CTLA-4 Synergizes With PD1/PD-L1 in the Inhibitory Tumor Microenvironment of Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is highly invasive and carries high mortality due to limited therapeutic strategies. In other solid tumors, immune checkpoint inhibitors (ICIs) target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD1), and the PD1 ligand PD-L1 has revolutionized treatment and improved outcomes. However, the relationship and clinical significance of CTLA-4 and PD-L1 expression in ICC remains to be addressed. Deciphering CTLA-4 and PD-L1 interactions in ICC enable targeted therapy for this disease. In this study, immunohistochemistry (IHC) was used to detect and quantify CTLA-4, forkhead box protein P3 (FOXP3), and PD-L1 in samples from 290 patients with ICC. The prognostic capabilities of CTLA-4, FOXP3, and PD-L1 expression in ICC were investigated with the Kaplan–Meier method. Independent risk factors related to ICC survival and recurrence were assessed by the Cox proportional hazards models. Here, we identified that CTLA-4+ lymphocyte density was elevated in ICC tumors compared with peritumoral hepatic tissues (P <.001), and patients with a high density of CTLA-4+ tumor-infiltrating lymphocytes (TILsCTLA-4 High) showed a reduced overall survival (OS) rate and increased cumulative recurrence rate compared with patients with TILsCTLA-4 Low (P <.001 and P = .024, respectively). Similarly, patients with high FOXP3+ TILs (TILsFOXP3 High) had poorer prognoses than patients with low FOXP3+ TILs (P = .021, P = .034, respectively), and the density of CTLA-4+ TILs was positively correlated with FOXP3+ TILs (Pearson r = .31, P <.001). Furthermore, patients with high PD-L1 expression in tumors (TumorPD-L1 High) and/or TILsCTLA-4 High presented worse OS and a higher recurrence rate than patients with TILsCTLA-4 LowTumorPD-L1 Low. Moreover, multiple tumors, lymph node metastasis, and high TumorPD-L1/TILsCTLA-4 were independent risk factors of cumulative recurrence and OS for patients after ICC tumor resection. Furthermore, among ICC patients, those with hepatolithiasis had a higher expression of CTLA-4 and worse OS compared with patients with HBV infection or undefined risk factors (P = .018). In conclusion, CTLA-4 is increased in TILs in ICC and has an expression profile distinct from PD1/PD-L1. TumorPD-L1/TILsCTLA-4 is a predictive factor of OS and ICC recurrence, suggesting that combined therapy targeting PD1/PD-L1 and CTLA-4 may be useful in treating patients with ICC.

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7 Prognostic factors for overall survival in patients with advanced melanoma treated with Anti-PD-1 therapy – the melimmune score

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0007 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A7-A7

Author(s):

Soraia Lobo-Martins ◽

Diogo Martins-Branco ◽

Patrícia Miguel Semedo ◽

Cecília Melo Alvim ◽

Ana Maria Monteiro ◽

...

Keyword(s):

Risk Factors ◽

Prognostic Factors ◽

Poor Prognosis ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Prognostic Score ◽

