ABSTRACT This study aims to identify the risk factors associated with clinical outcomes and the proteomic changes in organs related to fatal SARS‐CoV‐2 infection within the super‐elderly population. This retrospective analysis included all elderly individuals with COVID‐19 admitted to the Second Medical Center of PLA General Hospital from December 2022 to January 2023. The follow‐up period ended on March 30, 2023. During this time, epidemiological, demographic, laboratory, and outcome data were analyzed descriptively. Proteomic sequencing was performed on super‐elderly patients who died from COVID‐19 at different stages of the disease. A total of 352 elderly COVID‐19 patients, with a mean age of 89.84 ± 8.54 years, were included in this study. During a median follow‐up period of 98 days, 79 patients died. Deceased patients were older and more likely to have cardiovascular and cerebrovascular diseases, with a lower prevalence of lipid‐lowering therapy. The number of deaths in the acute and post‐acute phases were 34 and 45, respectively. Proteomics data suggest that the immune systems of patients who died in the acute phase underwent a more rapid and severe onslaught. Patients in the post‐acute phase showed higher levels of viral genome replication and a more robust immune response. However, the over‐activation of the immune system led to systemic organ dysfunction. Effective management of comorbidities may improve the prognosis of COVID‐19 in super‐elderly patients. The continuous replication of the SARS‐CoV‐2 virus and its subsequent impact on the immune system are critical determinants of survival time in this demographic.

Background Azvudine and nirmatrelvir/ritonavir are approved to treat mild -to -moderate coronavirus disease 2019 (COVID-19) in adults with a high risk for progression to severe infection. We sought to compare the antiviral effectiveness and clinical outcomes of elderly severe patients with COVID-19 receiving these two antiviral agents. Methods In this observational study, we identified 249 elderly patients with severe COVID-19 infection who were admitted to the Second Medical Center of the People's Liberation Army General Hospital from December 2022 to January 2023, including 128 azvudine recipients, 66 nirmatrelvir/ritonavir recipients and 55 patients not received antiviral treatments. We compared the cycle threshold (Ct) value dynamic change of all three groups. The primary outcome was a composite outcome of disease progression, including all -cause death, intensive care unit admission, and initiation of invasive mechanical ventilation. The outcomes of all enrolled patients were followed up from the electronic medical record system. Kaplan-Meier and Cox risk proportional regression analyses were used to compare the clinical outcomes of all three groups. To more directly compare the effectiveness of the two antiviral drugs, we performed propensity -score matching between the two antiviral groups and compared antiviral efficacy and clinical outcomes in the matched population. Findings Among 249 patients (mean age, 91.41 years), 77 patients died during the follow-up period. When compared to patients who did not receive any antivirals, neither nirmatrelvir/ritonavir nor azvudine demonstrated a survival benefit. The Cox analysis of the all -cause death of the three groups showed that the risk of death was 0.730 (0.423-1.262) in the azvudine group 0.802 (0.435-1.480) and in the nirmatrelvir/ritonavir group compared with the non -antiviral group. After propensity score matching, we included 58 azvudine recipients and 58 nirmatrelvir/ ritonavir recipients. The fitted curve of the Ct value after matching illustrated that the rate of viral decline in the early stage of nirmatrelvir/ritonavir treatment seems to surpass that of azvudine, but there was no statistical significance. Azvudine was seemly associated with a lower risk of composite outcomes (HR:1.676, 95% CI:0.805-3.488) and short-term all -cause death (HR: 1.291, 95%CI: 0.546-3.051).

