Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

BACKGROUND: Data on immune checkpoint inhibitor efficacy in patients with human epidermal growth factor receptor 2-positive (HER2+) advanced gastric/gastroesophageal junction (G/GEJ) cancer are lacking. Because HER2 status was not captured in the ATTRACTION-2 trial, we used patients with prior trastuzumab use (Tmab+) as surrogate for HER2 expression status to evaluate the efficacy and safety of nivolumab as third- or later-line therapy in these patients. METHODS: In ATTRACTION-2, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial, patients were randomized (2:1) to receive nivolumab (3 mg/kg) or placebo every 2 weeks until disease progression or toxicity requiring study discontinuation. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed. RESULTS: Of 493 enrolled patients, 81 (nivolumab, n = 59; placebo, n = 22) were Tmab+ and 412 (nivolumab, n = 271; placebo, n = 141) were Tmab-. In both groups, patients receiving nivolumab showed a longer median OS vs placebo (Tmab+, 8.3 [95% confidence interval, 5.3-12.9] vs 3.1 [1.9-5.3] months, hazard ratio, 0.38 [0.22-0.66]; P = 0.0006; Tmab-, 4.8 [4.1-6.0] vs 4.2 [3.6-4.9] months, 0.71 [0.57-0.88]; P = 0.0022). PFS was longer in both groups receiving nivolumab vs placebo (Tmab+, 1.6 [1.5-4.0] vs 1.5 [1.3-2.9] months, 0.49 [0.29-0.85]; P = 0.0111; Tmab-, 1.6 [1.5-2.4] vs 1.5 [1.5-1.5] months, 0.64 [0.51-0.80]; P = 0.0001). CONCLUSIONS: Nivolumab was efficacious and safe as third- or later-line therapy regardless of prior trastuzumab use in patients with advanced G/GEJ cancer.ope

Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab

Background: ATTRACTION-2 demonstrated that nivolumab improved overall survival (OS) vs placebo in patients with advanced gastric cancer treated with ≥ 2 chemotherapy regimens. However, its long-term efficacy and outcome of treatment beyond progression (TBP) with nivolumab have not been clarified. Methods: The 3-year follow-up data were collected. A subset analysis was performed to explore the efficacy of TBP by assessing postprogression survival (PPS) after the first event of disease progression. Results: Overall, 493 patients were randomized (2:1) to receive nivolumab (n = 330) or placebo (n = 163). With a median follow-up of 38.5 (range 36.1-47.5) months, OS of the nivolumab group was significantly longer compared to the placebo group (median 5.3 vs 4.1 months; 3-year survival rate, 5.6% vs 1.9%; hazard ratio [HR], 0.62 [95% confidence interval (CI) 0.50-0.75], P < 0.0001). The median OS of responders (n = 32) who achieved complete response or partial response was 26.7 months and the 3-year survival rate was 35.5% in the nivolumab group. Overall, 109 patients in the nivolumab group and 37 patients in the placebo group received TBP. PPS tended to be longer in the nivolumab group vs placebo group (median 5.8 vs 4.5 months; HR [95% CI], 0.69 [0.47-1.01], P = 0.057). In contrast, PPS was similar between both treatment groups in non-TBP patients (median 2.3 vs 2.2 months; HR 0.90, P = 0.42). Conclusions: Long-term efficacy of nivolumab was confirmed at the 3-year follow-up, and a survival benefit of TBP with nivolumab was suggested. Biomarkers for selecting patients suitable for TBP with nivolumab should be identified in the future.ope

