivary gland tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT165.

Background: The impact of blood transfusion on cancer survival and mortality has been widely studied. However, few studies have investigated its relationship with cancer incidence. This is the first systematic review and meta-analysis evaluating the correlation between blood transfusion and cancer incidence. Methods: Five studies were identified through Pubmed, Embase, and Cochrane library. Four cohort studies and one case-control study (N = 3,048,906) were included. Over seventy percent were female (N =2,167,580), and about thirty-one percent (N = 956,522) were transfused. Meta-analysis was conducted between blood transfusion and cancer incidence. Subgroup analyses were performed by cancer types, follow-up period, and units of transfused blood. We pooled available risk estimates, which were adjusted for confounding factors, including age and sex, were pooled. Results: Overall cancer risk increased statistically significantly in people who received transfusion compared to the population that did not (1.70, 95% CI, 1.30 to 2.10). The result was consistent regardless of time intervals from transfusion or units of transfused blood. Cancer incidences in all solid tumors, except breast, thyroid, and uterine cancer, were higher in blood transfusion recipients (Table 1). The elevated risk of stomach, bladder, and kidney cancer was sustained for up to fifteen years. Furthermore, lung cancer, liver cancer, and non-Hodgkin lymphoma risk remained high among the blood transfusions group even after fifteen years. The three types of cancer with the highest incidence following transfusion were leukemia, stomach cancer, and liver cancer. Conclusions: Blood transfusion increases the risk of cancer in transfusion recipients. The impact of blood transfusion on cancer development varies depending on the cancer type and the time from transfusion. Further prospective studies are warranted to validate the findings and investigate the underlying mechanism. The pooled risk of cancer according to cancer types, units of transfusion, and time from transfusion Risk* (95% CI) Total < 5 yrs 5-15 yrs ≧ 15 yrs All cancer types 1.70 (1.30 - 2.10) 1.89 (1.13 - 2.65) 1.18 (0.97 - 1.40) 1.10 (1.06 - 1.14) Leukemia 2.79 (2.00 - 3.57) 4.07 (2.72 - 5.42) 1.15 (1.04 - 1.27) 0.91 (0.66 - 1.16) Non Hodgkin lymphoma 1.94 (1.49 - 2.40) 2.66 (1.82 - 3.50) 1.43 (0.89 - 1.98) 1.23 (1.00 - 1.46) Stomach 2.37 (1.70 - 3.04) 2.37 (1.70 - 3.04) 1.13 (1.03 - 1.23) 1.17 (0.91 - 1.43) Liver 2.25 (1.67 - 2.84) 2.80 (1.80 - 3.80) 1.67 (1.48 - 1.86) 2.54 (1.85 - 3.23) Colon 2.34 (1.62 - 3.05) 3.49 (1.90 - 5.08) 1.02 (0.96 - 1.08) 1.05 (0.90 - 1.20) Pancreas 1.85 (1.36 - 2.34) 2.37 (1.50 - 3.24) 1.19 (0.72 - 1.66) 1.28 (0.97 - 1.59) Rectum 1.40 (1.06 - 1.75) 1.71 (1.04 - 2.39) 0.98 (0.91 - 1.05) 1.00 (0.81 - 1.19) Lung 1.49 (1.21 - 1.77) 1.71 (1.18 - 2.23) 1.24 (1.17 - 1.30) 1.27 (1.09 - 1.45) Kidney 2.27 (1.63 - 2.90) 3.30 (1.89 - 4.17) 1.15 (1.03 - 1.27) 1.39 (0.70 - 2.08) Bladder 1.40 (1.12 - 1.68) 1.56 (1.06 - 2.06) 1.19 (1.11 - 1.27) 1.35 (0.15 - 2.54) Breast 0.96 (0.84 - 1.09) 1.06 (0.91 - 1.22) 0.95 (0.90 - 1.00) 1.12 (1.03 - 1.21) Uterus 1.02 (0.84 - 1.19) 1.13 (0.85 - 1.25) 0.81 (0.46 - 1.16) 1.00 (0.78 - 1.22) Thyroid 1.16 (0.91 - 1.41) 1.32 (0.87 - 1.77) 0.92 (0.70 - 1.14) 1.12 (0.64 - 1.78) 1-2 units ≧ 3 units All cancer types 1.53 (1.15 - 1.90) 1.93 (1.39 - 2.48) *Risk is pooled from odds ratio, hazard ratio, relative risk, and standardized incidence ratio.Abbreviations: CI=Confidence Interval Citation Format: Youjin Oh, Soowon Lee, Sebin Bok, Chan Mi Jung, Ilene Hong, Liam Chung, Jeeyeon Lee, Young Kwang Chae. Systematic review and meta-analysis of cancer incidence after blood transfusion in the general population. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4207.

Background: Radiomics is an emerging tool that involves the extraction of high-throughput features from medical images. These quantitative values can be used to develop predictive models for clinical characteristics and treatment outcomes. We evaluated radiomic features-based models as imaging biomarkers in NSCLC patients. Methods: 71 patients with NSCLC treated with immunotherapy who had pretreatment CT chest with contrast were retrospectively evaluated. The main tumor and 1cm-thick peritumoral space surrounding the tumor were manually segmented using LIFEx software (IMIV/CEA, Orsay, France) by four physicians. Of 255 radiomic features collected, those with >0.4 of Fleiss’ kappa coefficient were selected. The Random Forest (RF) algorithm with mixed effects was used to develop multi-reader models and assess feature importance. The dataset was divided into a training set (75%) and a test set (25%). Bootstrapping with 1,000 iterations was conducted to estimate the model performance. Durable disease control was defined as having no progression of diseases per RECIST 1.1 up to 24 weeks from starting immunotherapy. Results: Among 71 patients, 35 (49.3%) are female and 36 (50.7%) are male. The median age was 66. 48 (67.6%) adenocarcinoma, 13 (18.3%) squamous cell carcinoma, and 10 (14.1%) other histologic types were included. 22 radiomic features were included based on importance in the prediction models from both the tumor and peritumoral space. Each model is trained to predict patients’ durable disease control, TTF1 expression, PD-L1 expression, histology (adenocarcinoma or not), and Neutrophils Lymphocyte Ratio (NLR; greater than 5 or not) status. The statistical results from the models to predict clinical outcomes are shown in Table. Conclusion: The radiomic features-based models lack accuracy in predicting clinical characteristics and outcomes. Further validation with larger cohorts is warranted. Statistics of radiomics-based models in predicting clinical characteristics and treatment outcomes Durable Disease Control(Yes/No)(n=64) TTF1 expression(Yes/No)(n=62) Histology(Adeno/Other)(n=71) NLR(>=5/ Citation Format: Jisang Yu, Yury Velichko, Hyeonseon Kim, Moataz Soliman, Nicolo Gennnaro, Leeseul Kim, Youjin Oh, Trie Arni Djunadi, Jeeyeon Lee, Liam Il-Young Chung, Sungmi Yoon, Zunairah Shah, Soowon Lee, Cecilia Nam, Timothy Hong, Rishi Agrawal, Pascale Aouad, Young Kwang Chae. Radiomics-based machine learning models to predict progression and biomarker status in non-small cell lung cancer (NSCLC) patients treated with immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5619.

