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Background The hormone receptor (HR)-positive metastatic breast cancer (MBC) patients show a diverse range of tumor mutational burden (TMB), but its biological and clinical implication has been largely unrevealed. Here we report genomic landscape of 117 HR+ MBC patients who were included in the pre-screening tissue genomic analysis of MUTATION-1 study (SABCS 2021; Abs P1-19-03) according to TMB of tumors. Patients and method The MUTATION-1 study (NCT03608865) enrolled HR-positive MBC patients who received prior ≥ 1 line of systemic therapy, and performed prescreening with whole exome sequencing (WES) and RNA-seq of fresh-frozen tissue of metastatic or recurred tumors. Patients who met upper 30% of TMB were eligible for treatment phase and received durvalumab plus tremelimumab. This study analyzed 117 prescreening tissues of MUTATION-1 study patients for mutation and transcriptomic landscape analysis. (WES, n=117; RNA-seq, n=107) Results The 117 patients showed diverse TMB (range 0~21.7 mut/Mb, median 2.0 mut/Mb) and genomic alterations. The most frequently mutated gene included PIK3CA (29.1%), TP53 (27.4%), ESR1 (23.9%), GATA3 (19.7%), and MAP3K1 (12.0%). There was no association between patient survival and TMB. We estimated single base substitution (SBS) mutational signature of patients with SigMA algorithm. The patients were classified according to their dominant mutational signatures: APOBEC (25.6%), HRD (41.0%), clockwise (28.2%), SBS8, and SBS17. The APOBEC patients showed higher TMB (median 3.47 mut/Mb) and higher mutation prevalence in PIK3CA (63.3% vs. 29.1%), ARID1A (16.7% vs. 6.0%), and NF1 (16.7% vs. 6.8%) compared with other patients. The high TMB positively correlated with time from MBC diagnosis to biopsy. Tumors with TMB ≥ 5 mut/Mb were exclusively found in patients diagnosed as MBC ≥ 36 months before the timing of biopsy. In the matched RNA-seq analysis, TMB was higher in luminal B and HER2-enriched intrinsic subtype patients than basal or luminal A subtype. The high TMB (≥ 3.16 mut/Mb, cutoff used for treatment phase patient selection) patients showed upregulation of G2/M checkpoint, MYC, E2F1, and MTORC1 signature compared to low TMB patients. In the tumor microenvironment analysis by CIBESORT, PIK3CA mutant patients showed lower score of cytotoxic T cell than others. Conclusions The high TMB in HR+ breast cancer was associated with longer time duration from MBC diagnosis to biopsy, high APOBEC signature, and cell cycle/MYC signature gene upregulation. Further therapeutic targeting of high TMB patients is warranted based on their genomic and immunologic characteristics. Citation Format: Min Hwan Kim, Yohan Yang, Eunyoung Kim, Yong Wha Moon, Gun Min Kim, Seul-Gi Kim, Yee Soo Chae, Jieun Lee, Jae Ho Jeong, Kyung-Hun Lee, Han Jo Kim, Joo Young Jung, Su-Jin Koh, Kyoung Eun Lee, Hee-Jun Kim, Kyong Hwa Park, Seungtaek Lim, Yeon Hee Park, Sangwoo Kim, Joo Hyuk Sohn. Genomic characterization of hormone receptor-positive advanced breast cancer with high tumor mutational burden: fresh-frozen tissue genomic analysis from MUTATION-1 study (KCSG BR17-04) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-04.

Backgrounds Low-pass whole-genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis is a versatile tool for somatic copy number aberration (CNA) detection, and this study aims to explore its clinical implication in breast cancer. Methods We analyzed LP-WGS ctDNA data from 207 metastatic breast cancer (MBC) patients to explore prognostic value of ctDNA CNA burden, and validated it in 465 stage II-III triple-negative breast cancer (TNBC) patients who received neoadjuvant chemotherapy in phase III PEARLY trial (NCT02441933). The clinical implication of locus-level LP-WGS ctDNA profiling was further evaluated. Results We found that a high baseline ctDNA CNA burden predicts poor overall survival and progression-free survival of MBC patients. The post-hoc analysis of PEARLY trial showed that a high baseline ctDNA CNA burden predicted poor disease-free survival independent from pathologic complete response (pCR), validating its robust prognostic significance. The 24-month disease-free survival rate was 96.9% and 55.9% in pCR (+)/Low I-score and non-pCR/High I-score patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into five molecular clusters and revealed targetable oncogenic CNAs. LP-WGS ctDNA and in vitro analysis identified the BCL6 amplification as a resistance factor for CDK4/6 inhibitors. We estimated ctDNA-based homologous recombination deficiency (HRD) status of patients by shallowHRD algorithm, which was highest in the TNBC and correlated with platinum-based chemotherapy response. Conclusions These results demonstrate LP-WGS ctDNA CNA analysis as an essential tool for prognosis prediction and molecular profiling. Particularly, ctDNA CNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients.

