Background: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC).Methods: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a >2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤ 2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry.Results: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than region disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P= 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p=0.0072), PD-L1 expression ≤1% (0.0355), and number of metastatic site ≥3 (0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment, immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group.Conclusions: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastases, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Background Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). Methods This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. Results Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. Conclusions Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

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Background Frailty is a health challenge related to adverse health outcomes in older adults. Older women are more likely to be frail than older men. However, few studies have reviewed the effectiveness of interventions for older women with frailty is scant. Objective: This systematic review aimed to explore the properties of interventions and to investigate their effectiveness in preventing the progression of frailty in older women with pre-frailty or frailty. Methods Narrative synthesis was conducted to identify the contents, outcome variables, and findings of the interventions. Then, a meta-analysis was performed to evaluate the effectiveness of exercise interventions on grip strength, sit-and-reach, sit-to-stand, and timed up and go tests. Results Twenty-six studies were selected, including 14 randomized controlled trials and 12 quasi-experimental studies. These studies implemented exercise (96.2%), nutrition (15.4%), hormone replacement (7.7%), toileting strategies (3.8%), and laughter interventions (3.8%). The selected studies assessed physical, psychological (11.5%), and cognitive health (11.5%), as well as quality of life (19.2%). The meta-analysis found significant effects of aerobic and resistance exercise interventions on the sit-to-stand (SMD = 1.30, 95% CI [0.70, 1.90], p < 0.001) and timed up and go scores (SMD = -0.56, 95% CI [-0.93, -0.19], p = 0.003). Conclusion Exercise interventions are essential to improve physical health, in particular mobility, in older women with pre-frailty or frailty. Future studies should consider theoretical frameworks and evaluate psychological and cognitive health as well as quality of life to develop and provide effective interventions to prevent the progression of frailty in older women.