Daily Practice ◽

Cox Proportional Hazards ◽

Time To Death ◽

Line Setting

BackgroundImmune checkpoint inhibitors (ICI) have changed the paradigm of advanced malignant melanoma (MM). Several prognostic factors, mostly linked to inflammation, have been under scope to better select patients for such therapies. We aimed to build and apply a prognostic score in this setting.MethodsBaseline characteristics and outcomes on 147 patients with advanced MM treated with an anti-PD1 (nivolumab or pembrolizumab) in monotherapy, between Jan-2016 and Oct-2019, in the 1st, 2nd or 3rd line setting were collected from two centres in Portugal. Data cut-off for follow-up was May-2020. Cox proportional hazards regression was used to identify independent prognostic factors for OS.ResultsWith a median FU of 28.93 months (95% CI [22.52–33.54]), mOS for the whole cohort was 14.75 months (95% CI, [10.80–18.71]). Overall, 43 and 104 patients were treated with nivolumab and pembrolizumab, respectively. We identified four adverse prognostic factors that were independent predictors of bad prognosis: number of metastatic sites >2 (p<0.001), baseline PS-ECOG =1 (p<0.001), presence of baseline lymphopenia (over lower limit of normal) (p=0.002) or very high baseline LDH (>2x upper limit of normal) (p<0.001).Patients were separated into three risk categories according to the number of risk factors present: favourable prognosis (no risk factors; n=34), intermediate prognosis (one risk factor; n=65) and poor prognosis (two or more risk factors; n=48). mOS was 43.41 (95% CI [32.13–54.69], 14.39 (95% CI [6.78–22.01]) and 6.53 months (95% CI [3.61–9.44]), for favourable, intermediate, and poor prognosis group, respectively (p<0.001; figure 1). AUC of ROC curve for OS was 0.737 (95% CI [0.654–0.819], p<0.001).Abstract 7 Figure 1Time to death - Kaplan-Meier survival plotConclusionsUsing easily accessible parameters from our daily practice, we propose the MELImmune prognostic score for advanced MM patients treated with anti-PD1 in monotherapy that could be incorporated to the daily clinical practice and clinical trials. We further aim to validate this score in an independent larger sample.Ethics ApprovalThe study was approved by both institutions’ Ethics Committee.

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Prevalence, Classification, and Risk Factors for Postoperative Lower Extremity Lymphedema in Women With Gynecologic Malignancies: A Retrospective Study

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000405 ◽

2015 ◽

Vol 25 (4) ◽

pp. 751-757 ◽

Cited By ~ 59

Author(s):

Hitoshi Hareyama ◽

Kenichi Hada ◽

Kumiko Goto ◽

Sawako Watanabe ◽

Minako Hakoyama ◽

...

Keyword(s):

Risk Factors ◽

Lower Extremity ◽

Lymph Nodes ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Cancer Type ◽

Kaplan Meier ◽

Gynecology And Obstetrics ◽

Independent Risk Factors ◽

Stage 1

ObjectiveLower extremity lymphedema (LEL) is a major long-term complication of radical surgery. We aimed to estimate the incidence and grading of LEL in women who underwent lymphadenectomy and to evaluate risk factors associated with LEL.Materials and MethodsWe retrospectively reviewed 358 patients with cervical, endometrial, and ovarian cancer who underwent transabdominal complete systematic pelvic and para-aortic lymphadenectomy between 1997 and 2011. Lower extremity lymphedema was graded according to criteria of the International Society of Lymphology. Incidence of LEL and its correlation with various clinical characteristics were investigated using Kaplan-Meier survival and Cox proportional hazards methods.ResultsOverall incidence of LEL was 21.8% (stage 1, 60%; stage 2, 32%; and stage 3, 8%). Cumulative incidence increased with observation period: 12.9% at 1 year, 20.3% at 5 years, and 25.4% at 10 years. Age, cancer type, stage (International Federation of Gynecology and Obstetrics), body mass index, hysterectomy type, lymphocyst formation, lymph node metastasis, and chemotherapy were not associated with LEL. Multivariate analysis confirmed that removal of circumflex iliac lymph nodes (hazard ratio [HR], 4.28; 95% confidence interval [CI], 2.09–8.77; P < 0.0001), cellulitis (HR, 3.48; 95% CI, 2.03–5.98; P < 0.0001), and number of removed lymph nodes (HR, 0.99; 95% CI, 0.98–0.99; P = 0.038) were independent risk factors for LEL.ConclusionsPostoperative LEL incidence increased over time. The results of the present study showed a significant correlation with removal of circumflex iliac lymph nodes and cellulitis with the incidence of LEL. Multicenter or prospective studies are required to clarify treatment efficacies.

