Expression and prognostic significance of the PD-1/PD-L1 pathway in AIDS-related non-Hodgkin lymphoma.

OBJECTIVE: Immune tolerance and evasion play a critical role in virus-driven malignancies. However, the phenotype and clinical significance of programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, in aggressive acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (AR-NHL) remain poorly understood, particularly in the Epstein-Barr virus (EBV)-positive subset. METHODS: We used in situ hybridization with EBV-encoded RNA (EBER) to assess the EBV status. We performed immunohistochemistry and flow cytometry analysis to evaluate components of the PD-1/PD-L1/L2 pathway in a multi-institutional cohort of 58 patients with AR-NHL and compared EBV-positive and EBV-negative cases. RESULTS: The prevalence of EBV+ in AR-NHL was 56.9% and was associated with a marked increase in the expression of PD-1/PD-L1/PD-L2 in malignant cells. Patients with AR-NHLs who tested positive for both EBER and PD-1 exhibited lower survival rates compared to those negative for these markers (47.4% vs. 93.8%, p = 0.004). Similarly, patients positive for both EBER and PD-L1 also demonstrated poorer survival (56.5% vs. 93.8%, p = 0.043). Importantly, PD-1 tissue-expression demonstrated independent prognostic significance for overall survival in multivariate analysis and was correlated to elevated levels of LDH (r = 0.313, p = 0.031), increased PD-1+ Tregs (p = 0.006), and robust expression of EBER (r = 0.541, p < 0.001) and PD-L1 (r = 0.354, p = 0.014) expression. CONCLUSIONS: These data emphasize the importance of PD-1-mediated immune evasion in the complex landscape of immune oncology in AR-NHL co-infected with EBV, and contribute to the diagnostic classification and possible definition of immunotherapeutic strategies for this unique subgroup.

A promising prognostic model for predicting survival of patients with HIV-related diffuse large B-cell lymphoma in the cART era.

BACKGROUND: Optimization of risk stratification is important for facilitating prognoses and therapeutic decisions regarding diffuse large B-cell lymphoma (DLBCL). However, a simple and applicable prognostic tool is lacking for individuals with human immunodeficiency virus (HIV)-related DLBCL in the era of combined antiretroviral therapy (cART). METHODS: This retrospective multicenter observational study included 147 HIV-related DLBCL patients with histologically confirmed DLBCL from 2013 to 2020. The total group was divided into training (n = 78) and validation (n = 69) cohorts to derive the best prognostic score. Clinicopathological and characteristic biomarkers correlated with clinical outcomes were analyzed. RESULTS: Age, Ann Arbor stage, lactate dehydrogenase (LDH) ratio, bulky disease, and red blood cell distribution width (RDW) ratio retained robust independent correlations with overall survival (OS) in multivariate analysis. A new and practical prognostic model was generated and externally validated, classifying patients into three categories with significantly different survival rates. Moreover, the new index outperformed the International Prognostic Index (IPI) score (area under the curve values of 0.94 vs. 0.81 in the training cohort and 0.85 vs. 0.74 in the validation cohort, C-indices of 0.80 vs. 0.70 in the training cohort and 0.74 vs. 0.70 in the validation cohort, and integrated discrimination improvement values of 0.203 in the training cohort and 0.175 in the validation cohort) and was better at defining intermediate- and high-risk groups. The calibration curves performed satisfactorily for predicting 3-year OS in the training and validation cohorts. CONCLUSIONS: We developed and validated a simple and feasible prognostic model for patients with HIV-related DLBCL that had more discriminative and predictive accuracy than the IPI score for risk stratification and individualized treatment in the cART era.

Factors Related to Smoking and Perceptions of a Behavioral Counseling and Messenger Service-Delivered Smoking Cessation Intervention for People With HIV in China: Qualitative Study.