Summary: Background: Azvudine and nirmatrelvir/ritonavir are approved to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with a high risk for progression to severe infection. We sought to compare the antiviral effectiveness and clinical outcomes of elderly severe patients with COVID-19 receiving these two antiviral agents. Methods: In this observational study, we identified 249 elderly patients with severe COVID-19 infection who were admitted to the Second Medical Center of the People's Liberation Army General Hospital from December 2022 to January 2023, including 128 azvudine recipients, 66 nirmatrelvir/ritonavir recipients and 55 patients not received antiviral treatments. We compared the cycle threshold (Ct) value dynamic change of all three groups. The primary outcome was a composite outcome of disease progression, including all-cause death, intensive care unit admission, and initiation of invasive mechanical ventilation. The outcomes of all enrolled patients were followed up from the electronic medical record system. Kaplan–Meier and Cox risk proportional regression analyses were used to compare the clinical outcomes of all three groups. To more directly compare the effectiveness of the two antiviral drugs, we performed propensity-score matching between the two antiviral groups and compared antiviral efficacy and clinical outcomes in the matched population. Findings: Among 249 patients (mean age, 91.41 years), 77 patients died during the follow-up period. When compared to patients who did not receive any antivirals, neither nirmatrelvir/ritonavir nor azvudine demonstrated a survival benefit. The Cox analysis of the all-cause death of the three groups showed that the risk of death was 0.730 (0.423–1.262) in the azvudine group 0.802 (0.435–1.480) and in the nirmatrelvir/ritonavir group compared with the non-antiviral group. After propensity score matching, we included 58 azvudine recipients and 58 nirmatrelvir/ritonavir recipients. The fitted curve of the Ct value after matching illustrated that the rate of viral decline in the early stage of nirmatrelvir/ritonavir treatment seems to surpass that of azvudine, but there was no statistical significance. Azvudine was seemly associated with a lower risk of composite outcomes (HR:1.676, 95% CI:0.805–3.488) and short-term all-cause death (HR: 1.291, 95%CI: 0.546–3.051). Interpretation: Patients who received azvudine have a similar antiviral effectiveness and survival curve trend compared to nirmatrelvir/ritonavir. In this limited series, antiviral treatment was not associated with a significant clinical benefit. This lack of clinical benefit might be attributed to potential bias. Funding: This study was supported by the “National Key R&D Program of China” (Funding No. 2020YFC2008900) and the National Defense Science and Technology Innovation Special Zone Project (223-CXCY-N101-07-18-01).

The adverse event after the CART-30 cell infusion.

Supplementary Table S1. Phonotypical characteristics of PBMCs and expanded T Cells as well as transduction efficiency of infused cell products. Supplementary Table S2. Detailed prior chemotherapy regimens for patients before CD30-CART treatment. Supplementary Table S3. Statistics of patient characteristics. Supplementary Table S4. The absolute doses of conditioning regimens for all enrolled patients. Supplementary Table S5. Toxicities possibly related to CD30-CART infusion-containing protocol. Supplementary Table S6. Maximum change from baseline of target measurable lesions. Supplementary Table S7. Clinical response in CD30-CAR T cell- treated patients.

Case selection criteria;Methods;Figure Legends

Lymphocyte recovery is a probable indictor of response.

Maximum reduction in target lesion size.

Progression-free survival by Kaplan-Meier method.

OBJECTIVE:To evaluate the efficacy and safety of CHOP regimen based on doxorubicin hydrochloride liposome in the initial treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL).METHODS:Thirty-one patients with DLBCL treated from January 1, 2012 to December 31, 2019 were analyzed retrospectively, their median age was 83 (71-95) years old, and all of them were in Ⅲ-Ⅳ stage, including 17 cases who had international prognostic index (IPI) ≥ 3. The patients were treated with R-CHOP and CHOP regimens based on doxorubicin hydrochloride liposome. The efficacy and safety were evaluated during and after treatment.RESULTS:A total of 219 chemotherapy cycles and 7 median cycles were performed in 31 patients. The overall response (OR) rate and complete remission (CR) rate was 80.7% (25/31) and 61.3% (19/31), respectively, as well as 2 cases (6.5%) stable, 4 cases (12.9%) progressive. The main toxicities were as follows: the incidence of grade Ⅲ -Ⅳ neutropenia was 29% (9/31); two patients (6.5%) developed degree Ⅰ-Ⅱ cardiac events, which were characterized by new degree Ⅰ atrioventricular block; there were no cardiac events requiring emergency treatment and discontinuation of chemotherapy. The 1-year, 2-year and 3-year overall survival rate was 83.9%, 77.4% and 61.3%, respectively. The 1-year, 2-year and 3-year progression-free survival rate was 77.4%, 64.5% and 61.3%, respectively.CONCLUSION:The chemotherapy regimen based on doxorubicin hydrochloride liposome has better efficacy and higher cardiac safety for elderly patients with DLBCL.