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Risk Factors of Delirium in Sequential Sedation Patients in Intensive Care Units

BioMed Research International ◽

10.1155/2017/3539872 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Jie Yang ◽

Yongfang Zhou ◽

Yan Kang ◽

Binbin Xu ◽

Peng Wang ◽

...

Keyword(s):

Risk Factors ◽

Intensive Care ◽

Sofa Score ◽

Maintenance Dose ◽

Proportional Hazards ◽

Confusion Assessment Method ◽

Assessment Method ◽

Cox Proportional Hazards ◽

Older Age ◽

Independent Risk Factors

Background. Delirium is a primary adverse event in ventilated patients who receive long-term monosedative treatment. Sequential sedation may reduce these adverse effects. This study evaluated risk factors for delirium in sequential sedation patients. Methods. A total of 141 patients who underwent sequential sedation were enrolled. Delirium was diagnosed using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale. Univariate and multivariate Cox proportional hazards regressions were used to predict risk factors. Results. Older age (≥51) (RR = 2.432, 95% CL 1.316–4.494, p=0.005), higher SOFA score (≥14) (RR = 2.022, 95% CL 1.076–3.798, p=0.029), regular smoking (RR = 2.366, 95% CL 1.277–4.382, p=0.006), and higher maintenance dose of midazolam (RR = 1.052, 95% CL 1.000–1.107, p=0.049) and fentanyl (RR = 1.045, 95% CL 1.019–1.072, p=0.001) when patients met sequential criteria, were independent risk factors of delirium. Sequential sedation with dexmedetomidine (RR = 0.448, 95% CL 0.209–0.963, p=0.040) was associated with a lower risk of delirium. Conclusions. Older age, higher SOFA score, regular smoking, and higher maintenance dose of midazolam and fentanyl when patients met sequential criteria were independent risk factors of delirium in sequential sedation patients. Sequential sedation with dexmedetomidine reduced risk of delirium.

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Prognostic impact of immune-related adverse events on patients with and without cardiovascular disease: a retrospective review

Cardio-Oncology ◽

10.1186/s40959-021-00112-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Shingo Kazama ◽

Ryota Morimoto ◽

Yuki Kimura ◽

Naoki Shibata ◽

Reina Ozaki ◽

...

Keyword(s):

Cardiovascular Disease ◽

Adverse Events ◽

Retrospective Review ◽

Proportional Hazards ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

Limited Information ◽

History Of

Abstract Background The emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history. Methods We performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019. Results Median patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs ( +) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality. Conclusions Although cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.

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Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom

European Heart Journal ◽

10.1093/eurheartj/ehaa574 ◽

2020 ◽

Vol 41 (35) ◽

pp. 3336-3342 ◽

Cited By ~ 1

Author(s):

Jemma C Hopewell ◽

Alison Offer ◽

Richard Haynes ◽

Louise Bowman ◽

Jing Li ◽

...

Keyword(s):

Risk Factors ◽

Risk Score ◽

Proportional Hazards ◽

Beta Blockers ◽

Absolute Risk ◽

Strong Association ◽

Cox Proportional Hazards ◽

Independent Risk Factors ◽

Muscle Symptom ◽

The Impact

Abstract Aims Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom. Methods and results An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73–92.69, P across thirds = 9·1 × 10−48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms. Conclusions The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.

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Systemic Sclerosis and the Risk of Tuberculosis

The Journal of Rheumatology ◽

10.3899/jrheum.131125 ◽

2014 ◽

Vol 41 (8) ◽

pp. 1662-1669 ◽

Cited By ~ 6

Author(s):

Shuo-Ming Ou ◽

Wen-Chien Fan ◽

Kun-Ta Cho ◽

Chiu-Mei Yeh ◽

Vincent Yi-Fong Su ◽

...