Background: Hormone-receptor (HR) positive breast cancer is the main subtype of breast cancer. Although overall survival of HR-positive metastatic breast cancer (MBC) patients has improved by various therapies including endocrine therapies, CDK4/6 inhibitors, and cytotoxic chemotherapy, it is still considered incurable. Immune checkpoint inhibitors have rarely been clinically tested in HR-positive breast cancer, despite proving anti-cancer activity in early and metastatic triple-negative breast cancer in various trials. We evaluated efficacy and safety of combined durvalumab and tremelimumab in the HR-positive MBC, which was enriched with high tumor mutational burden (TMB). Methods: HR-positive MBC patients who received prior 1 or more lines of therapy in metastatic setting were prescreened with whole exome sequencing (WES) using metastatic or recurred tumor biopsies. Criterion of high TMB was defined as upper 30%. In the beginning, the criterion of high TMB was 2.1 mutations per Mb, based on the retrospective WES database in Yonsei Cancer Center and this criterion was recalculated every 30 cases. Patients who met upper 30% of TMB were treated with combined durvalumab (1500mg every 4 weeks upto 13 doses) and tremelimumab (75mg every 4 weeks upto 4 doses). Response was evaluated every 2 cycles using RECIST 1.1 and toxicity was evaluated using NCI-CTCAE 4.03. Tumor-infiltrating lymphocyte (TIL) and PD-L1 expression were also analyzed to investigate a correlation with TMB. Results: Biopsies of recurrent or metastatic tumors were taken from a total of 119 patients for WES assay. A median turn-around-time of TMB data was 30.0 days (range, 16~67). Of these 119 patients, a median number of nonsynonymous mutations was 2.0 per Mb (range, 0~21.7) with upper 30% criterion of 3.1. High TMB showed a trend toward old age (P=0.074) and single positivity of estrogen receptor (ER) or progesterone receptor (PR) compared to positivity of both ER and PR (P=0.055). TMB was positively correlated with TILs (r=0.289, P=0.005). Thirty patients with high TMB received study treatment with a median 2 cycles (range, 1~13). A median prior lines of therapies in metastatic setting was 4 (range, 1~9). The objective response and clinical benefit rates were 6.3% (2 PRs of 30) and 20% (2 PRs plus 4 SDs of 30). There was one treatment-related mortality due to pneumonitis. Immune-related adverse events included endocrinopathy (n=3; hypothyroidism in 2, hyperthyroidism in 1), enteritis (n=2), skin rash (n=2), pneumonitis (n=1), and so on. Biomarker analyses are underway. Conclusions: WES-based TMB using metastatic tumor biopsy was a feasible platform to prescreen HR-positive MBC patients. Combined durvalumab and tremelimumab showed a modest activity and good tolerability in heavily treated, HR-positive MBC with high TMB. Citation Format: Yong Wha Moon, Eunyoung Kim, Min Hwan Kim, Gun Min Kim, Seul-Gi Kim, YeeSoo Chae, Jieun Lee, Jae Ho Jeong, Kyung-Hun Lee, Han Jo Kim, Joo Young Jung, Su-Jin Koh, Kyoung Eun Lee, Hee-Jun Kim, Kyong Hwa Park, Seungtaek Lim, Yeon Hee Park, Tae Hoen Kim, Sewha Kim, Yohan Yang, Sangwoo Kim, Joohyuk Sohn. Phase II trial of durvalumab and tremelimumab in the hormone receptor-positive metastatic breast cancer with high tumor mutational burden selected by whole exome sequencing: Korean cancer study group trial (KCSG BR17-04) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-19-03.

Background The real-world risk of disease recurrence in patients with HER2-positive early breast cancer who achieved pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) and/or HER2-targeted therapy is unclear. This study aims to identify the patterns and risk factors of disease recurrence after NAC in patients with HER2-positive early breast cancer who achieved a pCR or not. Methods 930 HER2 positive early breast cancer patients who received NAC were identified in the Severance Breast Cancer Registry at the Yonsei Cancer Center and Gangnam Severance Hospital in Seoul, Republic of Korea, between 2006 and 2020. NAC included 3 regimens: only chemotherapy. (CTx), chemotherapy plus trastuzumab (CTx+H), and chemotherapy plus dual anti-HER2 therapy (TCHP). The pCR was defined as the absence of residual invasive cancer in the resected breast specimen and the axillary lymph nodes (ypT0/TisN0) after neoadjuvant systemic therapy. Recurrence of disease was defined as recurrence of ipsilateral locoregional invasive breast cancer, distant disease recurrence, or death. Results The median follow-up duration was 42.0 months (range 4-171), and median age was 51 years old (range 22-80). The rate of pCR was 52.2% (485/930). Depending on the achieved a pCR, the loco-regional recurrence rate was 4.0% (18/445) vs 1.0% (5/485), and the distant recurrence rate was 11.0% (49/445) vs 3.9% (19/445). Of the 79 patients who relapsed, 30.4% (n=24) had achieved a pCR and 69.6% (n=55) had residual disease. The 4-year recurrence risk was 6.9% for patients who achieved pCR versus 12.8% for those who did not (p Citation Format: Jee Hung Kim, Jii Bum Lee, Soong Joon Bae, Sung Gwe Ahn, Joon Jeong, Min Hwan Kim, Seul-Gi Kim, Gun Min Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Joohyuk Sohn. Pattern of recurrence after pathologic complete response after neoadjuvant chemotherapy in patients with early HER2-positive breast cancer: Real-world evidence [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-14.

