Pure Red Cell Aplasia Secondary to Parvovirus B19 Infection as a Rare Cause of Anemia in a Dialysis Patient: A Case Report.

Parvovirus B19 infection can cause chronic pure red cell aplasia in immunosuppressed hosts or acute and transient aplastic crises in immunocompetent hosts. In dialysis patients, only transient aplastic crisis induced by parvovirus B19 infection has been reported. We herein report the first case of an adult dialysis patient who developed chronic pure red cell aplasia associated with parvovirus B19 infection. Repeated pneumonia and heart failure may contribute to an immunocompromised status, making the patient more vulnerable to parvovirus B19 infection. This case expands on the differential diagnosis of chronic anemia in patients undergoing dialysis.

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study.

Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.

Clinical significance of DNA damage response mutations in stage I and stage IIIa NSCLC.

BACKGROUND: DNA damage response (DDR) pathways are essential to sustain genomic stability and play a critical role in cancer development and progression. Here, we investigated the profile of DDR gene mutations in early-stage non-small cell lung cancer (NSCLC) and their prognostic values. METHODS: We first examined 74 DDR genes involved in seven DDR pathways and then focused on six specific genes: ATM, BRCA1, BRCA2, CHEK1, BARD1, and BRIP1. A total of 179 stage I and IIIa NSCLC patients who received curative resection in Peking Union Medical College Hospital and their corresponding samples were collected for DNA sequencing, immunohistochemistry and survival analysis. RESULTS: A total of 167 eligible patients were finally analyzed. Mutation frequencies were 82% and 26.3% for the selected 74 genes and six genes, respectively. Mismatch repair (MMR) and nucleotide excision repair (NER) alterations were observed more frequently in lung squamous cell carcinoma (LUSC) and smokers were more likely to develop the selected six DDR gene mutations than those who never smoked. Deleterious mutations in the six genes were independent prognostic indicators of significantly longer disease-free survival and overall survival. No association was found between DDR gene status and PD-L1 expression, CD8 positive lymphocyte and tumor-associated macrophage infiltration in tumor area. However, numbers of mutations were significantly increased among patients with DDR alterations. CONCLUSIONS: Deleterious mutations of these six genes were common in resected NSCLC and could serve as prognostic biomarkers.

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non-small-Cell Lung Cancer Patients.

INTRODUCTION: Platinum doublet chemotherapy is the standard of care in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC. MATERIALS AND METHODS: We retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy. RESULTS: Of the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively). CONCLUSION: The combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.

Circulating tumor cells PD-L1 expression detection and correlation of therapeutic efficacy of immune checkpoint inhibition in advanced non-small-cell lung cancer.

INTRODUCTION: This study investigated whether programmed death-ligand 1 (PD-L1) expression of circulating tumor cells (CTCs) in peripheral blood can serve as a predictive biomarker for immunotherapy efficacy in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: We employed a negative enrichment method to isolate CTCs. We identified PD-L1 + CTCs as PD-L1+/4',6-diamidino-2-phenylindole (DAPI)+/CD45-circulating tumor cells through an immunofluorescence method. Tumor tissue PD-L1 expression was determined by immunohistochemical staining. The correlation between CTC PD-L1 expression and patients' prognostic features was estimated through the Kaplan-Meier method. RESULTS: CTCs released a higher detection rate of PD-L1 expression than tumor tissues (53.0% vs. 42.1%). No correlation was observed between them. Forty-nine NSCLC patients received anti-PD-1/PD-L1 immunotherapy (three with combined anti-PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), two with four cycles of combined immune checkpoint inhibitors [ICIs] plus chemotherapy and ICI monotherapy for maintenance). Patients with PD-L1 expression on tissue or CTCs had a median progression-free survival (mPFS) of 5.6 months (n = 36, 95% confidence interval [CI] 3.6-7.5 months), significantly longer than those without PD-L1 detection (n = 9, mPFS of 1.4 months, 95% CI 1.3-1.5 months, log-rank p = 0.032). The multivariable Cox proportional-hazard model suggested that the tissue or CTC PD-L1 expression was associated with a lower risk of progression (hazard ratio 0.45, 95% CI 0.21-0.98, p = 0.043). CONCLUSIONS: CTCs and tumor tissues reveal heterogeneous expression of PD-L1 in NSCLC patients. Patients with baseline PD-L1 expression on CTCs or tissue showed prolonged mPFS and may help to identify the subsets of patients who potentially benefit from immunotherapy.