背景 多发性骨髓瘤(multiple myeloma,MM)患者接受以来那度胺为基础的治疗方案时血栓风险较高,目前的指南和临床实践关于血栓预防策略并不一致,血栓事件(thrombotic events,TEs)发生率的报道差异很大.目的 观察解放军总医院第一医学中心初治的MM患者接受含来那度胺方案治疗相关血栓事件的发生率.方法 回顾性分析2010年1月-2020年12月解放军总医院第一医学中心46例接受含来那度胺治疗方案的初治MM患者病例资料,分析TEs的发生率.结果 46例患者中男性27例,女性19例,确诊时平均年龄(60.0±12.7)岁,来那度胺用药中位时间为16(5～90)个月.有32例(69.6％)患者接受预防血栓治疗,其中31例患者接受阿司匹林抗血小板治疗,1例接受利伐沙班抗凝治疗.用药期间观察到6例TEs,占全部病例的13.04％,均为深静脉血栓栓塞事件,其中1例合并肺栓塞.另有1例发生上消化道出血事件.所有血栓事件都得到了及时处理,无患者因血栓事件停药或死亡.结论 接受含来那度胺方案治疗的MM患者血栓发生率较高,临床治疗中须加强预防.

The aim of the present study was to evaluate the relationship of Epstein-Barr virus (EBV) infection and multiple myeloma (MM) and its impact on clinical characteristics and prognosis. Fresh peripheral blood mononuclear cells (PBMCs) from 139 MM patients who had been diagnosed and treated from January 2010 to May 2018 and 50 PBMC samples from healthy donors were obtained. PCR was carried out for detection of EBV-DNA. The results indicated a significantly higher EBV-DNA concentration among 139 MM patients compared with healthy controls (P<0.05). Correlation analysis showed that the expression of EBV-DNA was positively correlated with the serum free light chain ratio (sFLCR) and progressive disease (PD)/relapse (P<0.05). Especially, in EBV-DNA high-expression MM patients, EBV-DNA concentration for patients with sFLCR >= 100 was higher than that of patients with sFLCR <100. EBV-DNA concentration was higher in patients with disease PD/relapse than those without disease PD/relapse. In univariate analysis, the progress free survival (PFS) was inferior in MM patients with high expression of EBV-DNA, high lactate dehydrogenase (LDH), and high-risk according to mSMART and International Myeloma Working Group (IMWG), stage III according to R-ISS staging, extramedullary lesions, and genetic changes (P<0.05). However, in multivariate analysis, LDH, poor karyotype, R-ISS staging, and mSMART were independent prognostic factors for PFS. Taken together, our studies suggest that an association exists between EBV infection and clinical characteristics of MM patients, and EBV infection appears to have a slight impact on the prognosis of MM. However, the results require further validation in other independent prospective MM cohorts.

目的 探讨老年人群贫血的状况及病因.方法 回顾性分析2013年1月1日至2013年3月31日在解放军总医院诊治的年龄≥60岁患者的病例资料共10307例.收集患者临床资料,按年龄进行分层,对各年龄段患者贫血发生率进行分析.考察性别、年龄、人员类别、就诊方式对贫血发生率的影响.依据患者临床诊断及各指标情况,分析贫血患者的病因分布特点.采用SPSS 22.0软件进行数据处理,依据数据类型,组间比较采用 χ2检验.结果 贫血患者总发生率为23.4％(2412/10307).随着年龄增加,贫血发生率逐渐升高(P<0.001).就诊方式对贫血发生率有显著影响(P<0.001).人员类别对贫血发生率无显著影响(P>0.05).在贫血病因构成方面,居于首位的是不明原因性贫血,占46.4％(1119/2412),其次为慢性病性贫血,占34.6％(835/2412),造血原料缺乏性贫血比例最小,占19.0％(458/2412).结论 老年人易发生贫血,且病因复杂,需要临床医师特别注意.