Background. Endocrine therapy plus CDK 4/6 inhibitors is the foremost treatment for hormone receptor (HR) positive metastatic breast cancers (mBC). Previously, we reported safety profiles of palbociclib use with grade 3 neutropenia in HR-positive mBC. Here, we investigated two cohorts’ patients who had received palbociclib with or without dose interruptions and/or reductions on afebrile grade 3 neutropenia in terms of efficacy outcomes. Patients and methods. The combined cohort of consecutive mBC patients who received palbociclib with letrozole in 1st line setting (in four major cancer centers in Republic of Korea) was reviewed. We classified patients into 4 groups: Group 1 (patients who maintained palbociclib dose on afebrile grade 3 neutropenia, representing limited dose modification scheme), Group 2 (patients who experienced any dose modification on afebrile grade 3 neutropenia, representing conventional dose modification scheme), Group 3 (patients without the event of afebrile grade 3 neutropenia), and Group 4 (patients who experienced only grade 4 neutropenia) within the first 5 cycles. The primary endpoint was PFS difference between Group 1 and Group 2, and secondary endpoints included PFS and overall survival difference in all groups, and safety profiles of each group. Results. A total of 434 eligible patients recruited from Jan 2017 to Sep 2020 were allocated into 4 groups; Group 1 (n=172, 40.1%), Group 2 (n=128, 29.5%), Group 3 (n=102, 23.5%), and Group 4 (n=30, 6.9%). The overall incidence of palbociclib dose reductions was 272 (62.7%) and dosing delay was 181 (42.2%) in all groups. The median time to first dose reduction for all eligible patients was 3 months (2-5 months) and the median time to second dose reduction was 9 months (2-30 months). At the 12th cycle of treatment, 70.5% (105/at-risk patients of 149) of Group 1 patients still remained on 125mg of palbociclib, whereas no patient was on 125mg dose level but 66.3% patients (65/at-risk patients of 98) were on 100mg in Group 2. At the median follow-up of 23.7 months (95% CI: 21.6-25.8), Group 1 patients showed significantly longer PFS than Group 2 patients (P-value = 0.036, 2-year PFS rate: 67.9% in Group 1 and 55.3% in Group 2). The OS between Group 1 and 2 was not significantly different. The favorable PFS trend of Group 1 over Group 2 was observed across all subgroups. The overall toxicity profiles were not significantly different between Group 1 and Group 2. Conclusion. Our study demonstrates that the clinical practice of limited dose modifications for palbociclib-related grade 3 neutropenia might have more therapeutic benefits than the conventional dose scheme without increasing toxicities. Permissive approach to afebrile grade 3 neutropenia and prospective clinical trials for this new dose scheme are warranted. Funding: This study was supported by a grant from Pfizer. Citation Format: Seul-Gi Kim, Min Hwan Kim, Sejung Park, Gun Min Kim, Jee Hung Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Jung Hwan Ji, Joon Jeong, Kabsoo Shin, Jieun Lee, Hyung-Don Kim, Kyung Hae Jung, Joohyuk Sohn. Efficacy of limited dose modifications for palbociclib-related grade 3 neutropenia in hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-09.

Objectives: Various sensory symptoms have been recognized after COVID-19 vaccination. Here, we aimed to explore the association between the suggestive symptom of restless legs syndrome (RLSss) and COVID-19 vaccination using an online survey.Methods: We prospectively studied participants who were working in our hospital after at least the first dose of the ChAdOx1 or BNT162b2 mRNA vaccine. The participants were invited via smartphone messages and voluntarily filled out an online questionnaire that included adverse events after vaccination. We considered the participants as having RLSss if they reported that they had three or more symptoms in the restless legs syndrome (RLS) diagnostic criteria.Results: A total of 628 participants (506 female; mean age, 37.7±12.4 years) responded fully to our online survey. 588 participants (93.6%) received the first dose of the ChAdOx1 vaccine (BNT162b2 mRNA vaccine for 40 participants). A total of 44 out of the 628 participants (7.0%) reported that they had RLSss. Myalgia was more common in participants with RLSss than in those without RLSss (97.7% vs. 67.3%, p

The indications for immune checkpoint inhibitors (ICIs) are expanding for various cancers because of their durable responses and tolerable safety profiles. Immune-related adverse events (irAEs), including neurological adverse events (nAEs), are associated with ICIs therapy. However, there have been few studies on whether re-challenge with ICIs can be clinically acceptable after neurological AE has improved.A 69-year-old woman with recurrent ovarian cancer undergoing palliative chemotherapy was admitted to our hospital with sudden development of diplopia, dizziness, and gait instability. The patient was administered ICI therapy with anti-angiogenic agents for 9 weeks for 3 cycles.We performed neurological examination, brain imaging, nerve conduction studies, and serology tests. The patient was diagnosed with Guillain-Barré syndrome variant, an immune-mediated polyneuropathy characterized by a triad of ataxia, areflexia, and ophthalmoplegia.After prompt discontinuation of pembrolizumab, the patient was taken intravenous methylprednisolone (2 mg/kg) was administered for 5 days, and her symptoms were partially resolved. With the addition of immunoglobulin 0.4 g/kg for 5 days, her symptoms gradually improved.The patient's neurological symptoms improved after immunosuppressive therapy, without sequelae. The NCV showed normal nerve conduction. Unfortunately, because there was little evidence for pembrolizumab rechallenge, pembrolizumab therapy was permanently discontinued, and the tumors eventually progressed.

Purpose To evaluate the feasibility of syngeneic mouse models of breast cancer by analyzing the efficacy of immune checkpoint inhibitors (ICIs) and potential predictive biomarkers. Methods Four syngeneic mouse models of triple-negative breast cancer (TNBC) JC, 4T1, EMT6 and E0771 cells were injected subcutaneously. When the tumor reached 50–100 mm3, each mouse model was divided into treatment (murine PD-1 antibody) and no-treatment control. Treatment group is further divided into the responder and nonresponder groups. Potential predictive biomarkers were evaluated by analyzing serum cytokines, peripheral blood T cells and tumor infiltrating immune cells. Results The JC model showed the highest tumor response rate (40%, 4/10) of syngeneic models: 4T1 (36%, 4/11), EMT6 (36%, 4/11), or E0771 model (23%, 3/13). Early change of tumor size at 7 days post PD-1 inhibitor treatment predicted the final efficacy of PD-1 inhibitor. Peripheral blood CD8 + and CD4 + T cells with or without Ki67 expression at 7 days post-PD-1 inhibitor treatment were higher in the finally designated responder group than in the nonresponder group. At the time of sacrifice, analyses of tumor infiltrating lymphocytes consistently supported these results. Furthermore, serum IFN-γ at 7 days post-PD-1 inhibitor treatment was also higher in responders than in nonresponders, suggesting that early changes of these markers could be predictive biomarkers of the final efficacy of ICIs. Conclusions Our syngeneic mouse model of TNBC is a feasible preclinical platform to evaluate ICI efficacies combined with other drugs and predictive biomarkers in the screening period of immune-oncology drug development.