Differentiating cellular leiomyoma from uterine sarcoma and atypical leiomyoma using multi-parametric MRI.

Objectives: To evaluate the diagnostic performance of conventional magnetic resonance imaging (cMRI) combined with diffusion-weighted MRI (DWI) in discrimination of cellular leiomyoma, uterine sarcoma, and atypical leiomyoma. Methods: This retrospective study enrolled 106 patients with uterine masses, including 51 cellular leiomyomas (CLs), 32 uterine sarcomas (USs) and 23 degenerated leiomyomas (LMs) confirmed by histopathologic examination. Clinical data and imaging findings were assessed. Chi-squared test for qualitative variables and one way ANOVA analysis for quantitative variables were performed. Logistic regression analysis and the receiver operating characteristic (ROC) analysis were performed to determine the cut-off point and diagnostic performances for significant numeric values or multiple models. Results: Morphology (Odds ratio [OR] = 6.36) and margin (OR = 13.84) derived from cMRI were independent indicators for differentiating CLs from USs, and T2WI signal (OR = 0.23) were an independent indicator for differentiating CLs from degenerated LMs (all P < 0.05). The cutoff value of apparent diffusion coefficient (ADC) derived from DWI for differentiating CLs from USs was 839 ×10-6 mm2/sec and was 1239 ×10-6 mm2/sec for differentiating CLs from degenerated LMs. Compared with the use of cMRI features and ADC value alone, combination of independent indicators and ADC value achieved higher AUCs for both differentiations (all P < 0.05). Conclusions: cMRI is a reliable tool for differentiating CLs from USs and atypical leiomyoma, especially degenerated LMs. The combined use of cMRI and DWI can improve the differential diagnostic performance.

Safety and efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients with preexisting antinuclear antibodies: a retrospective cohort study.

Background: Antinuclear antibodies (ANAs) predicting the safety and efficacy of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are still a matter of debate considering previous studies showed quite different results based on different ANA cut-off values. Thus, we investigated the associations between different ANA titers and the safety and efficacy of ICIs. Moreover, we also briefly discussed the effects of anti-thyroglobulin (ATG) and anti-thyroid peroxidase (ATPO) on the safety of ICIs. Methods: A total of 159 Chinese patients confirmed to have locally-advanced or metastatic NSCLC given ICIs or chemoimmunotherapy in Peking Union Medical College Hospital from January 2015 to December 2020 were analyzed retrospectively and were followed up until December 2020 or death or loss to follow-up. Patients' characteristics were retrieved from medical records. ANAs were detected by the indirect immunofluorescence assay, ATG and ATPO by the electrochemiluminescence immunoassay. The severity of immune-related adverse events (irAEs) was graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) and the efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results: The incidence of irAEs, median progression-free survival (mPFS) of the ANA negative and positive groups were 26.0% vs. 31.4% (P=0.457), 17.7 vs. 10 months (P=0.603) for the cut-off value of 1:80; 26.2% vs. 33.9% (P=0.305), 11.9 vs. 10.6 months (P=0.957) for 1:160; and 25.9% vs. 45.8% (P=0.047), and 11.9 vs. 7.7 months (P=0.471) for 1:320, separately. Besides, ANA titer ≥1:320 was associated with irAEs [odds ratio (OR) =4.9, 95% confidence interval (CI): 1.45-16.52, P=0.01] and the incidence of adverse skin reactions differed greatly between the negative and positive groups (9.7% vs. 32%, P=0.003). Moreover, a total of 52 out of 159 patients were tested for ATG and ATPO. 46 patients were negative and 6 were positive, with the incidence of abnormal thyroid function being 4.3% vs. 50% (P=0.005), respectively. Conclusions: Preexisting ANAs may not correlate with the clinical benefit of immunotherapy in patients with NSCLC but may be associated with adverse skin reactions. Besides, ATG or ATPO has the potential to predict thyroid dysfunction.