Background: High TMB is known to correlate with better response to immune checkpoint inhibitor (ICI) treatment in certain cancers. bTMB is now being used in place of tTMB at times due to difficulty in obtaining enough tissue samples for sequencing. Concordance between bTMB and tTMB values has been reported. However, the prognostic role of bTMB in relation to tTMB is not well understood. Method: Patients with NSCLC who had both tTMB and bTMB results (collected from 10/2020 to 10/2022) were included. Progression free survival (PFS) and overall survival (OS) were analyzed according to bTMB, tTMB levels (High defined as ≥ 10 Mut/Mb, Low defined as Results: Among 61 pts,18 pts (29%) received ICI monotherapy, 25 pts (41%) received ICI and chemotherapy combination therapy, 8 pts (14%) received chemotherapy, and 10 pts (16%) received targeted therapy. The median interval between bTMB collection and treatment initiation was 20 days (Q1:11, Q3:47) while 40 pts (66%) had the interval of Conclusion: High bTMB/tTMB ratio was associated with inferior OS regardless of treatment regimen in patients with NSCLC. A high bTMB/tTMB ratio may be indicative of increased tumor heterogeneity and/or higher metastatic tumor burden. Further studies are warranted to explore the role of bTMB/tTMB in various cancers. Citation Format: Leeseul Kim, Jewel Park, Youjin Oh, Young Kwang Chae. Non-small cell lung cancer (NSCLC) with higher blood tumor mutational burden (bTMB)/tissueTMB (tTMB) ratio is associated with inferior survival outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3376.

Background: Tissue tumor mutational burden (tTMB) is known to have predictive value for response to immune checkpoint inhibitor treatment of cancer. Utilization of next-generation sequencing of circulating tumor DNA added another data point of blood tumor mutational burden (bTMB). However, the concordance between tTMB and bTMB is not well understood. Method: A total of 119 patients with solid tumors who had both tTMB and bTMB (collected from 10/2020 to 10/2022) results were included in the analysis. Patients' tTMB and bTMB concordance were analyzed according to the interval between tTMB and bTMB collection, tumor type, and site of tTMB collection using the Pearson correlation coefficient. Result: Median tTMB was 4.2 mut/Mb and median bTMB was 9.61mut/Mb. bTMB was moderately correlated with tTMB (Pearson r 0.54) in total patient population. The median interval between tTMB and bTMB collection was 27 days (Q1:14, Q3:1834). Concordance did not significantly change when the interval was under 30 days (Pearson r 0.51). Patients with metastatic disease had higher concordance compared to patients without metastasis of cancer (Pearson r 0.58 vs 0.39). bTMB and tTMB were most strongly correlated when tTMB was collected from metastatic lesions (Pearson r 0.92). No significant correlation was observed when tTMB was collected from lymph nodes (Pearson r 0.20). Regarding cancer types, adenocarcinoma of the lung had a moderate correlation between bTMB and tTMB (Pearson r 0.63) while small cell lung cancer did not demonstrate a significant correlation between bTMB and tTMB (Pearson t -0.30). Correlation between tTMB and bTMB Total study population 119 Interval between bTMB and tTMB collection Citation Format: Leeseul Kim, Youjin Oh, Jewel Park, Ilene Hong, Lena Chae, Pedro Viveiros. Real-world concordance between tumor mutation burden from blood and tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2313.

Background: Globally, cancer results in 10.08 million deaths per year. A single blood-based screening tool that detects multiple cancer types could greatly reduce cancer burden. We aim to systematically review and statistically examine both the accuracy and applicability of blood-based MCED tests to strategize their utilization in improving cancer detection. Methods: Original articles were searched from Pubmed, Cochrane, and Embase for blood-based screening tests analyzing multiple cancer types and asymptomatic human subjects. We excluded studies with small sample size (n Findings: Of 1,074 records screened, 10 case-control and 6 cohort studies were analyzed, most of which utilized cfDNA-based diagnostic tests. Ten cfDNA studies selected for meta-analysis had a joint sensitivity of 0.66 (95%CI 0.54-0.75) and specificity of 0.98 (0.94-0.99) with an area under the curve of 0.883. For cohort studies, the joint positive and negative predictive values were 0.96 (0.29-1.00) and 0.81 (0.37-0.97) respectively. Sensitivity was higher for advanced staged cancers (III/IV 0.84 (0.84-0.86)) with breast cancer having the lowest sensitivity (0.42 (0.31-0.55)). Sensitivity and specificity were not affected by study type, gender, or assay type. Lastly, accuracy of tumor origin prediction was 0.792 (0.64-0.91) without significant differences across cancer types. Interpretation: Given high sensitivities and specificities, MCED tests show promise as additional screening tools. Although there exist multiple barriers to their application in clinic, MCED tests may improve patient outcomes for cancers with no conventional screening tools. Future prospective studies with large and diverse populations are warranted. Summarization of meta-analysis results on cfDNA based multi cancer early detection tests Sensitivity Specificity DOR PPV NPV No. of study included 10 10 10 4 4 Events/Total 5778/10033 14797/15020 Experimental group: 5778/6001 901/1373 10148/11216 Control group: 4202/19052 Proportion (95% CI) 0.652 [0.537; 0.751] 0.978 [0.936; 0.992] 69.290 [25.208; 190.457] 0.961 [0.293; 0.999] 0.812 [0.365; 0.970] Heterogeneity (p value) 98% ( Citation Format: Joo Hee Park, Youjin Oh, Liam Il-Young Chung, Richard Duan, Trie A. Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Young Kwang Chae. Systematic review and meta-analysis of the accuracy and applicability of blood-based multi-cancer early detection (MCED) in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 783.