Grade 3/4 anaemia, which is mainly induced by carboplatin, frequently occurs in patients treated with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP). However, dose reduction of carboplatin may raise concerns about the oncological outcome. This study investigated the pathologic complete response (pCR) rate, occurrence of grade 3/4 anaemia, and transfusion rate according to carboplatin dose in patients treated with neoadjuvant TCHP. We retrospectively analysed 294 patients treated with neoadjuvant TCHP between April 2015 and December 2020. Case matching was performed using propensity score matching. Among patients treated with neoadjuvant TCHP, carboplatin area under the plasma concentration-time curve 6 (AUC6) was used in 234 patients (79.6%) and upfront carboplatin AUC5 was used in 60 patients (20.4%). No significant difference in pCR rate was found between the two groups (AUC6: 70.9%, AUC5: 80.0%). In both oestrogen receptor-positive (ER+) and ER- patients, no significant differences were observed between the AUC6 and AUC5 groups (ER+: 54.3% vs. 50.0%, ER-: 81.7% vs. 86.0%). The case-matched cohort showed consistent findings. The AUC5 group had lower frequencies of grade 3/4 anaemia (18.3% vs. 34.2%) and transfusion events (10.0% vs. 21.8%) than the AUC6 group. Compared with AUC5, carboplatin at AUC6 would associate with a 2.7-fold increased risk of grade 3 or 4 chemotherapy-induced anaemia. Carboplatin AUC5 has comparable cytotoxic effects to carboplatin AUC6 in patients with HER2+ breast cancer treated with six cycles of neoadjuvant TCHP, with fewer complications associated with clinically meaningful anaemia. AUC5 may be the optimal carboplatin dose to reduce TCHP-induced anaemia in patients with HER2+ breast cancer treated with TCHP.

PARP inhibitors have prolonged the survival of various cancer patients with homologous recombination (HR) deficiencies. However, most patients eternally acquire resistance. Many attempts have been made, but there are no clear strategies to overcome resistance. We evaluated the efficacy and mechanism of JPI-547, a novel dual inhibitor of PARP1/2 and tankyrase1/2, in olaparib resistant breast and ovary preclinical cancer models. We established olaparib resistance models using mammalian cancer cell lines and patient-derived tumor xenografts (PDTXs). Two olaparib-resistant cells cell lines (BT474-OR/SNU251-OR) were established by exposing parent BRCA1/2 mutation carrying BT474 and SNU251 (breast and ovary cancer) to gradually increasing the concentration of olaparib for 8 months. An olaparib-resistant PDTX model [WJO-003(O2)], the parent BRCA1 mutation carrying ovary cancer PDTX was engrafted and treated with olaparib in 75mg/kg twice daily for 1 month and then 100mg/kg twice daily for 3 months. Using established olaparib resistance models, the anti-tumor efficacy of JPI-547 was compared with olaparib, niraparib, and talazoparib. IC50 of BT474-OR and SNU251-OR cell lines showed 5.5 and 6.7 fold increase compared to those of parent cell lines, respectively. While JPI-547 treatment in BT474-OR and SNU251-OR showed similar IC50 to the matching parent cells. In the PARPi-sensitive PDTX model, CPDX-013, JPI-547 inhibited tumor growth the greatest among other PARP inhibitors. Remarkably, 4 of 7 mice showed complete regression of the tumors. In the olaparib-resistant PDTX model, WJO-003(O2), JPI-547 inhibited tumor growth the most effectively compared to other PARP inhibitors (at day 60, the mean tumor volume: 2539, 1319, 871, 601, and 29 mm3 in control, niraparib, olaparib, talazoparib, and JPI-547, respectively; p Citation Format: Min Sil Kang, Nar Katuwal, Mithun Ghosh, Young kyu Jeong, Sa deok Hong, Sung Min Park, John Kim, Hyunju Cha, Banyoon Cheon, Seul-Gi Kim, Yong Wha Moon. JPI-547, a novel dual inhibitor of PARP 1/2 and tankyrase 1/2 overcomes olaparib resistance in BRCA 1/2 mutant ovary and breast cancer preclinical model. [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 4485.

Renal cell carcinoma (RCC) is the most common type of kidney malignancy worldwide with Pembrolizumab and axitinib treatment (Pembro/Axi) amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict treatment response and early resistance. Therefore, we evaluated whether baseline serum interleukin-6 (IL-6) could be a predictive biomarker. Between November 2019 and December 2021, 58 patients with advanced RCC were enrolled, administered first-line Pembro/Axi, and baseline blood samples were analyzed using flow cytometry. The mean baseline serum IL-6 concentration was 8.6 pg/mL in responders and 84.1 pg/mL in patients with progressive disease. The IL-6 cut-off value was set at 6.5 pg/mL using time-dependent receiver operating characteristic curves, with 37.9% of patients having high baseline serum IL-6 levels and 62.1% having low levels. Objective response rates were 58.3% and 36.4% in low and high IL-6 groups, respectively. Overall survival and progression-free survival were longer in patients with low IL-6 levels than in those with high levels. High IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production from CD8+ T cells. Overall, high baseline serum IL-6 levels were associated with worse survival outcomes and reduced T-cell responses in Pembro/Axi-treated advanced RCC patients.

Orbital apex syndrome (OAS) is a rare condition that usually occurs due to damage to surrounding inner and surrounding bone tissue. Orbital apex syndrome may result from a variety of conditions that cause damage to the superior orbital fissure and to the optic canal leading to optic nerve (II) dysfunction. We recently experienced a rare case of sphenoidal Aspergillosis, which damaged the adjacent cavernous sinus structures and led to the definite symptom of bilateral OAS in a 77-year-old male. We present this rare case with a brief review of these disease’s entities.