Keyword(s):

Risk Factors ◽

Systemic Sclerosis ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Pulmonary Involvement ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Research Database ◽

Independent Risk Factors ◽

Rate Ratios

Objective.Pulmonary involvement is common in patients with systemic sclerosis (SSc), and this condition causes substantial morbidity and mortality. Disrupted immunity from the disease or associated medication may render such patients subject to tuberculosis (TB) infection. However, the relationship between SSc and TB has not yet been investigated.Methods.Using the Taiwan National Health Insurance Research Database, 838 patients with SSc diagnosed in Taiwan during 2000–2006 were identified and followed for emergence of TB infection. Incidence rate ratios (IRR) of TB compared to 8380 randomly selected age-, sex-, and comorbidity-matched controls without SSc were calculated. The Cox proportional hazards model was used for multivariate adjustment to identify independent risk factors for TB infection.Results.The risk of TB infection was higher in the SSc cohort than in controls (IRR 2.81, 95% CI 1.36–5.37; p = 0.004), particularly for pulmonary TB (IRR 2.53, 95% CI 1.08–5.30; p = 0.022). Other independent risk factors for TB infection in patients with SSc were age ≥ 60 years [hazard ratio (HR) 3.52, 95% CI 1.10–11.33; p = 0.035] and pulmonary hypertension (PH; HR 6.06, 95% CI 1.59–23.17; p = 0.008). Mortality did not differ for SSc patients with or without TB.Conclusion.In this nationwide study, the incidence of TB infection was significantly higher among patients with SSc than in controls without SSc. Special care should be taken in managing patients with SSc who are at high risk for TB, especially those aged ≥ 60 years or who also have PH.

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Prognostic Impact of Immune-Related Adverse Events on Patients with and Without Cardiovascular Disease: A Retrospective Review

10.21203/rs.3.rs-282517/v1 ◽

2021 ◽

Author(s):

Shingo Kazama ◽

Ryota Morimoto ◽

Yuki Kimura ◽

Naoki Shibata ◽

Reina Ozaki ◽

...

Keyword(s):

Cardiovascular Disease ◽

Adverse Events ◽

Retrospective Review ◽

Proportional Hazards ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

Limited Information ◽

History Of

Abstract Background: The emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history.Methods: We performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019.Results: Median patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs (+) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality.Conclusions: Occurrence of irAEs had a prognostic impact regardless of cardiovascular history. Although non-cardiovascular irAEs may be related to cardiovascular irAEs under ICI therapy, occurrence of this cardiotoxicity had little impact on prognosis.

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Primary tumor resection improves survival in patients with multifocal intrahepatic cholangiocarcinoma based on a population study

Scientific Reports ◽

10.1038/s41598-021-91823-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Linlin Yin ◽

Si Zhao ◽

Hanlong Zhu ◽

Guozhong Ji ◽

Xiuhua Zhang

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Proportional Hazards ◽

Tumor Resection ◽

Original Data ◽

Cox Proportional Hazards ◽

Surgical Patients ◽

Cancer Specific Survival ◽

Surgery Group ◽

The Difference ◽

Cox Analysis

AbstractThe purpose of our study was to evaluate the effect of surgery on the survival and prognosis of patients with multifocal intrahepatic cholangiocarcinoma (ICCA). Patients with multifocal ICCA were selected from the SEER (Surveillance, Epidemiology, and End Results) database between 2010 and 2016. Kaplan–Meier analyses and log-rank tests were used to evaluate the difference in survival between the surgery group and the non-surgery group. We applied the Cox proportional hazards regression model to identify prognostic factors of overall survival (OS) and cancer-specific survival (CSS). In total, 580 patients were enrolled in our study, including 151 patients who underwent surgery and 429 patients who did not. The median survival time of surgical patients was longer than non-surgical patients (OS: 25 months vs. 8 months, p < 0.001; CSS: 40 months vs. 25 months, p < 0.001). Similarly, the 5-year survival rate in the surgery group was significantly higher than those in the non-surgery group (5-year OS rate: 12.91% vs. 0%; p < 0.001; 5-year CSS rate:26.91% vs. 0%; p < 0.001). Multivariate Cox analysis showed that the OS (HR:0.299, 95% CI: 0.229–0.390, p < 0.001) and CSS (HR:0.305, 95% CI:0.222–0.419, p < 0.001) of patients undergoing surgical resection were significantly improved. Meanwhile, after propensity score matching (PSM) of the original data, we come to the same conclusion.