Molecular diagnosis for personalized target therapy in gastric cancer

Gastric cancer is the second leading cause of cancer-related deaths worldwide. In advanced and metastatic gastric cancer, the conventional chemotherapy with limited efficacy shows an overall survival period of about 10 months. Patient specific and effective treatments known as personalized cancer therapy is of significant importance. Advances in high-throughput technologies such as microarray and next generation sequencing for genes, protein expression profiles and oncogenic signaling pathways have reinforced the discovery of treatment targets and personalized treatments. However, there are numerous challenges from cancer target discoveries to practical clinical benefits. Although there is a flood of biomarkers and target agents, only a minority of patients are tested and treated accordingly. Numerous molecular target agents have been under investigation for gastric cancer. Currently, targets for gastric cancer include the epidermal growth factor receptor family, mesenchymal-epithelial transition factor axis, and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways. Deeper insights of molecular characteristics for gastric cancer has enabled the molecular classification of gastric cancer, the diagnosis of gastric cancer, the prediction of prognosis, the recognition of gastric cancer driver genes, and the discovery of potential therapeutic targets. Not only have we deeper insights for the molecular diversity of gastric cancer, but we have also prospected both affirmative potentials and hurdles to molecular diagnostics. New paradigm of transdisciplinary team science, which is composed of innovative explorations and clinical investigations of oncologists, geneticists, pathologists, biologists, and bio-informaticians, is mandatory to recognize personalized target therapy.ope

Prognostic Factor Analysis of Overall Survival in Gastric Cancer from Two Phase III Studies of Second-line Ramucirumab (REGARD and RAINBOW) Using Pooled Patient Data

PURPOSE: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer. MATERIALS AND METHODS: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters. RESULTS: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor. CONCLUSIONS: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies.ope

Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial

Background: Cancer-related fatigue (CRF) is a common symptom and has a negative impact on prognosis in cancer patients. CRF could be improved by Korean red ginseng (KRG). Patients and methods: For this randomised and double-blinded trial, colorectal cancer patients who received mFOLFOX-6 were randomly assigned to either KRG 2000 mg/day (n = 219) or placebo (n = 219) for 16 weeks. CRF was evaluated using the mean area under the curve (AUC) change from baseline of brief fatigue inventory (BFI) as the primary endpoint. Fatigue-related quality of life, stress, and adverse events were evaluated as secondary endpoints. Results: In the full analysis group, KRG up to 16 weeks improved CRF by the mean AUC change from baseline of BFI compared to placebo, particularly in "Mood" and "Walking ability" (P = 0.038, P = 0.023, respectively). In the per-protocol group, KRG led to improved CRF in the global BFI score compared with the placebo (P = 0.019). Specifically, there were improvements in "Fatigue right now," "Mood," "Relations with others," "Walking ability," and "Enjoyment of life" at 16 weeks (P = 0.045, P = 0.006, P = 0.028, P = 0.003, P = 0.036, respectively). In subgroups of female patients, >60 years old, with high compliance (>80%) or more baseline fatigue, the beneficial effects of KRG were more enhanced than that of placebo. Although neutropenia was more frequent in KRG than placebo, the incidence of all adverse events was similar. Conclusions: KRG could be safely combined with mFOLFOX-6 chemotherapy in colorectal cancer patients, and reduced CRF compared with placebo.ope

Design of precise third-line therapy for gastric cancer: target or chemotherpy?