Owing to the safety and cost effectiveness of conditioned medium (CM), its therapeutic effects have attracted significant attention from many researchers. To date, numerous studies have been conducted on CM; however, little has been done with regard to erectile dysfunction (ED). In this research, the potential of human mesenchymal stem cell-derived CM (MSC-CM) for the treatment of ED was investigated.A high concentration of MSC-CM was prepared through 3D spheroid culturing with bone marrow-derived MSCs and cut-off filtering. The composition of CM was analyzed using biochemical assays, and the effect of the preparation process on the quality of CM was investigated. The therapeutic effects of MSC-CM were evaluated through animal studies using a cavernous nerve (CN) injury rat model.3D spheroid culturing afforded a 278-fold increase in the total protein content of CM, as compared to that from 2D cultures; the protein concentration increased by 19 times on increasing the centrifugation time for cut-off filtering. Biochemical assays indicated that the CM contains various types of angiogenic, neurotrophic, and anti-inflammatory factors. Histological assay results showed that MSC-CM has angio- and neuro-trophic effect in a CN injury rat modelThe experimental results confirmed the therapeutic effect of MSC-CM in healing damaged cavernosal tissue and restoring erectile function. These results successfully demonstrated that MSC-CM has significant potential for the treatment of ED.

Background Previous studies proposed low-pass whole genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis as a versatile tool for genomic profiling and therapeutic monitoring of cancer patients. Here we demonstrate LP-WGS ctDNA genomic profiles and its clinical significance in metastatic breast cancer patients. Patients and methods This prospective exploratory study enrolled 207 treatment-naïve metastatic breast cancer patients from Feb 2017 to September 2020 in Yonsei Cancer Center. The median follow-up duration of patients was 35 months. The baseline (n=207) and post-progression (n=48) plasma samples were prospectively collected on first-line systemic therapy, and LP-WGS was employed for ctDNA somatic copy number alteration (CNA) analysis. The CNA burden of ctDNA was scored by “I-score” method, which was developed to measure genome-wide chromosomal instabilities, to be matched with therapy response. The unsupervised molecular clustering and homologous recombination deficiency (HRD) estimation by shallowHRD algorithm were performed using locus-level CNA profiles with 1 mega base pair resolution. Results The baseline I-score ctDNA CNA burden was highest in triple-negative breast cancer (TNBC) patients among subtypes, and the patients were dichotomized by median I-score level 5.54 (range 2.55 to 12.98). The high baseline ctDNA I-score was independently associated with poor overall survival (hazard ratio [HR] = 3.98, p < 0.001) with adjustment of tumor subtype, visceral metastasis, and disease status (de novo stage IV versus recurrent). The progression-free survival (PFS) on endocrine plus CDK4/6 inhibitors (HR = 2.75, p = 0.005), anti-HER2 therapy (HR = 2.52, p = 0.032), and cytotoxic chemotherapy (HR = 2.33, p = 0.012) was also shorter in high baseline I-score patients than in low I-score patients. The locus-level CNA profile was analyzed in high I-score patients (n=103), and the patients were classified into five molecular clusters with distinct overall survival by unsupervised k-means clustering of CNA profile: basal-like, EGFR-high basal-like, CCND1-high, luminal, and HER2-enriched clusters. Patients with BCL6 (p = 0.009) and PIK3CA amplification (p < 0.001) on baseline ctDNA showed significantly shorter PFS on CDK4/6 inhibitor treatment. The matched baseline and post-progression ctDNA analysis found emergence of FGFR1 amplification and MYC amplification after CDK4/6 inhibitor treatment (n=1, each). The ctDNA shallowHRD score was highest in TNBC patients among subtypes, and TNBC patients with high shallowHRD score (≥10) showed high response rate on (58.3% versus 28.6%) on platinum-based chemotherapy. Conclusion LP WGS-based ctDNA analysis provides a robust tool for non-invasive genomic clustering, therapy response prediction, and HRD estimation in metastatic breast cancer patients. All patients (n=207)Low I-score (n=104)High I-score (n=103)N (%)N (%)N (%)Age, Median (Interquartile range)54 (46-62)53 (47-60)54(44-62)GenderFemale205 (99)102 (98.1)103Male2 (1)2 (1.9)0SubtypeHR+ HER2-106 (51.2)61 (58.7)45 (43.7)HR- HER2+33 (15.9)14 (13.5)19 (18.4)HR+ HER2+22 (10.6)11 (10.6)11 (10.7)HR- HER2- (TNBC)46 (22.2)18 (17.3)28 (27.2)Disease statusDe novo stage IV74 (35.7)31 (29.8)43 (41.7)Recurrent133 (64.3)73 (70.2)60 (58.3)Primary therapyEndocrine + CDK 4/6 inhibitor97 (46.9)55 (52.9)42 (40.8)Anti-HER2 based therapy54 (26.1)24 (23.1)30 (29.1)Chemotherapy45 (21.7)16 (15.4)29 (28.2)Others11 (5.3)9 (8.7)2 (1.9)Visceral metastasisYes142 (68.6)60 (57.7)82 (79.6)No65 (31.4)44 (42.3)21 (20.4)Metastasis SitesLung89 (43)43 (41.3)46 (44.7)Brain19 (9.2)4 (3.8)15 (14.6)Liver59 (28.5)13 (12.5)46 (44.7)Bone120 (58)47 (45.2)73 (70.9)Lymph node90 (43.7)32 (30.8)58 (56.9)Pleura33 (15.9)17 (16.3)16 (15.5) Citation Format: Joohyuk Sohn, Min Hwan Kim, Jin Mo Ahn, Won-Ji Ryu, Seul-Gi Kim, Jee Hung Kim, Tae Yeong Kim, Hyun Ju Han, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Eun Hae Cho, Gun Min Kim. Whole genome sequencing-based circulating tumor DNA profiling of metastatic breast cancer patients for molecular characterization and therapy response prediction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-07.