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The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer

Oncology ◽

10.1159/000516671 ◽

2021 ◽

pp. 1-7

Author(s):

Oded Jacobi ◽

Yosef Landman ◽

Daniel Reinhorn ◽

Oded Icht ◽

Michal Sternschuss ◽

...

Keyword(s):

Diabetes Mellitus ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Negative Relationship ◽

Progression Free Survival ◽

Significant Negative Correlation ◽

Cox Proportional Hazards ◽

Diabetic Patients

Introduction: Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients. Methods: All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, t tests, and χ2 tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate. Results: Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01–2.06], p = 0.011, and HR 1.5 [1.08–2.08], p = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61–1.93], p = 0.79, and HR 1.29 [0.69–2.39], p = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. Conclusion: Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.

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Air Pollution Is Associated with Cognitive Deterioration of Alzheimer’s Disease

Gerontology ◽

10.1159/000515162 ◽

2021 ◽

pp. 1-9

Author(s):

Feng Cheng Lin ◽

Chih Yin Chen ◽

Chung Wei Lin ◽

Ming Tsang Wu ◽

Hsuan Yu Chen ◽

...

Keyword(s):

Risk Factors ◽

Air Pollution ◽

Social Engagement ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Rank Test ◽

Cognitive Deterioration ◽

Clinical Dementia Rating ◽

Severe Stage ◽

Increased Risk

Introduction: Dementia is one of the major causes of disability and dependency among older people worldwide. Alzheimer’s disease (AD), the most common cause of dementia among the elderly, has great impact on the health-care system of developed nations. Several risk factors are suggestive of an increased risk of AD, including APOE-ε4, male, age, diabetes mellitus, hypertension, and low social engagement. However, data on risk factors of AD progression are limited. Air pollution is revealed to be associated with increasing dementia incidence, but the relationship between air pollution and clinical AD cognitive deterioration is unclear. Methods: We conducted a case-control and city-to-city study to compare the progression of AD patients in different level of air-polluted cities. Clinical data of a total of 704 AD patients were retrospectively collected, 584 residences in Kaohsiung and 120 residences in Pingtung between 2002 and 2018. An annual interview was performed with each patient, and the Clinical Dementia Rating score (0 [normal] to 3 [severe stage]) was used to evaluate their cognitive deterioration. Air pollution data of Kaohsiung and Pingtung city for 2002–2018 were retrieved from Taiwan Environmental Protection Administration. Annual Pollutant Standards Index (PSI) and concentrations of particulate matter (PM10), sulfur dioxide (SO2), ozone (O3), nitrogen dioxide (NO2), and carbon monoxide (CO) were obtained. Results: The PSI was higher in Kaohsiung and compared with Pingtung patients, Kaohsiung patients were exposed to higher average annual concentrations of CO, NO2, PM10, and SO2. AD patients living in Kaohsiung suffered from faster cognitive deterioration in comparison with Pingtung patients (log-rank test: p = 0.016). When using multivariate Cox proportional hazards regression analysis, higher levels of CO, NO2, PM10, and SO2 exposure were associated with increased risk of AD cognitive deterioration. Among all these air pollutants, high SO2 exposure has the greatest impact while O3 has a neutral effect on AD cognitive deterioration. Conclusions: Air pollution is an environment-related risk factor that can be controlled and is associated with cognitive deterioration of AD. This finding could contribute to the implementation of public intervention strategies of AD.

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