[Blocking Adenosine/A2AR Pathway for Cancer Therapy].

Adenosine is a metabolite produced abundantly in the tumor microenvironment, dampening immune response in inflamed tissues via adenosine A2A receptor (A2AR) which is widely expressed on immune cells, inhibiting anti-tumor immune response accordingly. Therefore, blocking adenosine signaling pathway is of potential to promote anti-tumor immunity. This review briefly introduces adenosine signaling pathway, describes its role in regulating tumor immunity and highlights A2AR blockade in cancer therapy. Prospective anti-tumor activity of adenosine/A2AR inhibition has been revealed by preclinical data, and a number of clinical trials of A2AR antagonists are under way. Primary results from clinical trials suggest that A2AR antagonists are well tolerated in cancer patients and are effective both as monotherapy and in combination with other therapies. In the future, finding predictive biomarkers are critical to identify patients most likely to benefit from adenosine pathway blockade, and further researches are needed to rationally combine A2AR antagonists with other anti-tumor therapies.
.

Case Report: A Programmed Cell Death-1 Inhibitor-Related Abdominal Fibroinflammatory Reaction Affecting Multiple Organs in A Non-Small-Cell Lung Cancer Patient.

Immunotherapy utilizing programmed cell death-1 (PD-1)/PD-L1 inhibitors has been regarded as a rising hope for tumor patients, and their effects have been demonstrated in many clinical trials. However, immune-related adverse events also occur in patients and can sometimes have severe consequences. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD-1 antibody that has been approved by the US Food and Drug Administration for non-small-cell lung cancer. Here, we report a rare case of an abdominal fibroinflammatory reaction that affected multiple organs during anti-PD-1 immunotherapy using pembrolizumab in a non-small-cell lung cancer patient. The patient's case demonstrates that immunotherapy-related abdominal fibroinflammatory reactions need to be considered, especially for patients with a history of pre-existing conditions in the abdomen. Glucocorticoids may be useful as a treatment when a diagnosis is confirmed.

Clinical characteristics and outcomes of immune checkpoint inhibitor-induced diabetes mellitus.

OBJECTIVE: To better understand immune checkpoint inhibitor (ICI)-induced diabetes mellitus (DM) in cancer patients. DESIGN AND METHOD: We present a case of ICI-induced diabetic ketoacidosis (DKA) and conduct a systematic review of the PubMed and Web of Science databases up to September 2021 to identify all published cases of ICI-induced diabetes. RESULTS: In addition to our case, a total of 171 published cases were identified during the literature search. Summary and statistical analyzes were conducted for all 172 cases. The median onset time from ICI initiation to DM diagnosis was 12 weeks (range: 0-122). DKA was present in 67.4% (116/172) of the cases, and low C-peptide levels were detected in 91.8% (123/134), indicating an acute onset of diabetes. Patients with positive glutamic acid decarboxylase antibodies (GADA) had an earlier onset of ICI-induced diabetes (median time 7 weeks vs. 16 weeks for GADA-negative patients, p < 0.001) and a higher frequency of DKA development (82.8 vs. 62.1%, p = 0.006). All but two patients developed insulin-dependent diabetes permanently. Immunotherapy rechallenge was reported in 53 cases after glycemia was well controlled. CONCLUSION: ICI-induced DM is a serious adverse event that often presents with life-threatening ketoacidosis. GADA positivity is related to an earlier onset of ICI-induced diabetes and a higher frequency of DKA development. Close monitoring of glucose levels is needed in patients receiving ICI treatment. ICI-induced DM is usually insulin-dependent since damage to ß cells is irreversible. On the premise of well-controlled glycemia, immunotherapy rechallenge is feasible.

Risk factors for acute respiratory distress syndrome in sepsis patients: a retrospective study from a tertiary hospital in China.