BACKGROUND Hypernatremia is associated with poor outcomes in critically ill patients, and an accurate assessment of water volume is important to determine appropriate fluid hydration. Bioelectrical impedance analysis (BIA) is a new, noninvasive, and relatively easy method for measuring hydration status. This study aimed to investigate whether bioelectrical impedance measurements of body water could reduce the frequency of blood sampling for fluid replacement in patients with hypernatremia. MATERIAL AND METHODS Fifty-one hospitalized patients were studied with hypernatremia, defined as a serum sodium ≥150 mmol/L determined by laboratory testing. Laboratory and BIA measurements were compared, and water deficiency was calculated with a conventional formula (sodium-corrected Watson formula) and measured by BIA. RESULTS The value of the absolute fluid overload (AFO) equivalent to the overhydration (OH) value, determined using BIA, did not accurately represent water deficit in patients with hypernatremia (r=0.137, P=0.347). Although the total body water (TBW) measured by BIA showed a significant correlation with that determined by the conventional formula (r=0.861, P

Background Fast growing cancer cells require greater amounts of ATP than normal cells. Although glycolysis was suggested as a source of anabolic metabolism based on lactate production, the main source of ATP to support cancer cell metabolism remains unidentified. Methods We have proposed that the oxoglutarate carrier SLC25A11 is important for ATP production in cancer by NADH transportation from the cytosol to mitochondria as a malate. We have examined not only changes of ATP and NADH but also changes of metabolites after SLC25A11 knock down in cancer cells. Findings The mitochondrial electron transport chain was functionally active in cancer cells. The cytosolic to mitochondrial NADH ratio was higher in non-small cell lung cancer (NSCLC) and melanoma cells than in normal cells. This was consistent with higher levels of the oxoglutarate carrier SLC25A11. Blocking malate transport by knockdown of SLC25A11 significantly impaired ATP production and inhibited the growth of cancer cells, which was not observed in normal cells. In in vivo experiments, heterozygote of SLC25A11 knock out mice suppressed KRASLA2 lung tumor formation by cross breeding. Interpretation Cancer cells critically depended on the oxoglutarate carrier SLC25A11 for transporting NADH from cytosol to mitochondria as a malate form for the purpose of ATP production. Therefore blocking SLC25A11 may have an advantage in stopping cancer growth by reducing ATP production. Fund The Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT to SYK (NRF-2017R1A2B2003428).

Background The molecular selective pressure on anti-tumor therapy drives lineage plasticity in several cancer types to develop drug resistance. The subtype conversion from luminal to triple-negative breast cancer (TNBC) subtype fuels endocrine resistance and disease aggressiveness. In this study, we analyzed mechanisms of luminal to basal subtype conversion by clinical sample sequencing and molecular study. Method We performed whole-exome sequencing (WES) of primary and metastatic tumor tissues from breast cancer patients with luminal to basal [from HR(+)/HER2(-) to TNBC] subtype conversion (experimental, n=14) and patients with subtype maintenance (luminal to luminal subtype, control, n= 36) after adjuvant endocrine therapy. For RNA-sequencing, the subset of patients (experimental, n=14; control n=7) was further analyzed. The differences in genetic alterations and gene expression were compared between two patient groups to identify genetic predictors of subtype conversion. We also manipulated genetic factors related to subtype conversion in MCF7 cells to identify molecular signaling to drive lineage change. Results In WES analysis, TP53 mutation was more frequently observed in luminal breast cancer patients with subtype conversion to TNBC [60% (12 out of 20 tissues in experimental group) versus 20% (8/40 tissues in control group)]. Whereas, GATA3 mutations were only observed in patients of subtype maintenance (0% versus 20%), and the mRNA level of GATA3 was downregulated after luminal-to-basal conversion. The TP53 and GATA3 mutations were both observed in the matched primary and metastatic tissues, suggesting that these mutations predisposed subtype conversion but were not acquired during the adjuvant endocrine therapy. In expression signature analysis, the patients with subtype conversion showed the upregulation of KRAS signaling and the suppression of GATA3 signature in metastatic TNBC tumors compared to primary luminal tumors. In primary tumors, RELA and MYC signatures were only upregulated in tumors that underwent subtype conversion later. We found ESR1 expression was decreased by knockdown of TP53 and GATA3 in MCF7 cells. The knockdown of TP53 and GATA3 also induced basal marker expressions, cytokeratin 5 and 14, in MCF7 cells. ESR1 expression and luminal markers were also decreased by GATA3 suppression in T47D harboring TP53 mutation. Conclusion In luminal-type breast cancer, the subtype conversion is the one of the major obstacles for their treatment and preventing recurrence. We found the genetic alterations of TP53 mutation was the key predisposing factor of luminal to basal subtype conversion, whereas GATA3 mutation is a protecting factor for subtype conversion in luminal breast cancers. Thus, targeting TP53-GATA3 axis would be a potential therapeutic strategy to overcome endocrine resistance and block the subtype conversion in luminal type breast cancer. Citation Format: Won-Ji Ryu, Hyun-Yi Kim, Tae Yeong Kim, Yeona Choi, Hyun Ju Hahn, Seul-Gi Kim, Gun Min Kim, Ja Seung Koo, Seung Il Kim, Joohyuk Sohn, Min Hwan Kim. TP53-GATA3 mutation status predisposes luminal-to-basal subtype conversion in advanced breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6082.