ope

중앙재난안전상황실 재난상황관리 업무담당자의 직무분석에 관한 연구

학위논문 (석사)-- 서울대학교 행정대학원 : 행정학과 행정학전공, 2016. 8. 이수영.이 연구의 목적은 국민안전처 중앙재난안전상황에서 재난 상황관리 업무를 담당하는 재난상황관리 담당자의 직무를 분석하는 것이다. 이를 위해 재난상황관리 담당자에 대한 DACUM 직무분석을 통해 책무와 과업을 도출하여 직무를 규명하고, 재난상황관리 업무담당자에게 중요한 핵심과업이 무엇인지 파악하여 어떠한 교육적 요구가 있는지 분석하는 것이다. 이 연구의 대상은 국민안전처 중앙재난안전상황실 재난상황관리 업무담당자 125명이다. DACUM 직무분석을 위하여 DACUM 위원회에 7명이 참여하였고, 예비설문조사로 10명이 대상자로 참여하였으며, 본 설문조사 인원으로 115명이 참여하였다. 설문조사는 2016년 5월 6일부터 5월 17일까지 12일간 진행되었으며 배포된 115매 설문지 중 105매가 회수되었고, 유효한 103매 자료가 통계분석에 활용되었다. DACUM 직무분석과정은 다음과 같다. 첫째, 준비단계에서는 직무분석의 목적을 명확히 설정하고, 재난상황관리 업무담당자와 관련된 정보와 자료는 기존 문헌을 검토하고 각종 직무분석 연구자료 등을 수집하였으며 DACUM위원회와 전문가협의회의 패널을 구성하였다. 둘째, DACUM 위원들로 구성된 DACUM 워크숍를 통해 책무, 과업을 식별하고 이에 대한 검증을 위해 예비설문조사와 전문가협의회를 통한 직무모형인 DACUM 차트를 완성했다. 직무모형에서 도출된 7개 책무와 47개 과업으로 구성된 설문조사를 통해 책무와 과업에 대한 중요도, 난이도, 수행 빈도 분석을 통해 인식수준차이를 분석하였다. 셋째, 재난상황관리 업무담당자의 과업 우선순위와 19개 1순위 핵심과업을 도출하였다. 재난상황관리 업무담당자는 국민안전처 중앙재난안전상황실에서 우리나라에서 발생하는 모든 재난에 대해서 위험징후 경보발령 등 각종 재난상황을 관리하는 전문가이다. 그동안 재난상황관리 업무담당자는 관련 법령과 매뉴얼에 명시된 임무만으로 주로 개인의 경험과 노하우에 의존하여 재난상황관리 업무담당자 직무를 수행 해왔다. 그러나 본 연구를 통해 이론적이고 체계적이며 과학적인 방법을 통하여 재난상황관리 업무담당자 직무에 대한 기틀을 마련하여 다양한 분석의 틀을 제공하였고 직무 체계를 공고히 하는 계기를 마련하였다는 점에서 의의가 있다 하겠다. 본 연구를 통해서 재난상황관리 업무담당자의 직무 체계를 공고히 할 수 있는 계기를 마련하고 국가직무능력표준에 따라 평생경력개발 모형과 직무기술서, 채용, 배치, 자가진단 도구 등을 개발하는데 기반으로 활용되어야 할 것이다.제 1 장 서론 1 제 1 절 연구의 목적과 필요성 1 제 2 절 연구문제 2 제 3 절 연구의 범위와 방법 3 제 2 장 이론적 배경과 선행연구의 검토 4 제 1 절 재난관리와 재난상황관리 4 1. 재난관리의 개념 4 2. 재난관리의 과정 5 3. 재난상황관리 9 제 2 절 중앙재난안전상황실 10 1. 중앙재난안전상황실 변천과정 10 2. 중앙재난안전상황실 업무 12 제 3 절 직무분석 14 1. 직무분석의 개념 14 2. 직무분석 방법 17 3. DACUM 기법 20 4. DACUM 기법을 활용한 직무분석 선행연구 25 제 3 장 연구분석의 틀 26 제 1 절 연구대상 27 제 2 절 연구과정 및 절차 29 1. 책무와 과업 도출 29 2. 책무와 과업 인식수준 차이 조사 32 3. 과업 우선순위 및 핵심과업 도출 34 4. 책무와 과업에 대한 통계 분석 36 제 4 장 분석결과 37 제 1 절 재난상황관리 업무담당자의 책무와 과업 37 1. DACUM위원회 워크숍 결과 도출된 책무와 과업 37 2. 도출된 책무와 과업의 검증 43 3. 재난상황관리 업무담당자 책무와 과업 도출 47 제 2 절 책무와 과업에 대한 중요도, 난이도, 수행 빈도의 인식수준 분석 51 1. 조사대상자의 인구통계학적 특성 51 2. 책무 및 과업에 대한 중요도, 난이도, 수행 빈도의 인식수준 분석 53 3. 입직경로별 책무 및 과업에 대한 중요도, 난이도, 수행 빈도의 인식수준 차이 분석 58 제 3 절 재난상황관리 업무담당자의 핵심과업 도출 63 제 5 장 논의 69 제 1 절 재난상황관리 업무담당자의 책무와 과업에 대한 논의 69 제 2 절 책무와 과업에 대한 중요도, 난이도 및 수행 빈도의 인식수준에 대한 논의 72 1. 책무에 대한 중요도, 난이도 및 수행 빈도의 인식수준에 대한 논의 72 2. 과업에 대한 중요도, 난이도 및 수행 빈도의 인식수준에 대한 논의 73 제 3 절 입직 경로별 책무와 과업에 대한 중요도, 난이도 및 수행 빈도의 인식수준에 대한 논의 73 1. 입직 경로별 책무에 대한 중요도, 난이도 및 수행 빈도의 인식수준 차이에 대한 논의 74 2. 입직 경로별 과업에 대한 중요도, 난이도 및 수행 빈도의 인식수준 차이에 대한 논의 74 제 4 절 재난상황관리 업무담당자의 1순위 핵심 과업 도출에 대한 논의 75 제 6 장 결론 및 제언 76 참고문헌 80 부록 85 abstract 108Maste