Background: Among the recently developed blood-based multi-cancer early detection (MCED) tests, determining the location of tumors is pivotal to guiding appropriate treatment. We aim to systematically review and statistically examine the accuracy of tumor of origin prediction among blood-based MCED tests. Methods: Original articles were searched from Pubmed, Cochrane, and Embase that featured blood-based screening tests, multiple cancer types, and asymptomatic human subjects. We excluded studies with small samples (n Findings: Of 1,074 records identified and screened, 4 cohort studies were analyzed using cfDNA-based diagnostic tests. The accuracy of tissue-of-origin (TOO) prediction for 3,762 cancer samples across cancer types was 0.79 (95% CI 0.64 - 0.91). Among six cancer types, colorectal cancers had the highest accuracy, and liver & bile duct cancers had the lowest, although the difference was statistically insignificant (0.89 (95% CI 0.79-0.97) vs. 0.68 (95% CI 0.40-0.90)). Additionally, cases were most frequently misclassified as colorectal cancer (Table 1). Lastly, two studies reported increased prediction accuracies when two sites of origin were assigned rather than a single site. The information for localizing TOO was derived from methylation patterns of cfDNA in two studies, fragmentation profiles of cfDNA in another study, and protein markers in the other research. Interpretation: Our results demonstrate that the primary site of cancers was accurately discerned in 79% of cases by MCED tests. However, the performance varies across cancer types. Further research on performance according to cancer stages and in combination with other molecular profiling is warranted. Table 1. Events/Total Accuracy of prediction (95% CI) misclassification type freqeuncy Total 3,129/3,762 0.79 (0.64 - 0.91) Colorectal 638/723 0.89 (0.79 - 0.97) stomach & esophagus 26/553 breast 8/553 Breast 443/538 0.86 (0.64 - 0.99) colorectal 20/349 pancreas & GB 4/349 lung 4/349 Ovarian Breast 132/159 0.85 (0.62 - 0.99) colorectal 39/261 uterus 13/147 Pancreatic & GB 289/338 0.82 (0.69 - 0.93) colorectal 12/300 stomach & esophagus 10/300 Stomach & Esophagus 225/311 0.75 (0.48 - 0.95) colorectal 39/261 lung 10/261 Lung 530/656 0.72 (0.45 - 0.92) colorectal 29/560 head and neck 8/560 Liver & Bile duct 95/144 0.68 (0.40 - 0.90) colorectal 13/220 pancreatic & GB 8/220 Abbreviations: CI = confidence interval; GB = gallbladder Citation Format: Youjin Oh, Joo Hee Park, Liam Il-Young Chung, Richard Duan, Trie Arni Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Horyun Choi, Young Kwang Chae. Systematic review and meta-analysis of the accuracy of tumor origin detection in blood-based multi-cancer early detection (MCED) in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 784.