Background To validate a stratification method using an inverse of treatment decision rules that can classify non-small cell lung cancer (NSCLC) patients in real-world treatment records. Methods (1) To validate the index classifier against the TNM 7th edition, we analyzed electronic health records of NSCLC patients diagnosed from 2011 to 2015 in a tertiary referral hospital in Seoul, Korea. Predictive accuracy, stage-specific sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and c-statistic were measured. (2) To apply the index classifier in an administrative database, we analyzed NSCLC patients in Korean National Health Insurance Database, 2002–2013. Differential survival rates among the classes were examined with the log-rank test, and class-specific survival rates were compared with the reference survival rates. Results (1) In the validation study (N = 1375), the overall accuracy was 93.8% (95% CI: 92.5–95.0%). Stage-specific c-statistic was the highest for stage I (0.97, 95% CI: 0.96–0.98) and the lowest for stage III (0.82, 95% CI: 0.77–0.87). (2) In the application study (N = 71,593), the index classifier showed a tendency for differentiating survival probabilities among classes. Compared to the reference TNM survival rates, the index classification under-estimated the survival probability for stages IA, IIIB, and IV, and over-estimated it for stages IIA and IIB. Conclusion The inverse of the treatment decision rules has a potential to supplement a routinely collected database with information encoded in the treatment decision rules to classify NSCLC patients. It requires further validation and replication in multiple clinical settings.

The self-renewal properties of human pluripotent stem cells (hPSCs) contribute to their efficacy in tissue regeneration applications yet increase the likelihood of teratoma formation, thereby limiting their clinical utility. To address this issue, we developed a tool to specifically target and neutralize undifferentiated hPSCs, thereby minimizing tumorigenicity risk without negatively affecting regenerated and somatic tissues. Specifically, we conjugated a monoclonal antibody (K6-1) previously generated in our laboratory against desmoglein 2 (Dsg2), which is highly differentially expressed in undifferentiated hPSCs versus somatic tissues, to the chemotherapeutic agent doxorubicin (DOX). The K6-1-DOX conjugates were selectively targeted and incorporated into Dsg2-positive hPSCs, leading to pH-dependent endosomal release and nuclear localization of DOX with subsequent cytotoxicity via an apoptotic caspase cascade. Conversely, Dsg2-negative fibroblasts showed minimal conjugate uptake or cytotoxicity, suggesting that K6-1-DOX treatment would yield few side effects owing to off-target effects. Selective removal of undifferentiated stem cells was also supported by in vivo studies using a mouse xenograft model, wherein hIgG-DOX- but not K6-1-DOX-pretreated-hPSC injection led to teratoma development. Together, these results validated the ability of the Dsg2-targeted antibody-anticancer drug conjugate to facilitate the safety of stem cell therapies.

The kinase Aurora B forms the chromosomal passenger complex (CPC) together with Borealin, INCENP, and Survivin to mediate chromosome condensation, the correction of erroneous spindle-kinetochore attachments, and cytokinesis. Phosphorylation of histone H3 Thr3 by Haspin kinase and of histone H2A Thr120 by Bub1 concentrates the CPC at the centromere. However, how the CPC is recruited to chromosome arms upon mitotic entry is unknown. Here, we show that asymmetric dimethylation at Arg2 on histone H3 (H3R2me2a) by protein arginine methyltransferase 6 (PRMT6) recruits the CPC to chromosome arms and facilitates histone H3S10 phosphorylation by Aurora B for chromosome condensation. Furthermore, in vitro assays show that Aurora B preferentially binds to the H3 peptide containing H3R2me2a and phosphorylates H3S10. Our findings indicate that the long-awaited key histone mark for CPC recruitment onto mitotic chromosomes is H3R2me2a, which is indispensable for maintaining appropriate CPC levels in dynamic translocation throughout mitosis., The proteins of the chromosomal passenger complex help chromosomes condense before cell division, but how this complex arrives at chromosomes was not known. Here the authors show that PRMT6 methylates histone H3 to recruit the chromosomal passenger complex.

BACKGROUND: Quantitative assessment of rotator cuff muscle activity is important in the treatment of shoulder disorders. However, the known methods for assessing rotator cuff muscle activity thus far have been inaccurate, invasive, and inconvenient. QUESTIONS/PURPOSES: (1) Does the activity of the deltoid, supraspinatus, and infraspinatus muscles measured using ultrasound shear wave elastography have a linear correlation with muscle activity assessed using generally used methods, including isokinetic dynamometry and electromyography? (2) Does the activity of the deltoid, supraspinatus, and infraspinatus muscles measured using shear wave elastography show good intraobserver and interobserver reliability? METHODS: Twelve volunteers participated in intrasession reliability experiments. They were asked to perform isometric abduction, external rotation, and scaption contractions (defined as elevation of the arm within the plane of the scapula with neutral arm rotation) gradually increased from 0% to 75% of maximal voluntary contraction. The joint torque, electromyographic activity, and shear elastic modulus were synchronously measured in the middeltoid, supraspinatus, and infraspinatus muscles. The validity of the elastic modulus value was assessed using regression analysis between normalized torque and electromyographic root mean square values. For intraobserver and interobserver reliability measurements, repeated experiments were performed with the same protocol. RESULTS: The shear elastic modulus and normalized joint torque with isokinetic dynamometry showed a linear relationship in all muscles (deltoid, supraspinatus, and infraspinatus) and each of the ultrasonography planes (longitudinal and transverse) (mean R(2) > 0.8 and p < 0.001 for all measurements). For the supraspinatus muscle, the mean slope of the relationship between shear elastic modulus in the longitudinal plane and the normalized joint torque during scaption contraction was 1.28 ± 0.39 kPa/%MVC (mean R(2) = 0.93 ± 0.21, p < 0.001). Furthermore, similar results were obtained in relation to electromyography root mean square values (mean R(2) > 0.8 and p < 0.001 in all measurements). For the supraspinatus muscle, the mean slope of the relationship between shear elastic modulus in the longitudinal plane and electromyographic (EMG) root mean square was 0.96 ± 0.27 kPa/%EMG (mean R(2) = 0.91 ± 0.08, p < 0.001). The intraobserver and interobserver reliabilities were excellent in all positions (abduction, external rotation, and scaption) and in both the longitudinal and transverse ultrasonography planes (all intraclass correlation coefficients are > 0.85). CONCLUSIONS: Shoulder muscle activity can be noninvasively evaluated with ultrasound shear wave elastography. Clinician and scientists should consider the application of this technique in cases in which evaluation of shoulder muscle activity is required. The next step after this study will be to check the shear elastic modulus of rotator cuff muscle in patients with rotator cuff tear. We plan to evaluate the correlation between shear elastic modulus and joint torque according to tear size and fatty infiltration status of rotator cuff muscle. CLINICAL RELEVANCE: Shear wave electrography can be used to measure various tissue elasticities in both static and dynamic modes. It may be a useful tool to evaluate pre- and postoperative rotator cuff muscle activity in a relatively simple manner. Shoulder function after reverse total shoulder arthroplasty associated with deltoid muscle activity also may be evaluated. Changes in tissue tightness in shoulder disorders caused by increase soft tissue stiffness (ie, adhesive capsulitis and glenohumeral internal rotation deficit) can be evaluated.

