신장 재이식 환자의 다발성 내장 침범 카포시육종에서 Sirolimus 치료를 통한 부분 관해 및 이식신 보존 1예

The use of immunosuppressant's increases the risk of developing malignancies in renal allograft patients. One of the most important malignancies, Kaposi's sarcoma, can cause mortality and graft failure among renal allograft patients. We report the case of a 39-year-old male diagnosed with multiple visceral Kaposi's sarcoma 6 months after a second cadaveric renal allograft. The patient's renal function was markedly deteriorated at admission and required hemodialysis initially. Radiologic studies revealed Kaposi's sarcoma in multiple lymph nodes, liver, lung, and peritoneum. The excisional biopsy of an inguinal lymph node confirmed this diagnosis. After diagnosis, tacrolimus treatment was gradually decreased, and sirolimus treatment initiated. The patient did not receive any chemotherapy or radiotherapy. The Kaposi's sarcoma lesions decreased dramatically (both in size and number) 1 month after sirolimus treatment, and kidney graft function improved. This case thus shows successful sirolimus treatment of visceral Kaposi's sarcoma in a renal allograft patient.ope

Formulation of Nanostructured Lipid Carriers(NLCs) of 20(S)-Protopanaxadiol(PPD) by Box-Behnken design

학위논문 (석사)-- 서울대학교 대학원 : 약학대학 약학과, 2018. 2. 김대덕.20(S)-Protopanaxadiol(PPD)는 Compound K와 ginsenoside Rb1에서 당이 떨어진 대사체로서, matrix metalloproteinase-1 (MMP-1) 활성 감소에 의한 피부노화방지 작용을 가지고 있다. 활성 성분의 피부 흡수과정에서 각질층을 통과하는 것이 가장 중요한 단계인데, PPD는 물에 잘 녹지 않고 분자량이 크기 때문에 각질층을 잘 통과하지 못하여 피부 흡수가 잘 안 될 것으로 예측이 된다. 그러므로 Fick의 확산 법칙에 근거하여, PPD의 피부 흡수를 증가시키기 위해서는 이를 가용화 할 수 있는 제형 개발이 필요하다. Lipid nanoparticle의 한 종류인 Nanostructured Lipid Carrier(NLC)는 기존에 알려진 리포좀이나 에멀젼에 비해 여러 장점을 가지고 있는데, 피부수화효과, 약물의 지속방출, 안정성 증가 등이 대표적이다. 본 연구의 목적은 반응표면법 중 하나인 Box-Behnken Design을 이용하여 지용성 물질인 PPD의 피부 흡수를 증가시키기 위한 최적의 NLC 조성을 얻는 것이다. PPD의 양(X1), 오일의 양(X2), 계면활성제의 양(X3)을 세 개의 변수로 설정하였고, 입자의 크기(Y1), polydispersity index (PDI) (Y2), 봉입율(Y3)을 바탕으로 최적화를 진행하였다. 최적 조성으로부터 얻은 예측 값과 실측 값을 비교함으로써 실제로 최적화가 되었는지를 확인 하였다. Y1, Y2, Y3 값 모두 예측 값과 실측 값의 차이가 5%이내인 것으로부터 최적의 조성이 잘 도출되었음을 확인하였다. 또한, X-ray diffraction (XRD)를 통하여 PPD가 NLC 제형에 무정형의 상태로 봉입되어있음을 알 수 있었다. 최적 조성의 NLC를 피부 대체 인공막인 Strat-M™에 적용한 후 시간에 따른 PPD의 잔류량을 평가하였다. PPD를 함유한 suspension과 oil solution에 비해 최적화된 NLC 조성을 적용하였을 때, 3시간과 6시간 후의 PDD 잔류량이 모두 유의성 있게 높은 값을 나타내었다. 이를 통해, PPD의 피부 적용을 위한 최적의 NLC 조성이 Box-Behnken design을 통해 성공적으로 도출되었음을 알 수 있었다.1. Introduction 1 2. Materials and Methods 5 2.1. Materials 5 2.2. HPLC analysis 5 2.3. Selecting liquid lipid and surfactant 7 2.4. Preparation of APPD-loaded NLCs 7 2.5. Experimental design 8 2.5.1. Size and PDI 9 2.5.2. Entrapment efficiency 9 2.5.3. TEM analysis 10 2.5.4. Power X-ray diffraction (XRD) 10 2.6. In vitro deposition test in Strat-M™ membrane 10 2.7. Statistical analysis 11 3. Results and Discussion 12 3.1. Solubility test 12 3.2. Experimental design using Box-Behnken design 12 3.2.1 Effect on particle size 12 3.2.2 Effect on PDI 13 3.2.3 Effect on EE 14 3.2.4 optimization and validation 15 3.3 Transmission electron microscopy (TEM) 15 3.4 X-ray diffraction study 16 3.5 In-vitro deposition study in Strat-M™ 16 4. Conclusion 18 References 19 국문초록 37 APPENDIX 39Maste