BACKGROUND: China, where half of the adult male population smoke tobacco, has one of the highest global burdens of smoking. Smoking rates are even higher among people with HIV. People with HIV can be affected by smoking in multiple ways, including more severe HIV-related symptoms and worse antiretroviral therapy treatment outcomes. However, smoking cessation services targeted for people with HIV are not routinely integrated into HIV care in China. Given the widespread mobile phone ownership, an exploration of factors related to smoking among people with HIV in China who smoke could inform the design and implementation of mobile smoking cessation interventions that target the needs of this vulnerable population. OBJECTIVE: This study aims to explore the perspectives of smoking, barriers and facilitators to quitting, and perceptions related to a smoking cessation intervention delivered through behavioral counseling sessions and brief daily messenger service (WeChat)-delivered messages. METHODS: We recruited people with HIV from the People's 4th Hospital of Nanning, Guangxi, China, and conducted semistructured face-to-face interviews. All interviews were audio-recorded, transcribed verbatim in Chinese, and translated into English for data analysis. We conducted a thematic analysis using a codebook, which was guided by a team-based consensus approach to identify 5 main themes. We also explored themes according to the demographic groups. RESULTS: A total of 24 participants were enrolled in the study. The mean age was 37.2 (SD=13.5) years. The participants had lived with HIV for a mean of 2.4 years. The majority were male (18/24, 75%) and lived in urban or metropolitan settings (19/24, 79%). We identified five main themes: variable knowledge of the harms of smoking, both related and unrelated to HIV; willpower perceived as the primary quitting strategy; a duality of the effect of social factors on quitting; perceptions about optimal features of the smoking cessation intervention (eg, messages should be brief and most frequent during the first few weeks); and the largely negative impact of their HIV diagnosis on smoking behaviors. In addition, some themes differed according to participant demographic characteristics such as age, sex, and education level. CONCLUSIONS: We identified barriers to and facilitators of smoking cessation among people with HIV in China by conducting semistructured qualitative interviews. Owing to the adverse impact of smoking on HIV outcomes, targeting cessation interventions to the unique needs and preferences of people with HIV in China may be needed to increase the effectiveness of future interventions. A pilot clinical trial will be conducted in the future to evaluate this behavioral counseling and brief daily messenger service (WeChat)-delivered messages approach among people with HIV who smoke in China.

A Novel Prognostic Score Including the CD4/CD8 for AIDS-Related Lymphoma.

Background: A simple and clinically applicable prognostic scoring system for AIDS-related lymphoma (ARL) in the era of combination antiretroviral therapy (cART) is needed to better stratify patients' risks and to assist in the decision-making of therapeutic strategies. Methods: We conducted a retrospective multicenter cohort study in 138 primary ARL patients over an 8-year period from 2013 to 2020. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard models were performed to identify the association between patient-, lymphoma-, and HIV-specific variables with progression-free survival (PFS) and overall survival (OS). The incremental prognostic value of novel inflammatory biomarkers in the International Prognostic Index (IPI) was evaluated by comparing the receiver operating characteristic (ROC) curves, the concordance index (C-index), and the integrated Brier score (IBS). Results: The median age was 49.14 ± 14.20 (range 18-79) years, 81.9% were men, and the median follow-up was 44.94 (95% CI = 37.05-52.84) months. The 3-year OS and PFS were 39.4% (95% CI = 16.3-21.2) and 38.7% (95% CI = 14.5-19.7), respectively. We found that age, extranodal sites, bulky mass, CD4 T-cell counts, CD4/CD8 ratio, and hypoalbuminemia were associated with OS (all P < 0.05) at both univariate and multivariate analyses. Of the new inflammatory markers, only the CD4/CD8 ratio was an independent prognostic parameter of OS and PFS. A lower CD4/CD8 ratio was strongly associated with adverse clinical factors, including older age, advanced Ann Arbor stage, more extranodal sites, elevated erythrocyte sedimentation rate, prior history of HIV, higher red cell distribution width ratio, hypoproteinemia, and emaciation. When the CD4/CD8 ratio was added to the IPI, the composite HIV-IPI score showed significantly better discrimination than IPI alone [AUC (95% CI): HIV-IPI, 0.83 (0.77-0.89) vs. IPI, 0.72 (0.70-0.85)]. The HIV-IPI model provided good predictive performance [C-index (95% CI): HIV-IPI, 0.82 (0.81-0.83) vs. IPI, 0.75 (0.73-0.77), P < 0.001] and a satisfactory calibration function. Conclusions: The CD4/CD8 ratio, an inexpensive and readily available marker, is a powerful independent prognostic parameter in patients with ARL. Furthermore, when the CD4/CD8 ratio is used in combination with IPI, it increases prognostic ability. The useful prediction of expected outcomes in ARL can inform treatment decisions.

Hypoalbuminemia predicts inferior outcome in patients with AIDS-related lymphoma.

BACKGROUND: The prognostic value of serum albumin in acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL) remains covered. METHODS: We retrospectively analyzed de novo ARL patients from 2013 to 2019 across three centers. Factors correlated with progression-free survival (PFS) and overall survival (OS) were evaluated in Kaplan-Meier, univariate and multivariate Cox proportional hazard models. RESULTS: A total of 86 ARL patients were enrolled with a median follow-up of 34 months. In the cohort, the OS and 2-year PFS rates were 37.5% and 35.4%, respectively. In multivariate models, older age (PFS, hazard ratios [HR] = 1.035, p = 0.037; OS, HR = 1.034, p = 0.041) and hypoalbuminemia (OS, HR = 0.910, p = 0.038) predicted inferior survival. ARL patients with hypoalbuminemia showed worse OS and 2-year PFS (p = 0.028 and p = 0.01, respectively), which was associated with poor Eastern Cooperative Oncology Group performance status (ECOG PS) and higher International Prognosis Index (IPI) score. CONCLUSION: In conclusion, serum albumin at diagnosis is an independent prognostic factor for overall survival in AIDS-related lymphoma.