A Phase III Study to Compare the Efficacy and Safety of Paclitaxel Versus Irinotecan in Patients with Metastatic or Recurrent Gastric Cancer Who Failed in First-line Therapy (KCSG ST10-01)

Background This phase III study compared the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer (MRGC) who had experienced disease progression following first-line chemotherapy. Methods Patients were randomized to receive either paclitaxel (70 mg/m(2); days 1, 8, 15, every 4 weeks) or irinotecan (150 mg/m(2) every other week). The primary endpoint was progression-free survival (PFS). Results This study was stopped early due to low accrual rate. A total of 112 patients were enrolled; 54 were allocated to paclitaxel and 58 to irinotecan. Median PFS for the paclitaxel and irinotecan groups was 3.5 and 2.1 months, respectively (hazard ratio [HR], 1.27; 95% confidence interval [CI], 0.86-1.88; p = .234). Noninferiority of irinotecan to paclitaxel was not proved because the upper boundary of the 95% CI (1.88) exceeded the predefined upper margin of noninferiority (1.32). Median overall survival (OS) was 8.6 months in the paclitaxel group and 7.0 months in the irinotecan group (HR, 1.39; 95% CI, 0.91-2.11; p = .126). Among toxicities greater than or equal to grade 3, neutropenia (11.5%) was the most common, followed by peripheral neuropathy (7.7%) in the paclitaxel group, and neutropenia (34.5%) followed by nausea, vomiting, and anemia (8.6%, respectively) in the irinotecan group. Conclusion Although paclitaxel showed numerically longer PFS and OS compared with irinotecan, this was statistically insignificant. Both irinotecan and paclitaxel are valid second-line treatment options in MRGC.ope

A Case of Primary Breast Lymphoma with Brain Metastasis Detected during Pregnancy

Primary breast lymphoma (PBL) is a rare clinical presentation of localized non-Hodgkin’s lymphoma (NHL), and it makes up 0.04～1.1% of all breast tumors and it is 0.38～0.7% of all NHLs. The prognosis and patterns of relapse of PBL are still not clearly defined. The clinical features of PBL are different from those of breast carcinoma and the usual form of lymphoma. These features are a rapidly enlarging breast mass, multiple lesions, the absence of nipple discharge and retraction, and softer axillary lymph nodes as compared to the metastatic lymph nodes from breast carcinoma. B symptoms are unusual in PBL. A 30-year-old pregnant woman was admitted due to dysarthria and right side weakness that she had experienced for 7 days. She had several medical problems: intrauterine pregnancy at 34 weeks, some neurologic deficits and enlargement of both breasts. A biopsy from the breast and a brain magnetic resonance image (MRI) revealed diffuse large B cell lymphoma and multiple brain metastases, respectively. After delivery of a healthy, premature infant by Cesarean section, whole brain radiation therapy and combination chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine and prednisone) were started. She showed good response to therapy. We report here on this unusual case and we review the related literature.ope

Impact of the Double Mutants on Spike Protein of SARS-CoV-2 B.1.617 Lineage on the Human ACE2 Receptor Binding: A Structural Insight

The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these "variants of concern" has increased immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (kappa and delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.ope