Molecular Characterization of BRCA1 c.5339T>C Missense Mutation in DNA Damage Response of Triple-Negative Breast Cancer

BRCA1 L1780P BRCT domain mutation has been recognized as a pathogenic mutation in patients with breast cancer. However, the molecular significance of this mutation has not yet been studied in triple-negative breast cancer (TNBC) cells in vitro. We established MDA-MB 231, HCC1937, and HCC1395 TNBC cell lines expressing BRCA1 L1780P mutant. BRCA1 L1780P mutant TNBC cells showed increased migration and invasion capacity, as well as increased sensitivity to olaparib and carboplatin compared to BRCA1 wild-type cells. BRCA1 L1780P mutant TNBC cells showed decreased RAD51 expression and reduced nuclear RAD51 foci formation following carboplatin and olaparib treatment. The molecular interaction between p-ATM and BRCA1 was abrogated following introduction of BRCA1 L1780P mutant plasmid in TNBC cells, suggesting that the BRCA1 L1780P mutation disrupts the p-ATM-BRCA1 protein-protein interaction. We established an olaparib-resistant BRCA1 L1780P mutant TNBC cell line by chronic drug treatment. Olaparib-resistant cell lines showed upregulation of RAD51 expression upon olaparib treatment, and reduction in RAD51 expression in olaparib-resistant cells restored olaparib sensitivity. Collectively, these results suggest that the BRCA1 L1780P mutation impairs RAD51 recruitment by disrupting p-ATM-BRCA1 interaction, which is a crucial molecular factor in homologous recombination and olaparib sensitivity. Further therapeutic targeting of RAD51 in BRCA1 L1780P mutant breast cancer is warranted.ope

Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer: The Neo-PATH Phase 2 Nonrandomized Clinical Trial

Importance: Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects. Objective: To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase. Design, setting, and participants: This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2-positive breast cancer (primary tumor size >2 cm or pathologically confirmed lymph node-positive cancer, without distant metastases) with a clinical stage of II or III. Interventions: Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m2), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks. Main outcomes and measures: The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes. Results: A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor-negative disease vs hormone receptor-positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1-positive expression vs programmed cell death 1-negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase. Conclusions and relevance: In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2-positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2-positive early breast cancer is warranted. Trial registration: ClinicalTrials.gov Identifier: NCT03881878.ope

Real-world efficacy and safety of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancers: a multicenter retrospective analysis

Background: A recent phase II trial reported prolonged survival in patients with advanced biliary tract cancer (BTC) following treatment with nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P). We aimed to evaluate the clinical outcomes of Gem/Cis/nab-P in Asian patients with advanced BTC in a real-world setting. Methods: We reviewed the data of patients who received Gem/Cis/nab-P for the management of advanced BTC between September 2019 and April 2021 at four institutes in Korea. Patients were classified into the Gem/Cis/nab-P and nab-P addition groups depending on the starting point of nab-P administration. Results: A total of 178 patients treated with Gem/Cis/nab-P were included in the study. Of these, 43.8% had intrahepatic cholangiocarcinoma (CCA), 34.8% had extrahepatic CCA, and 21.3% had gall bladder cancer. A total of 117 (65.7%) patients received Gem/Cis/nab-P as the first-line treatment, while 61 (34.3%) were treated with gemcitabine-cisplatin-based chemotherapy followed by nab-P addition. The objective response rate (ORR) and disease control rate in all patients were 42.1% and 84.8%, respectively. The ORR in the Gem/Cis/nab-P group was 47.9%, while that in the nab-P addition group was 31.1%. The median progression-free survival and overall survival were 8.5 months [95% confidence interval (CI), 6.9-10.1] and 14.6 months (95% CI, 10.2-19.0), respectively. In patients who received Gem/Cis/nab-P as initial treatment, the median PFS was 9.4 months (95% CI, 7.9-10.9) and the median OS was not-reached (95% CI, not available). Anemia (n = 42, 23.6%), neutropenia (n = 40, 22.5%), and thrombocytopenia (n = 16, 9.0%) were the most common grade 3-4 toxicities. A total of 20 patients (11.2%) had conversions from unresectable to resectable disease and underwent surgery with curative intent. Conclusion: Gem/Cis/nab-P showed favorable real-life efficacy and safety outcomes in Korean patients with advanced BTC, which was consistent with the phase II trial outcomes.ope