In cases of vertebral collapse after a trivial injury in elderly patients with severe osteoporosis, it can be a diagnostic challenge to determine whether the cause is a benign compression fracture or malignant metastasis. A 78-year-old male patient was referred to the emergency department for the evaluation of weakness of the left lower limb. He had undergone percutaneous vertebroplasty four months earlier after being diagnosed with L3 osteoporotic compression fracture. He was treated with foraminotomy at the L3-4 level after being diagnosed with foraminal stenosis two months earlier at a spine clinic. Magnetic resonance (MR) images showed significant signal change from the vertebral body to the posterior element, and widely spreading extraspinal extension of soft tissue at L3. Computed tomography scan revealed osteolytic changes in regions including the ventral body and pedicle. Emergent decompressive laminectomy and bone biopsy were performed, and the histologic evaluation showed metastatic squamous cell carcinoma. A retrospective review of previous MR images showed obvious pedicle and facet involvement, and paraspinal extension of soft tissue, which are highly suggestive of malignant metastasis.

Reactive oxygen species (ROS)-responsive materials for the selective and sensitive electrochemical detection of cancer cells have been studied comprehensively, especially owing to the variable concentration of H2O2 in normal and tumor cells. In this report, we develop a real-time electrochemical sensor based on diselenide-functionalized dopamine-conjugated hyaluronic acid polymer dots (PD(HA/DP)-DiSe) nanoparticles coated on a substrate that could be used for selective tumor diagnosis by tuning the coated surface morphology. The hyaluronic acid-based cancer cell-targeted PD(HA/DP)-DiSe-coated surface demonstrates selectivity and sensitivity toward ROS because of the change in the optical fluorescence after treatment. Owing to cleavage of the Se-Se bond and the formation -Se-OH/-Se-OOH, the PD(HA/DP)-DiSe coated-surface is tuned from a sphere-like to a sheet-like form with smaller size changing the electronic impedance of the sensor. A real-time in vitro selective diagnosis conducts by connecting the sensor to the wireless system and produces an accurate result to distinguish different ratios of MDCK:MDA-MB-231 and MDCK:HeLa cells. Finally, the developed ROS-responsive sensor could specifically differentiate the cancer microenvironment, which is helpful for advanced and selective biomedical purposes.

A self-repairable and reusable self-powered electronic skin sensor is developed from NIR/pH-responsive polymer dot (PD) embedded hydrogel with amplified mechanical and electrochemical properties after self-healing. The pH/NIR-controlled mechanical, electrochemical and self-healing performance of the designed hydrogel is achieved by manipulating the hydrogen bond formation with tunable mobility from the PD components. The hydrogel formed at pH 7.4, after treatment with pH 10 and NIR-driven healing, the mechanical stretchability (585%), conductivity (6.8 mS cm−1), capacitance (184.2 mF cm−2), and gauge factor (1.09) was increased by 125%, 4.9 times, 37%, and 72%, respectively. Further, the hydrogel system was explored as a reusable physiological strain sensor which showed excellent strain sensitivity of 0.36 kPa−1 with remarkable repeatability of 12,000 stretching-bending operations over two cutting-healing cycles. The real-time pH/NIR-dependent amplified sensing performance is effectively monitored remotely by using a wireless connection via a smartphone. Additionally, the hydrogel-based supercapacitor was attached with a solar cell for a self-powered body sensor that works seamlessly under sunlight. The integrated system obtains enhanced energy storage upon healing, reaching an overall power conversion efficiency of 2.32%. The NIR/pH-driven durability, the reproducible amplified mechanical and electrical performance of the self-powered electronic skin can be efficiently used for detecting movements ranging from a subtle human wrist pulse to rough finger motions presenting their potential application in wearable human-health monitoring systems.

Objective: Children with spastic diplegic cerebral palsy show weakness especially in the lower-ex-tremity rather than upper-extremity muscles and display characteristics such as asymmetric alignment, deficits in postural control or balance ability, and slow walking speed. Various therapeutic interventions are applied to children with cerebral palsy, of which taping is widely used in the field of rehabilitation, however, there are few studies of the effects of kinesio taping on gait patterns of children with cerebral palsy. The present study investigated the effects of kinesio taping on gait parameters of children with cerebral palsy. Design: Cross-sectional study. Methods: Four children with spastic diplegia participated in this study. The participants` gait parameters while walking 10 m with and without kinesio taping (tibialis anterior, quadriceps femoris, and gluteus maximus) were recorded. Gait parameters including gait velocity, cadence, step length, stride length, single support time, and double support time were evaluated using the GAITRite. Mean values were obtained after having the subjects walk three times in each condition with a 5-minute rest period between each condition. The order of each condition was assigned randomly. Results: There were significant improvements in gait velocity, step length, stride length, and single support time of the right leg with kinesio taping condition compared to the without kinesio taping condition taping (p