目的 探讨老年人血常规指标的参考值范围.方法 回顾性分析2013年1月～2013年3月在解放军总医院第二医学中心就诊的60岁以上老年患者的资料.按照不同年龄段分为60～ 69岁组、70～79岁组、80～89岁组和≥90岁组4组,收集所有老年人血常规指标:血红蛋白(Hb)浓度、红细胞计数(RBC)、平均红细胞体积(MCV)、平均红细胞血红蛋白量(MCH)、平均红细胞血红蛋白浓度(MCHC)、血小板计数(PLT)、白细胞计数(WBC)、中性粒细胞(N)、淋巴细胞(L)、单核细胞(M)、嗜酸性粒细胞(E)、嗜碱性粒细胞(B),并使用非参数95％百分位数法计算每个年龄组的血常规参考范围.结果 男性、女性Hb 95％的参考范围分别为(110～168)g/L、(107～152)g/L,随着年龄的增长,男性和女性的血红蛋白水平逐渐下降.不同年龄组和性别Hb、RBC、红细胞比容(Hot)、MCV、MCHC、PLT参考范围不同,差异有统计学意义(P＜0.05).不同年龄组的MCH差异无统计学意义;不同性别的MCH参考范围不同,差异有统计学意义(P＜0.05).不同年龄组WBC、N、L、M、E、B的参考范围不同,差异有统计学意义(P＜0.05),不同性别之间差异无统计学意义(P＞0.05).结论 随着国家人口的老龄化,建立老年人血常规参考值范围数据库将为临床医生提供一种有价值的新工具.

The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re-sensitivity property to chemo- and immunotherapy of low-dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low-dose decitabine-primed chemo-immunotherapy in patients with drug-resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty-five patients received either the 5-day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine-primed chemotherapy, D-C cohort) or the aforementioned regimen followed by cytokine-induced killer cells therapy (D-C and cytokine-induced killer [CIK] cell treatment, D-C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment-related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment-free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D-C + CIK cohort. Consistently, the progression-free survival (PFS) of the D-C + CIK cohort compared favorably to the best PFS of the pre-resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non-significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine-primed re-sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large-scale evaluation of drug-resistant R/R AT cancer patients with advanced stage disease.

Despite advances in the treatment of Hodgkin lymphoma (HL), there is a need for development of reliable prognostic biomarkers and improved stratification of patients for effective therapeutic intervention. The immune microenvironment is the key to HL pathophysiology. The aim of this study was to identify expression of microenvironment-related biomarkers (PD-1, FOXP3, and CSF-1R) immunohistochemically and determine their association with clinicopathological features and prognosis in HL. We found that a high number of non-HRS cells expressing CSF-1R confers inferior overall survival (OS), which is associated with the presence of Epstein-Barr virus in neoplastic cells (P=0.009). Increased FOXP3 expression confered superior OS and progression-free survival (PFS). PD-1 expression had no significant association with OS and PFS. The combination of FOXP3 and PD-1 or CSF-1R may yield better prognostic stratification.

BACKGROUNDA survey of early stage follicular lymphoma(FL) revealed that the rigorously staged FL patients at first diagnosis had a better outcome as compared with non-rigorous staged FL patients, but there were no similar reports in China.OBJECTIVETo explore the relationship between the rigorous staging at first diagnosis and the prognosis of FL patients at different stages.METHODSThe clinical data of 111 patients with newly diagnosed FL from 2008 to 2014 year were collected and analyzed. The rigorous staging included: (1) bone marrow aspiration and biopsy, (2) imaging examination of whole body including CT and ultrasounic scan, or PET/CT, either or both is defined as rigorous staging, or else as non-rigorous staging.RESULTSThe FL patients at I-II stages by rigorous staging showed a superior progression-free survival(PFS) compared with non-rigorous staging patients(P=0.048). For all the patients, the age, serum LDH, bone marrow lesion and more than 3 foci of diameter larger than 3 cm correlated with prognosis in univariate analysis, and multivariate analysis revealed that the age, serum LDH and bone marrow imolvement were the independent prognostic factors.CONCLUSIONRigorous staging leads to better outcomes, suggesting that accurate and appropriate testing is important for the patients at the first treatment. The close correlation of bone marrow with prognosis indicates that the evaluation of bone marrow is very important for the daily clinical practice.