BackgroundHyperprogressive disease (HPD) is a distinct pattern of rapid tumor progression observed in patients with cancer who are undergoing immune checkpoint inhibitor therapy. Despite the growing evidence, a universal definition of HPD remains to be established, and incidence rates vary based on the defining criteria. Therefore, a refinement of currently existing criteria is warranted to better characterize this phenomenon and evaluate its incidence.MethodsTwo independent investigators performed a systematic literature search in EMBASE and MEDLINE using keywords selected in Park et al.1: checkpoint, immunotherapy, pd1, pdl1, ctla4, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab and hyperprogress. Studies published from March 3, 2020 to April 20, 2020 that included the incidence and definition of HPD in patients receiving immunotherapy were included for analysis. Selected studies were then combined with those included in the meta-analysis by Park et al.1 Duplicates were removed, and the study with a larger cohort was selected in instances of overlap between two cohorts. In total, 50 studies were included for meta-analysis.2–51 Pooled incidence rates of HPD and prespecified subgroup analyses based on four categories defining HPD (tumor growth rate ratio, tumor growth kinetics ratio, early tumor burden increase, and combination) were obtained with 95% confidence intervals (CI) using a random effects model performed on R.ResultsA total of 6009 patients from 50 studies were included in the meta-analysis. Incidences varied from 0.0% to 43.1% (figure 1), and the overall pooled incidence of HPD was 12.9% (95%CI, 11.1%–14.7%). Significant heterogeneity was observed (I2= 77%; pAbstract 238 Table 1Subgroup analyses based on definitions of HPDAbbreviationTGR, tumor growth rate; TGK, tumor growth kinetics.Abstact 238 Figure 1Overall pooled incidence of HPD. The overall pooled incidence of HPD was 12.9% (95% CI, 11.1%–14.7%). Significant heterogeneity was observed (I2 = 77%; pConclusionsThe overall incidence of HPD from 50 studies was 12.9% (95%CI, 11.1%–14.7%). HPD incidence varied from 0% to 43.1% depending on the definition each investigator chose. There is a growing need for a more uniform definition of HPD that does not underestimate or overestimate its incidence.ReferencesPark HJ, Kim KW, Won SE, et al. Definition, incidence, and challenges for assessment of hyperprogressive disease during cancer treatment with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Netw Open 2021;4(3):1–16. doi:10.1001/jamanetworkopen.2021.1136Champiat S, Dercle L, Ammari S, et al. 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Capturing hyperprogressive disease with immune-checkpoint inhibitors using RECIST 1.1 criteria. Clin Cancer Res 2020;26(8):1846–1855. doi:10.1158/1078–0432.CCR-19-2226Sasaki A, Nakamura Y, Mishima S, et al. Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer. Gastric Cancer 2019;22(4):793–802. doi:10.1007/s10120-018-00922-8Scheiner B, Kirstein MM, Hucke F, et al. Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort. Aliment Pharmacol Ther 2019;49(10):1323–1333. doi:10.1111/apt.15245Ten Berge DMHJ, Hurkmans DP, den Besten I, et al. Tumour growth rate as a tool for response evaluation during PD-1 treatment for non-small cell lung cancer: a retrospective analysis. ERJ Open Res 2019;5(4):00179–02019. doi:10.1183/23120541.00179-2019Tunali I, Gray JE, Qi J, et al. 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Author correction: hyperprogression under immune checkpoint inhibitor: a potential role for germinal immunogenetics (Scientific Reports, (2020), 10, 1, (3565), 10.1038/s41598-020-60437-0). Sci Rep 2020;10(1):1–8. doi:10.1038/s41598-020-66841-wRuiz-Patiño A, Arrieta O, Cardona AF, et al. Immunotherapy at any line of treatment improves survival in patients with advanced metastatic non-small cell lung cancer (NSCLC) compared with chemotherapy (Quijote-CLICaP). Thorac Cancer 2020;11(2):353–361. doi:10.1111/1759-7714.13272Kim CG, Kim C, Yoon SE, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol 2021;74(2):350–359. doi:10.1016/j.jhep.2020.08.010Kas B, Talbot H, Ferrara R, et al. Clarification of definitions of hyperprogressive disease during immunotherapy for non-small cell lung cancer. JAMA Oncol 2020;6(7):1039–1046. doi:10.1001/jamaoncol.2020.1634Jin T, Zhang Q, Jin QF, Hua YH, Chen XZ. Anti-PD1 checkpoint inhibitor with or without chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma. Transl Oncol 2021;14(2):100989. doi:10.1016/j.tranon.2020.100989Rimola J, Da Fonseca LG, Sapena V, et al. Radiological response to nivolumab in patients with hepatocellular carcinoma: a multicenter analysis of real-life practice. Eur J Radiol 2021;135(December 2020). doi:10.1016/j.ejrad.2020.109484Gomes da Morais AL, de Miguel M, Cardenas JM, Calvo E. Comparison of radiological criteria for hyperprogressive disease in response to immunotherapy. Cancer Treat Rev 2020;91(September). doi:10.1016/j.ctrv.2020.102116Schuiveling M, Tonk EHJ, Verheijden RJ, Suijkerbuijk KPM. Hyperprogressive disease rarely occurs during checkpoint inhibitor treatment for advanced melanoma. Cancer Immunol Immunother 2021;70:1491-1496. doi:10.1007/s00262-020-02716-331. Yilmaz M. Atypical response patterns in metastatic melanoma and renal cell carcinoma patients treated with nivolumab: a single center experience. J Oncol Pharm Pract 2021;27(5):1106–1111. doi:10.1177/1078155220949642Kim SH, Choi CM, Lee DH, et al. Clinical outcomes of nivolumab in patients with advanced non-small cell lung cancer in real-world practice, with an emphasis on hyper-progressive disease. J Cancer Res Clin Oncol 2020;146(11):3025–3036. doi:10.1007/s00432-020-03293-9Ji Z, Cui Y, Peng Z, et al. Use of radiomics to predict response to immunotherapy of malignant tumors of the digestive system. Med Sci Monit 2020;26:1–9. doi:10.12659/MSM.924671Petrova MP, Donev IS, Radanova MA, et al. Sarcopenia and high NLR are associated with the development of hyperprogressive disease after second-line pembrolizumab in patients with non-small-cell lung cancer. Clin Exp Immunol 2020;202(3):353–362. doi:10.1111/cei.13505Zheng B, Shin JH, Li H, Chen Y, Guo Y, Wang M. Comparison of radiological tumor response based on iRECIST and RECIST 1.1 in metastatic clear-cell renal cell carcinoma patients treated with programmed cell death-1 inhibitor therapy. Korean J Radiol 2021;22(3):366–375. doi:10.3348/kjr.2020.0404Karabajakian A, Garrivier T, Crozes C, et al. Hyperprogression and impact of tumor growth kinetics after PD1/PDL1 inhibition in head and neck squamous cell carcinoma. Oncotarget 2020;11(18):1618–1628. doi:10.18632/oncotarget.27563Park JH, Chun SH, Lee YG, et al. Hyperprogressive disease and its clinical impact in patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with immune-checkpoint inhibitors: Korean cancer study group HN 18–12. J Cancer Res Clin Oncol 2020;(0123456789). doi:10.1007/s00432-020-03316-5Vaidya P, Bera K, Patil PD, et al. Novel, non-invasive imaging approach to identify patients with advanced non-small cell lung cancer at risk of hyperprogressive disease with immune checkpoint blockade. J Immunother Cancer 2020;8(2). doi:10.1136/jitc-2020-001343Abbar B, De Castelbajac V, Gougis P, et al. Definitions, outcomes, and management of hyperprogression in patients with non-small-cell lung cancer treated with immune checkpoint inhibitors. Lung Cancer 2021;152(December 2020):109–118. doi:10.1016/j.lungcan.2020.12.026Choi YJ, Kim T, Kim EY, Lee SH, Kwon DS, Chang YS. Prediction model for hyperprogressive disease in non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer 2020;11(10):2793–2803. doi:10.1111/1759-7714.13594Castello A, Rossi S, Mazziotti E, Toschi L, Lopci E. Hyperprogressive disease in patients with non-small cell lung cancer treated with checkpoint inhibitors: the role of 18F-FDG PET/CT. J Nucl Med 2020;61(6):821–826. doi:10.2967/jnumed.119.237768Nakamoto R, C Zaba L, Rosenberg J, et al. Imaging characteristics and diagnostic performance of 2-deoxy-2-[18F]fluoro-d-Glucose PET/CT for melanoma patients who demonstrate hyperprogressive disease when treated with immunotherapy. Mol Imaging Biol 2021;23(1):139–147. doi:10.1007/s11307-020-01526-4Zhang L, Wu L, Chen Q, et al. Predicting hyperprogressive disease in patients with advanced hepatocellular carcinoma treated with anti-programmed cell death 1 therapy. EClinicalMedicine 2021;31:100673. doi:10.1016/j.eclinm.2020.100673Matsuo N, Azuma K, Kojima T, et al. Comparative incidence of immune-related adverse events and hyperprogressive disease in patients with non-small cell lung cancer receiving immune checkpoint inhibitors with and without chemotherapy. Invest New Drugs Published online 2021. doi:10.1007/s10637-021-01069-7Economopoulou P, Anastasiou M, Papaxoinis G, et al. Patterns of response to immune checkpoint inhibitors in association with genomic and clinical features in patients with head and neck squamous cell carcinoma (HNSCC). Cancers (Basel) 2021;13(2):1–15. doi:10.3390/cancers13020286Kim SR, Chun SH, Kim JR, et al. The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy. BMC Cancer 2021;21(1):1–11. doi:10.1186/s12885-020-07727-yHagi T, Kurokawa Y, Kawabata R, et al. Multicentre biomarker cohort study on the efficacy of nivolumab treatment for gastric cancer. Br J Cancer 2020;123(6):965–972. doi:10.1038/s41416-020-0975-7Okamoto I, Sato H, Tsukahara K. Overall survival and PD-L1 expression in patients with recurrent or metastatic head and neck cancer treated with nivolumab. Auris Nasus Larynx 2020;47(4):676–686. doi:10.1016/j.anl.2020.04.001Kim KH, Hur JY, Koh J, et al. Immunological characteristics of hyperprogressive disease in patients with non-small cell lung cancer treated with anti-pd-1/pd-l1 abs. Immune Netw 2020;20(6):1–11. doi:10.4110/in.2020.20.e48Ku BM, Kim Y, Lee KY, et al. Tumor infiltrated immune cell types support distinct immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. Eur J Immunol Published online 2021:1–9. doi:10.1002/eji.202048966Miyama Y, Morikawa T, Miyakawa J, et al. Squamous differentiation is a potential biomarker predicting tumor progression in patients treated with pembrolizumab for urothelial carcinoma. Pathol Res Pract 2021;219(February):153364. doi:10.1016/j.prp.2021.153364