BACKGROUND: Less is known about the risk factors for acute respiratory distress syndrome (ARDS) in sepsis patients diagnosed according to sepsis 3.0 criteria. Moreover, the risk factors for ARDS severity remain unclear. METHODS: We retrospectively collected the characteristics of sepsis patients from the intensive care unit of the First Affiliated Hospital of China Medical University from January 2017 to September 2018. Logistic regression was used in determining the risk factors. RESULTS: 529 patients with sepsis were enrolled and 179 developed ARDS. The most common infection sites were acute abdominal infection (n = 304) and pneumonia (n = 117). Multivariate analysis showed that patients with pancreatitis with local infection (odds ratio [OR], 3.601; 95% confidence interval [CI], 1.429-9.073, P = 0.007), pneumonia (OR 3.486; 95% CI 1.890-6.430, P < 0.001), septic shock (OR 2.163; 95% CI 1.429-3.275, P < 0.001), a higher sequential organ failure assessment (SOFA) score (OR 1.241; 95% CI 1.155-1.333, P < 0.001) and non-pulmonary SOFA score (OR 2.849; 95% CI 2.113-3.841, P < 0.001) were independent risk factors for ARDS. Moreover, pneumonia is associated with increased severity of ARDS (OR 2.512; 95% CI 1.039-6.067, P = 0.041). CONCLUSIONS: We determined five risk factors for ARDS in sepsis patients. Moreover, pneumonia is significantly associated with an increased severity of ARDS.

Prognostic Factors and Survival Benefits of Antitumor Treatments for Advanced Non-Small Cell Lung Cancer Patients With Central Nervous System Metastasis With or Without Driver Genes: A Chinese Single-Center Cohort Study.

Background: The prognosis of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastasis is poor. The treatment for CNS metastasis could prolong the overall survival of NSCLC patients. We aimed to investigate the prognostic factors of Chinese NSCLC patients with CNS metastasis and the survival benefits of various treatments for CNS metastasis in NSCLC patients with or without driver genes. Methods: Based on the CAPTRA-Lung database, NSCLC patients with CNS metastasis admitted at the Peking Union Medical College Hospital between January 2010 and October 2018 were enrolled in the study. The prognostic factors were analyzed using univariate and multivariate Cox regression analyses. Results: Overall, 418 patients were enrolled in the study. A total of 206 patients (49.3%) had CNS metastasis with positive driver genes, while 97 patients (23.2%) had negative driver genes. The median survival time after CNS metastasis was 20.8 months. In the multivariable analysis, an Eastern Cooperative Oncology Group performance status of ≥2 (hazard ratio [HR]: 1.750, 95% confidence interval [CI]: 1.184-2.588, P=0.005), number of CNS metastases ≥5 (HR: 1.448, 95% CI: 1.084 -1.934, P=0.012), and CNS metastasis developed during treatment (HR: 1.619, 95% CI: 1.232-2.129, P=0.001) were independent risk factors for poor survival. Lung adenocarcinoma (HR: 0.490, 95% CI: 0.279-0.861, P=0.013) and driver gene positivity (HR: 0.464, 95% CI: 0.302-0.715, P=0.001) were independent predictors of prolonged survival. Radiotherapy for CNS metastasis showed a survival benefit in NSCLC patients in the entire groups (HR: 0.472, 95% CI: 0.360-0.619, P <0.001), and in patients with positive driver genes. Conclusion: Performance status, number of CNS metastases, timing of CNS metastasis, histological subtype, and driver gene status are prognostic factors for NSCLC patients with CNS metastasis. Furthermore, radiotherapy improved the survival in NSCLC patients with CNS metastasis.

Circulating cytokines associated with clinical outcomes in advanced non-small cell lung cancer patients who received chemoimmunotherapy.