Clinical Characteristics of HIV-Associated Talaromyces marneffei Infection of Intestine in Southern China.

Intestinal Talaromyces marneffei (TM) infection among patients with HIV/AIDS is rare. Herein, we report 31 cases of intestinal TM infection in Guangxi. Most patients exhibited fever, lymphadenectasis in the abdominal cavity, and chronic intestinal symptoms. CD4+ T-cell counts <50 cells/µL were reported in 28 patients. TM was cultured from the blood of 23 patients and from the marrow of 7 patients, whereas TM-like fungal spores in the cytoplasm of tissues with erosion, ulceration, and/or polyps were found in all 31 patients. We suggest that intestinal TM infection should be considered among patients infected with HIV with extremely low CD4+ T-cell counts (<50 cells/µL) who are manifesting fever, chronic gastrointestinal symptoms, and endoscopic evidence of erosion and/or ulceration.

Implications of the accumulation of CXCR5+ NK cells in lymph nodes of HIV-1 infected patients.

BACKGROUND: B cell follicles are immune-privileged sites where intensive HIV-1 replication and latency occur, preventing a permanent cure. Recent study showed that CXCR5+ NK cells in B cell follicles can inhibit SIV replication in African green monkeys, but this has not been reported in HIV-1 infected patients. METHODS: Lymphocytes and tissue sections of lymph node were collected from 11 HIV-1 positive antiretroviral therapy (ART)-naive and 19 HIV-1 negative donors. We performed immunofluorescence and RNA-scope to detect the location of CXCR5+ NK cells and its relationship with HIV-1 RNA, and performed flow cytometry and RNA-seq to analyze the frequency, phenotypic and functional characteristics of CXCR5+ NK cells. The CXCL13 expression were detected by immunohistochemistry. FINDINGS: CXCR5+ NK cells, which accumulated in LNs from HIV-1 infected individuals, expressed high levels of activating receptors such as NKG2D and NKp44. CXCR5+ NK cells had upregulated expression of CD107a and ß-chemokines, which were partially impaired in HIV-1 infection. Importantly, the frequency of CXCR5+NK cells was inversely related to the HIV-1 viral burden in LNs. In addition, CXCL13-the ligand of CXCR5-was upregulated in HIV-1 infected individuals and positively correlated with the frequency of CXCR5+ NK cells. INTERPRETATION: During chronic HIV-1 infection, CXCR5+ NK cells accumulated in lymph node, exhibit altered immune characteristics and underlying anti-HIV-1 effect, which may be an effective target for a functional cure of HIV-1.

SLC1A1, SLC16A9, and CNTN3 Are Potential Biomarkers for the Occurrence of Colorectal Cancer.

BACKGROUND: This study is aimed at identifying unknown clinically relevant genes involved in colorectal cancer using bioinformatics analysis. METHODS: Original microarray datasets GSE107499 (ulcerative colitis), GSE8671 (colorectal adenoma), and GSE32323 (colorectal cancer) were downloaded from the Gene Expression Omnibus. Common differentially expressed genes were filtered from the three datasets above. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed, followed by construction of a protein-protein interaction network to identify hub genes. Kaplan-Meier survival analysis and TIMER database analysis were used to screen the genes related to the prognosis and tumour-infiltrating immune cells of colorectal cancer. Receiver operating characteristic curves were used to assess whether the genes could be used as markers for the diagnosis of ulcerative colitis, colorectal adenoma, and colorectal cancer. RESULTS: A total of 237 differentially expressed genes common to the three datasets were identified, of which 60 were upregulated, 125 were downregulated, and 52 genes that were inconsistently up- and downregulated. Common differentially expressed genes were mainly enriched in the cellular component of extracellular exosome and integral component of membrane categories. Eight hub genes, i.e., CXCL3, CXCL8, CEACAM7, CNTN3, SLC1A1, SLC16A9, SLC4A4, and TIMP1, were related to the prognosis and tumour-infiltrating immune cells of colorectal cancer, and these genes have diagnostic value for ulcerative colitis, colorectal adenoma, and colorectal cancer. CONCLUSION: Three novel genes, CNTN3, SLC1A1, and SLC16A9 were shown to have diagnostic value with respect to the occurrence of colorectal cancer and should be verified in future studies.