In this letter, we propose a method to model architectural components in large-scale indoor spaces from point cloud measurements. The proposed method enables the modeling of curved surfaces, cylindrical pillars, and slanted surfaces, which cannot be modeled using existing approaches. It operates by constructing the architectural points from the raw point cloud after removing non-architectural (objects) points and filling in the holes caused by their exclusion. Then, the architectural points are represented using a set of piece-wise planar segments. Finally, the adjacency graph of the planar segments is constructed to verify the fact that every planar segment is closed. This ensures a watertight mesh model generation. Experimentation using 14 different real-world indoor space datasets and 2 public datasets, comprising spaces of various sizes—from room-scale to large-scale (12,557 m $^{2}$ ), verify the accuracy of the proposed method in modeling environments with curved surfaces, cylindrical pillars, and slanted surfaces.

Although laparoscopic total gastrectomy (LTG) compared to open total gastrectomy (OTG) has been widely used for advanced gastric cancer patients, its oncologic validity is yet to be proven. We performed systemic review and meta-analysis to compare LTG versus OTG for early and advanced stages of gastric cancer. Short- and long-term outcomes of both procedures were analyzed using original studies collected by searching Google Scholar, Medline, PubMed, Embase, and Cochrane library in accordance with the PRISMA guidelines. To analyze procedures more precisely, we categorized studies into advanced gastric cancer (AGC) and early gastric cancer (EGC) groups and matched lymph node (LN) dissection, and metastasis ratio. Nineteen studies with a total of 3943 patients were included. LTG required more operative time and had less dissected LNs, indicating a favorable quality of OTG. However, LTG was superior with less blood loss, a shorter postoperative hospital stay, and lower postoperative complication rates. The 5-year survival rate was similar in both groups in which extent of LN dissection and lymph node metastasis ratio were controlled. Although more LNs were removed in OTG, the discrepancy had an insignificant impact on the survival rate. To the best of our knowledge, this study is the first to employ quantitative synthesis in evaluation of long-term oncologic validity of LTG and OTG in AGC, with LN dissection and N stage controlled setting. Non-inferiority of LTG on oncologic outcome and superiority of LTG on perioperative outcome lead to a conclusion that LTG has potential as a valid treatment modality in AGC.

Triptans are a class of commonly prescribed antimigraine drugs. Here, we report a previously unrecognized role for them to suppress appetite in mice. In particular, frovatriptan treatment reduces food intake and body weight in diet-induced obese mice. Moreover, the anorectic effect depends on the serotonin (5-HT) 1B receptor (Htr1b). By ablating Htr1b in four different brain regions, we demonstrate that Htr1b engages in spatiotemporally segregated neural pathways to regulate postnatal growth and food intake. Moreover, Htr1b in AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) contributes to the hypophagic effects of HTR1B agonists. To further study the anorexigenic Htr1b circuit, we generated Htr1b-Cre mice. We find that ARH Htr1b neurons bidirectionally regulate food intake in vivo. Furthermore, single-nucleus RNA sequencing analyses revealed that Htr1b marks a subset of AgRP neurons. Finally, we used an intersectional approach to specifically target these neurons (Htr1bAgRP neurons). We show that they regulate food intake, in part, through a Htr1bAgRP→PVH circuit.

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by hyperextensible skin, hypermobile joints, easy bruisability, and fragility of the connective tissues. The diagnosis is based on clinical assessment and phenotype-guided genetic testing. Most EDS subtypes can be confirmed by genetic testing except for hypermobile EDS. This study explored the utility of applying the 2017 EDS classification criteria and molecular genetic testing in establishing an EDS diagnosis in children. In this retrospective study, we reviewed 72 patients referred to a tertiary care center for evaluation of EDS who underwent one or more forms of genetic testing. Eighteen patients (18/72, 25%) met the clinical criteria for one of the EDS subtypes and of these, 15 (15/18, 83%) were confirmed molecularly. Fifty-four patients (54/72, 75%) had features that overlapped EDS and other syndromes associated with joint hypermobility but did not fully meet clinical criteria. Twelve of them (12/54, 22%) were later shown to have a positive molecular genetic diagnosis of EDS. Different molecular genetic tests were performed on the cohort of 72 patients (EDS panel, n = 44; microarray, n = 25; whole exome sequencing [WES], n = 9; single gene sequencing, n = 3; familial variant testing, n = 10; other genetic panels n = 3). EDS panel was completed in 44 patients (61%), and a molecular diagnosis was confirmed in nine of the patients who satisfied criteria for one of the EDS subtypes (9/12, 75%) and in nine of the patients who did not fully meet criteria (9/32, 28%). We observed a correlation between generalized joint hypermobility, poor healing, easy bruising, atrophic scars, skin hyperextensibility, and developmental dysplasia of the hip with a positive molecular result. This study provides guidance for the use of molecular genetic testing in combination with the 2017 clinical diagnostic criteria in children presenting with EDS characteristics.