BACKGROUND: Pretreatment and on-treatment plasma cytokine levels in predicting clinical benefit in patients with advanced non-small cell lung cancer (NSCLC) treated with anti-programmed death-1 (PD-1)-based chemotherapy is still a matter of debate. METHODS: We measured 12 kind of plasma cytokines in patients with stage III/IV NSCLC before and during treatment with anti-PD-1 based chemotherapy. Associations with best overall response, and survival including progression-free survival (PFS) and overall survival (OS) were assessed using Chi-square test and Kaplan-Meier plots with log-rank test, respectively. Logistic regression and Cox regression were used to determine independent risk factors. RESULTS: Of a total of 60 patients, high-level of pretreatment interleukin-2 was associated with longer PFS (log rank p = 0.049), while high-level of pretreatment interleukin-8 was associated with shorter OS (log rank p = 0.006). Increased on-treatment interleukin-1ß (IL-1ß) was associated with both better response (odds ratio [OR] 6.233, 95% confidential interval [CI]: 1.451-26.344, p = 0.013) and longer PFS (hazard ratio [HR] 0.305, 95% CI: 0.127-0.730, p = 0.008). On the contrary, increased on-treatment interleukin-6 (IL-6) was associated with a worse response (OR 0.015, 95% CI: 0.001-0.400, p = 0.012), worse PFS (HR 2.639, 95% CI: 1.163-5.991, p = 0.020) and worse OS (HR 2.742, 95% CI: 1.063-7.074, p = 0.037). Increased interferon-γ (IFN-γ) was found to be associated with better PFS (HR 0.336, 95% CI: 0.153-0.745, p = 0.007). CONCLUSIONS: In patients with advanced NSCLC who received chemoimmunotherapy, on-treatment increased IL-1ß and IFN-γ may serve as positive indicator of efficacy, while on-treatment increased IL-6 might play a predictive role of worse clinical outcome.

Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune-related adverse events (irAEs) remain poorly understood, especially in a real-world setting. METHODS: A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD-L1) monotherapy, anticytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy. RESULTS: In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28-87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3-5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0-1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD-L1 expression (≥1%) and who received first-line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001). CONCLUSIONS: The incidence rate of irAEs was 26.9% in a real-world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Sarcoidosis-like reaction after neoadjuvant pembrolizumab combined with chemotherapy mimicking disease progression of NSCLC induced encouraging discovery of pathological complete response.

Neoadjuvant chemoimmunotherapy has demonstrated improved efficacy and prognosis in stage IIa-IIIb patients with non-small cell lung cancer (NSCLC). Drug-induced sarcoidosis-like reaction (DISR), an autoimmune reaction, has been reported as a type of immune-related adverse event that may mimic disease progression. Here, we report the case of patient with NSCLC who developed DISR during neoadjuvant chemoimmunotherapy and finally achieved pathological complete response after surgery.

Risk factors for immune-related adverse events: what have we learned and what lies ahead?

Immune checkpoint inhibitors (ICIs) have heralded the advent of a new era in oncology by holding the promise of prolonged survival in severe and otherwise treatment-refractory advanced cancers. However, the remarkable antitumor efficacy of these agents is overshadowed by their potential for inducing autoimmune toxic effects, collectively termed immune-related adverse events (irAEs). These autoimmune adverse effects are often difficult to predict, possibly permanent, and occasionally fatal. Hence, the identification of risk factors for irAEs is urgently needed to allow for prompt therapeutic intervention. This review discusses the potential mechanisms through which irAEs arise and summarizes the existing evidence regarding risk factors associated with the occurrence of irAEs. In particular, we examined available data regarding the effect of a series of clinicopathological and demographic factors on the risk of irAEs.

Normative Analysis of Individual Brain Differences Based on a Population MRI-Based Atlas of Cynomolgus Macaques.

The developmental trajectory of the primate brain varies substantially with aging across subjects. However, this ubiquitous variability between individuals in brain structure is difficult to quantify and has thus essentially been ignored. Based on a large-scale structural magnetic resonance imaging dataset acquired from 162 cynomolgus macaques, we create a species-specific 3D template atlas of the macaque brain, and deploy normative modeling to characterize individual variations of cortical thickness (CT) and regional gray matter volume (GMV). We observed an overall decrease in total GMV and mean CT, and an increase in white matter volume from juvenile to early adult. Specifically, CT and regional GMV were greater in prefrontal and temporal cortices relative to early unimodal areas. Age-dependent trajectories of thickness and volume for each cortical region revealed an increase in the medial temporal lobe, and decreases in all other regions. A low percentage of highly individualized deviations of CT and GMV were identified (0.0021%, 0.0043%, respectively, P < 0.05, false discovery rate [FDR]-corrected). Our approach provides a natural framework to parse individual neuroanatomical differences for use as a reference standard in macaque brain research, potentially enabling inferences regarding the degree to which behavioral or symptomatic variables map onto brain structure in future disease studies.