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer

Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co-regulator YAP. The marked induction of YAP-targeted oncogenes (EGFR, AXL, CYR61, and TGFβR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient-derived xenografts, and EML4-ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post-treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK-TKIs. Our findings highlight a crucial role of YAP in ALK-TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK-rearranged patients with acquired resistance to ALK inhibitors.ope

EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines

Although treatment of BRAF V600E-mutant non-small cell lung cancer (NSCLC(V600E)) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLC(V600E), we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLC(V600E) to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR-RAS-CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF-CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLC(V600E) with acquired resistance to BRAF inhibitors.ope

Protective effect of bisphosphonate on the cortical bone at key locations of the femur in aromatase inhibitor-associated bone loss: A three-dimensional cortical bone mapping study

Aromatase inhibitor treatment in breast cancer is associated with accelerated bone loss and an increased risk of fracture. Bisphosphonates (BPs) are the mainstay treatment of aromatase inhibitor-associated bone loss (AIBL), which might improve femoral bone at key locations prone to fracture. To test this hypothesis, we performed three-dimensional cortical bone mapping based on quantitative computed tomography (QCT) scans in postmenopausal women with early breast cancer who were receiving aromatase inhibitors. Data of subjects who had both baseline and at least one follow-up QCT at Severance Hospital (South Korea) between 2005 and 2015 were analyzed (BP users, n = 93; BP non-users, n = 203). After exclusion of BP users with low medication persistence (proportion of days covered: <50%), BP users and non-users were 1:1 matched (n = 54 for each group) in terms of age, lumbar spine volumetric bone mineral density (LSvBMD), femoral neck areal BMD (FNaBMD), and total hip areal BMD (THaBMD). During a median follow-up of 2.1 years, BP use attenuated bone loss in LSvBMD (+7.2% vs. -3.8%, p < 0.001), FNaBMD (+1.3% vs. -2.7%, p < 0.001), and THaBMD (-0.3% vs. -2.5%, p = 0.024). BP had a protective effect on cortical parameters of femoral bone: estimated cortical thickness (CTh) (+3.3% vs. + 0.1%, p = 0.007) and cortical mass surface density (CMSD, cortical mass per unit surface area was calculated by multiplying cortical BMD with CTh) (+3.4% vs. -0.3%, p < 0.001). CMSD increased by up to 15% at key locations such as the superior part of the femoral neck and greater trochanter. BP prevented the thinning of average CTh of the femoral neck (-1.4% vs. -6.1%, p < 0.001), particularly at the superior anterior quadrant of femoral neck (absolute difference: +12.8% point vs. non-users). Compared to BP non-users, BP users had improved cross-sectional moment of inertia (+4.4% vs. -0.7%, p = 0.001) and less increase in buckling ratio (+1.3% vs. + 7.5%, p < 0.001). In summary, BP use prevented cortical bone deficits observed in AIBL at key locations of the proximal femur.ope

Ifosfamide-induced Fanconi syndrome with diabetes insipidus

Ifosfamide-induced Fanconi syndrome is a rare complication that typically occurs in young patients due to a cumulative dose of ifosfamide > 40–60 g/m2, a reduction in kidney mass, or concurrent cisplatin treatment. It is usually characterized by severe and fatal progression accompanied by type II proximal renal tubular dysfunction, as evidenced by glycosuria, proteinuria, electrolyte loss, and metabolic acidosis. Diabetes insipidus is also a rare complication of ifosfamide-induced renal disease. We herein describe a case involving a 61-year-old man who developed ifosfamide-induced Fanconi syndrome accompanied by diabetes insipidus only a few days after the first round of chemotherapy. He had no known risk factors. In addition, we briefly review the mechanisms and possible therapeutic options for this condition based on other cases in the literature. Patients who receive ifosfamide must be closely monitored for renal impairment to avoid this rare but fatal complication.ope

Anaemia and pathologic complete response rate according to carboplatin dose in HER2+ breast cancer treated with neoadjuvant TCHP

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.ope