Melanocortin-4 receptors (MC4Rs) expressed by the central nervous system are essential regulators of energy homeostasis, and Mc4r mutation is the most common cause of human monogenic obesity. Notably, patients with obesity carrying Mc4r mutations are protected against obesity-induced hypertension, and MC4R agonists elevate blood pressure (BP). Although increased sympathetic tone by MC4Rs is suggested to underlie this phenotype, the detailed mechanisms remain unclear. Here, we investigate how MC4Rs regulate the sympathetic preganglionic neurons and find that MC4Rs activate these neurons via the protein kinase A-dependent activation of the transient receptor potential vanilloid 1 (TRPV1) channel. Importantly, we demonstrate that the inhibition of TRPV1 prevents MC4R-induced elevation of BP but does not affect MC4R-induced anorexia. We further show that TRPV1 is responsible for MC4R-dependent activation of the sympathetic preganglionic neurons by high-fat diet. Together, our results provide insight into how MC4Rs regulate sympathetic function.

e21025 Background: HPD is an unexpected and rapid acceleration of tumor growth in patients following treatment with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinicopathological and genetic predictive factors. Methods: A total of 203 patients with NSCLC treated with ICI at Northwestern Memorial Hospital during 2015-2020 were included. Clinicopathological data were retrospectively gathered and analyzed. Tumor growth kinetics (TGK) of pre-immunotherapy and post-immunotherapy were collected and TGK ratio (TGKr) was calculated. HPD was defined as TGKr≥2. Results: HPD was observed in 16% (33/203) of patients. There was a statistically significant difference in overall survival(OS) between the two groups (non-HPD vs. HPD) [OR = 2.39, P < 0.01]. The progression-free survival(PFS) also showed a statistically significant difference in patients (non-HPD vs HPD) [OR = 3.4, P < 0.01]. The median OS and PFS of patients with HPD were 13.57 months and 2.2 months respectively. The median OS and PFS of patients without HPD were 30.67 months and 7.3 months respectively. HPD was significantly associated with performance status (3-4 vs. 1-2) [OR = 4.52, P = 0.01], presence of bone metastasis [OR = 2.51, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, P = 0.01], thrombocytosis (platelet count > 450k) [OR = 5.31, P < 0.01], and treatment with PD-L1 inhibitor vs. PD-1 inhibitor [OR = 2.14, P = 0.06]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, P = 0.01], ICI combined with chemotherapy vs. ICI monotherapy [OR = 0.24, P = 0.04], and positive TTF-1 expression [OR = 0.46, P = 0.06]. HPD was not associated with histological subtypes of NSCLC, age(< 70, ≥70), sex, smoking history, number of metastatic lesions (< 3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, TNM staging, tumor mutational burden (TMB) (< 10, ≥10), microsatellite stability index (MSI), human leukocyte antigen-1 (HLA-1) heterozygosity, hemoglobin(≤12, > 12), albumin(≤3.5, > 3.5), and LDH(≤240, > 240). Conclusions: The incidence of HPD, 16%, was consistent with current literature. NLR ≥5, platelet count > 450k, poor performance status, presence of bone metastasis, treatment with PD-L1 inhibitor, negative PD-L1 expression, negative TTF-1 expression, and ICI monotherapy were predictors of HPD. To our knowledge, this is the first study to report an inverse correlation of TTF-1 expression, and non correlation of HLA-1 heterozygosity with HPD. The strength of our study is that we analyzed recently emerging next-generation sequencing (NGS) data to find novel predictors of HPD. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted.

BACKGROUND: Despite common use in clinical practice, the impact of blood transfusions on prognosis among patients with lung cancer remains unclear. The purpose of the current study is to perform an updated systematic review and meta-analysis to evaluate the influence of blood transfusions on survival outcomes of lung cancer patients. METHODS: We searched PubMed, Embase, Cochrane Library, and Ovid MEDLINE for publications illustrating the association between blood transfusions and prognosis among people with lung cancer from inception to November 2019. Overall survival (OS) and disease-free survival (DFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the random-effects model. Study heterogeneity was evaluated with the I(2) test. Publication bias was explored via funnel plot and trim-and-fill analyses. RESULTS: We included 23 cohort studies with 12,175 patients (3,027 cases and 9,148 controls) for meta-analysis. Among these records, 22 studies investigated the effect of perioperative transfusions, while one examined that of transfusions during chemotherapy. Two studies suggested the possible dose-dependent effect in accordance with the number of transfused units. In pooled analyses, blood transfusions deleteriously influenced both OS (HR=1.35, 95% CI: 1.14–1.61, P

BackgroundHomozygosity at HLA-I locus has been reported to be an unfavorable predictive biomarker of second-line or beyond immunotherapy in patients with different types of cancer. The linkage between HLA-I zygosity and survival in NSCLC patients treated with first-line immunotherapy with or without chemotherapy has not been reported.MethodsNext generation sequencing with HLA genotyping was performed for patients with advanced NSCLC treated with immune checkpoint inhibitors with or without chemotherapy as first-line (N = 29). Progression free survival was compared between HLA-I homozygous (defined as homozygosity in at least one locus A, B, or C) and heterozygous patients. Kaplan-Meier curves were built, and log-rank test was used.ResultsAmong 29 enrollees, 25 patients (86.2%) were HLA-I heterozygous and four patients (13.8%) were HLA-I homozygous. Treatment response was not available in five patients with HLA-I heterozygosity. Among 20 patients with HLA-I heterozygosity, five patients (20.0%) had partial response, 10 patients (50.0%) had stable disease, two patients (8.0%) had non-complete response/non-progressive disease, and three patients (12.0%) had progressive disease. Among four patients with HLA-I heterozygosity, one patient (25.0%) had partial response, one patient (25.0%) had stable disease, and two patients (50.0%) had progressive disease. The median progression free survival was not reached in heterozygous group and was 2.97 months in homozygous group (log-rank p = 0.68).ConclusionsWe observed a trend toward an inverse association between HLA-I homozygosity and survival outcomes in patients with NSCLC treated with first-line therapy containing immunotherapy. Further prospective studies to validate such a relationship are warranted.