Correlations between peripheral blood biomarkers and clinical outcomes in advanced non-small cell lung cancer patients who received immunotherapy-based treatments.

BACKGROUND: Peripheral blood-based biomarkers (PBB) predicting response, survival and immune-related adverse events (irAEs) in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are still a matter of debate. Thus, we investigated the associations between PBB, the efficacy of ICIs and the incidence of irAEs. METHODS: Patients with advanced NSCLC, who had been treated at Peking Union Medical College Hospital and received ICIs or chemoimmunotherapy from January 2015 to December 2020, were retrospectively identified. PBBs results were retrieved from medical records. Associations with overall response rate, survival, and incidence of irAEs were assessed using Kruskal-Wallis, Kaplan-Meier analysis, Pearson's chi-squared and Student's t-tests as required. Cox proportional hazards and logistic regression models were used to determine independent risk factors. Analyses were performed on the whole population (n=103), patients receiving ICIs only (n=32), and patients receiving chemoimmunotherapy (n=71). Changes in pretreatment and on-treatment PBB were also analyzed. RESULTS: Among 103 patients, 38 (36.9%) developed irAEs. Pretreatment absolute lymphocyte count (ALC) was related to an increased risk of irAEs in the whole population [odds ratio (OR), 2.165; 95% confidence interval (CI): 1.040 to 4.509, P=0.039] and patients receiving ICIs only (OR, 6.461; 95% CI: 1.067 to 39.112; P=0.042). A low prognostic nutritional index (PNI ≤45) was associated with worse progression-free survival (PFS) and overall survival (OS) in the whole population, in patients receiving ICIs only, and in patients receiving chemoimmunotherapy. High pretreatment interleukin (IL)-6 was associated with both worse PFS and OS in the whole population (IL-6 >13.80 pg/mL), in patients receiving ICIs only (IL-6 >11.30 pg/mL), and in patients receiving chemoimmunotherapy (IL-6 >11.85 pg/mL). Increase of IL-6 during treatment was associated with inferior OS in the whole population (P<0.001). CONCLUSIONS: Pretreatment ALC has the potential to predict irAEs in patients with advanced NSCLC treated with ICIs. Additionally, a low level of pretreatment PNI and high level of IL-6 may be associated with shorter survival.

Heightened perception of illusory motion is associated with symptom severity in schizophrenia patients.

Abnormal perceptual processing in schizophrenia may contribute to the development of positive symptoms such as hallucinations. Experimental findings suggest that such abnormalities result from impaired processing of local signals into complex cortical representations. Because complex processing is needed to generate the perception of illusory motion from local signals, deteriorated perception of illusory motion would be expected in schizophrenia. However, findings are mixed, and the relationship between complex motion processing and symptoms is unclear. Illusions with multiple flow components (e.g. rotation/expansion) are known to strongly engage specialized complex processing mechanisms that may be abnormal in schizophrenia, but have not yet been investigated. We used a recently constructed paradigm based on the Pinna-Brelstaff illusion to manipulate complex-flow illusory perception in a quantitative manner and probe associations with dimensional symptoms. In 102 patients and 90 controls, perceived speed and perceptual variability for the PBF were measured across a range of parameters. Meanwhile, eye movement was recorded and gaze parameters were analysed to examine effects on illusory perception. Our results showed that patients experienced faster illusory rotation than controls, while they made fewer eye fixations. This heightened illusory perception was significantly correlated with positive and general, but not negative, symptom scores. Our results indicate that unusual processing of complex-flow motion in patients may be specifically related to dimensional symptoms, which could provide a promising strategy for parsing heterogeneity in the schizophrenia syndrome. This further highlights the role of motion perception abnormalities in the pathophysiology of schizophrenia, thus encouraging future investigation into visual remediation therapeutics.