Background Homozygosity at HLA-I locus has been reported to be an unfavorable predictive biomarker of second-line or beyond immunotherapy in patients with different types of cancer. The linkage between HLA-I zygosity and survival in NSCLC patients treated with first-line immunotherapy with or without chemotherapy has not been reported. Methods Next generation sequencing with HLA genotyping was performed on patients with advanced NSCLC treated with immune checkpoint inhibitors with or without chemotherapy as first-line (N = 29). Progression free survival was compared between HLA-I homozygous (defined as homozygosity in at least one locus A, B, or C) and heterozygous patients. Kaplan-Meier curves were built, and log-rank test was used. Results Among 29 enrollees, 25 patients (86.2%) were HLA-I heterozygous and four patients (13.8%) were HLA-I homozygous. Treatment response was not available in five patients with HLA-I heterozygosity. Among 20 patients with HLA-I heterozygosity, five patients (20.0%) had partial response, 10 patients (50.0%) had stable disease, two patients (8.0%) had non-complete response/non-progressive disease, and three patients (12.0%) had progressive disease. Among four patients with HLA-I heterozygosity, one patient (25.0%) had partial response, one patient (25.0%) had stable disease, and two patients (50.0%) had progressive disease. The median progression free survival was not reached in heterozygous group and was 2.97 months in homozygous group (Log-rank p = 0.68). Conclusions We observed a trend toward an inverse association between HLA-I homozygosity and survival outcomes in patients with NSCLC treated with first-line therapy in conjunction with immunotherapy. Further prospective studies to validate aforementioned relationship are warranted.

In 2014, the results derived from the nationwide data of the Korean Anti-reflux Surgery Study (KARS) demonstrated short-term feasibility and safety of anti-reflux surgery. This study aimed to update the longer-term safety and feasibility of laparoscopic anti-reflux surgery up to 1-year follow-up with the KARS nationwide cohort.The data of 310 patients with GERD who received anti-reflux surgery up to 2018 were analyzed. Baseline patient characteristics, postoperative symptom resolution, and postoperative complications were evaluated at postoperative 3 months and 1 year using the questionnaire designed by KARS. We divided the patients into two groups according to the operation period (up to and after 2014) to identify changes in the trends of the characteristics of surgical patients and operative qualities.The typical preoperative symptoms were present in 275 patients (91.7%), and atypical symptoms were present in 208 patients (71.0%). Ninety-seven (35.5%) and 124 patients (46.1%) had inadequate PPI responses and hiatal hernia, respectively. At postoperative 1 year, typical and atypical symptoms were either completely or partially controlled in 90.3% and 73.5.0% of patients, respectively. Moderate-to-severe dysphagia, inability to belch, gas bloating, and flatulence at postoperative 1 year were identified in 23.5%, 29.4%, 23.2%, and 22.0% of patients, respectively. The number of surgical patients continuously increased from 2011 to 2018 in Korea. The proportion of patients with hiatal hernia and comorbidities increased (p 0.01, p = 0.053), and the operation time decreased significantly (p 0.01) in the late period (2015-2018) as compared with the early period (2011-2014). Symptom control and complication rate were equivalent between the two periods.Anti-reflux surgery was effective with 90% of typical symptom resolution and posed a comparable postoperative complication rate with those in Western studies with mid-term to long-term follow-up. This result supports the feasibility and safety of anti-reflux surgery as a treatment for GERD in the Korean population.

Drosophila neural stem cells, or neuroblasts, ingress from the neuroepithelium in an EMT-like process, during which the apical cell domain is lost. Apical constriction of neuroblasts and the serial loss of cell–cell contacts require periodic pulses of actomyosin that cause progressively stronger ratcheted contractions of the neuroblast apical cortex., Epithelial–mesenchymal transitions play key roles in development and cancer and entail the loss of epithelial polarity and cell adhesion. In this study, we use quantitative live imaging of ingressing neuroblasts (NBs) in Drosophila melanogaster embryos to assess apical domain loss and junctional disassembly. Ingression is independent of the Snail family of transcriptional repressors and down-regulation of Drosophila E-cadherin (DEcad) transcription. Instead, the posttranscriptionally regulated decrease in DEcad coincides with the reduction of cell contact length and depends on tension anisotropy between NBs and their neighbors. A major driver of apical constriction and junctional disassembly are periodic pulses of junctional and medial myosin II that result in progressively stronger cortical contractions during ingression. Effective contractions require the molecular coupling between myosin and junctions and apical relaxation of neighboring cells. Moreover, planar polarization of myosin leads to the loss of anterior–posterior junctions before the loss of dorsal–ventral junctions. We conclude that planar-polarized dynamic actomyosin networks drive apical constriction and the anisotropic loss of cell contacts during NB ingression.

In vitro culture systems for primary neurons have served as useful tools for neuroscience research. However, conventional in vitro culture methods are still plagued by challenging problems with respect to applications to neurodegenerative disease models or neuron-based biosensors and neural chips, which commonly require long-term culture of neural cells. These impediments highlight the necessity of developing a platform capable of sustaining neural activity over months. Here, we designed a series of polymeric bilayers composed of poly(glycidyl methacrylate) (pGMA) and poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA), designated pGMA:pDMAEMA, using initiated chemical vapor deposition (iCVD). Harnessing the surface-growing characteristics of iCVD polymer films, we were able to precisely engraft acetylcholine-like functionalities (tertiary amine and quaternary ammonium) onto cell culture plates. Notably, pGD3, a pGMA:pDMAEMA preparation with the highest surface composition of quaternary ammonium, fostered the most rapid outgrowth of neural cells. Clear contrasts in neural growth and survival between pGD3 and poly-l-lysine (PLL)-coated surfaces became apparent after 30 days in vitro (DIV). Moreover, brain-derived neurotrophic factor level continuously accumulated in pGD3-cultured neurons, reaching a 3-fold increase at 50 DIV. Electrophysiological measurements at 30 DIV revealed that the pGD3 surface not only promoted healthy maturation of hippocampal neurons but also enhanced the function of hippocampal ionotropic glutamate receptors in response to synaptic glutamate release. Neurons cultured long-term on pGD3 also maintained their characteristic depolarization-induced Ca

e21519 Background: Homozygosity at human leukocyte antigen class I (HLA-I) locus has been reported to be an unfavorable predictive biomarker of second line or beyond immunotherapy in patients with different types of cancer including melanoma and NSCLC. The linkage between HLA-I homozygosity and survival outcomes in NSCLC patients treated with first-line immunotherapy has not been reported. Methods: Next generation sequencing with HLA genotyping was performed for patients with unresectable stage III or IV NSCLC treated with pembrolizumab plus chemotherapy as first line (N = 25). Progression free survival (PFS) was compared between HLA-I homozygous (defined as homozygosity in at least one locus A, B, or C) and heterozygous patients. Kaplan-Meier curves were built and Log-rank test was used to compare unadjusted survival statistics between the groups. Cox Proportional Hazards were then used to adjust for potential confounders; age, sex, and tumor mutation burden status (TMB, above vs. below median). Results: The median follow up time was 259 days [interquartile range,163 to 350]. Among 25 enrollees, 21 patients (84%) were HLA-I heterozygous and 4 patients (16%) were HLA-I homozygous. Treatment response was not available in 6 patients with HLA-I homozygosity. Among 15 patients with HLA-I homozygosity, 4 patients (26.7%) had partial response (PR), 7 patients (46.7%) had stable disease(SD), and 4 patients (26.7%) had progressive disease (PD). Among 4 patients with HLA-I heterozygosity, 1 patient (25%) had PR, 1 patient (25%) had SD, and 2 patients (50%) had PD. The disease control rates (PR and SD) were 73.4% in heterozygous group and 50% in homozygous group. The heterozygous group showed longer median PFS than the homozygous group (19 vs. 9.4 months, Log-rank p = 0.14). Patients with HLA-I homozygosity demonstrated shorter PFS (HR = 2.35, 95% CI = 0.56-9.9, p = 0.25). Adjusted HRs controlled for age, sex, and TMB were 3.6[0.65-20], 2.3[0.55-9.9] and 1.7[0.34-8.6] respectively. Conclusions: We observed a trend toward an inverse association between HLA-I homozygosity and survival outcomes in patients with NSCLC treated with first-line immunotherapy. Further perspective studies to validate such relationship are warranted.

Three functionalized metal-organic frameworks (MOFs), MOF-205-NH2, MOF-205-NO2, and MOF-205-OBn, formulated as Zn4O(BTB)4/3(L), where BTB is benzene-1,3,5-tribenzoate and L is 1-aminonaphthalene-3,7-dicarboxylate (NDC-NH2), 1-nitronaphthalene-3,7-dicarboxylate (NDC-NO2) or 1,5-dibenzyloxy-2,6-naphthalenedicarboxylate (NDC-(OBn)2), were synthesized and their gas (H2, CO2, or CH4) adsorption properties were compared to those of the un-functionalized, parent MOF-205. Ordered structural models for MOF-205 and its derivatives were built based on the crystal structures and were subsequently used for predicting porosity properties. Although the Brunauer-Emmett-Teller (BET) surface areas of the three MOF-205 derivatives were reduced (MOF-205, 4460; MOF-205-NH2, 4330; MOF-205-NO2, 3980; MOF-205-OBn, 3470 m(2) g(-1)), all three derivatives were shown to have enhanced H2 adsorption capacities at 77 K and CO2 uptakes at 253, 273, and 298 K respectively at 1 bar in comparison with MOF-205. The results indicate the following trend in H2 adsorption: MOF-205MOF-205-NO2MOF-205-NH2MOF-205-OBn. MOF-205-OBn showed good ideal adsorbed solution theory (IAST) selectivity values of 6.5 for CO2/N2 (15/85 in v/v) and 2.7 for CO2/CH4 (50/50 in v/v) at 298 K. Despite the large reduction (-22%) in the surface area, MOF-205-OBn displayed comparable total volumetric CO2 (at 48 bar) and CH4 (at 35 bar) storage capacities with those of MOF-205 at 298 K: MOF-205-OBn, 305 (CO2) and 112 (CH4) cm(3) cm(-3), and for MOF-205, 307 (CO2) and 120 (CH4) cm(3) cm(-3), respectively.

Insulin secretion is elaborately modulated in pancreatic ß cells within islets of three-dimensional (3D) structures. Using human pluripotent stem cells (hPSCs) to develop islet-like structures with insulin-producing ß cells for the treatment of diabetes is challenging. Here, we report that pancreatic islet-like clusters derived from hESCs are functionally capable of glucose-responsive insulin secretion as well as therapeutic effects. Pancreatic hormone-expressing endocrine cells (ECs) were differentiated from hESCs using a step-wise protocol. The hESC-derived ECs expressed pancreatic endocrine hormones, such as insulin, somatostatin, and pancreatic polypeptide. Notably, dissociated ECs autonomously aggregated to form islet-like, 3D structures of consistent sizes (100–150 μm in diameter). These EC clusters (ECCs) enhanced insulin secretion in response to glucose stimulus and potassium channel inhibition in vitro. Furthermore, ß cell-deficient mice transplanted with ECCs survived for more than 40 d while retaining a normal blood glucose level to some extent. The expression of pancreatic endocrine hormones was observed in tissues transplanted with ECCs. In addition, ECCs could be generated from human induced pluripotent stem cells. These results suggest that hPSC-derived, islet-like clusters may be alternative therapeutic cell sources for treating diabetes.