Introduction: Drug resistance often tempers the clinical benefit of chemotherapy in gastrointestinal (GI) cancers. The potential chemosensitization of low-dose decitabine has been evident both preclinically and in previous phase I trials. We assessed the safety and efficacy of low-dose decitabine primed chemotherapy in a phase II trial in patients with chemoresistant relapsed/refractory GI cancers. Methods: Forty-five patients with advanced stage esophageal, gastric or colorectal cancers were enrolled based on documented disease progression within six months of first-line chemotherapy. All patients received decitabine intravenously daily for 5 days, and then readministered the previously, ineffective first-line chemotherapy on day 6 to 7 of a 28-day cycle. This phase II trial evaluated efficacy and adverse events (AEs) continuously per RECIST and CTCAE, respectively. The primary endpoint was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Preliminary plasma microRNAs analyses were performed to identify putative predictive biomarkers. Results: Grade 3 to 4 AEs were reported in 11 (24.4%) of 45 patients. All AEs were controllable and no patient experienced a treatment-related death. The median PFS was 4 months (95% CI, 4.36 to 8.76 months), which compared favorably to the PFS of the pre-resistant unprimed first-line chemotherapy (0 month; 95% CI, 1.71 to 5.62 months). ORR and DCR were 24.4% (95% CI, 11.9 to 36.9) and 82.2% (95% CI, 71 to 93.4), respectively, including 2 patients who achieved durable complete responses. The median OS, 6-month PFS and 1-year OS rates were 11 months, 40% and 42.2%, respectively. The toxicity and objective response rates exhibited were nonsignificantly different between cancer types. Preliminary data of correlative studies of expression patterns of 5 miRNAs are promising as putative predictive markers of response. Conclusion: The safety and efficacy of decitabine primed resensitization to chemotherapy is attractive and promising. These data warrant further large-scale evaluation of chemoresistant relapsed/refractory GI cancers in patients with advanced stage disease.

Abstract Purpose: Relapsed or refractory Hodgkin lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma. Experimental Design: Patients with relapsed or refractory Hodgkin lymphoma received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR). Results: Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions and received a mean of 1.56 × 107 CAR-positive T cell per kg (SD, 0.25; range, 1.1–2.1) in total during infusion. CART-30 cell infusion was tolerated, with grade ≥3 toxicities occurring only in two of 18 patients. Of 18 patients, seven achieved partial remission and six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors. Conclusions: CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment. Clin Cancer Res; 23(5); 1156–66. ©2016 AACR.

BACKGROUND:Elderly multiple myeloma (MM) patients often tend to suffer a variety of diseases, so the treatment of choice is very difficult for the elderly myeloma patients. The overall survival (OS) time and side effects with elderly patients are unclear in China. The study tried to find out the role of geriatric assessment in the Chinese elderly MM. METHODS:We retrospectively analyzed the data of 628 newly diagnosed patients from six hospitals from June 2011 to June 2013. A geriatric assessment had been performed to assess comorbidities, cognitive, and physical status for these patients. The primary endpoint was to evaluate different physical states of elderly patients with OS time and treatment-related side effects. RESULTS:An additive scoring system (range: 0-5), based on age, Katz's Activity of Daily Living (ADL) and Lawton's Instrumental Activity of Daily Living (IADL) ≤5 and Charlson Comorbidity Index (CCI) was developed to identify three groups: fit (score = 0); intermediate-fitness (score = 1); and frail (score ≥2). The 3-year OS was 63% in fit patients, 63% in intermediate-fitness patients, and 49% in frail patients ≥3 hematologic adverse events (AEs) were documented in 45 (35.4%) fit, 34 (34%) intermediate-fitness, and 121 (30.2%) frail patients. The risk of a grade ≥3 hematologic AEs was not significantly increase in intermediate-fitness (hazard ratios [HR]: 0.99, 95% confidence interval [CI]: 0.54-1.47, P = 1.000) and in frail patients (HR: 1.16, 95% CI: 0.70-1.93, P = 0.558) compared with fit ones. CONCLUSIONS:MM occurs earlier in life and being advanced when the diagnosis is made in the mainland of China. The overall survival in frailty with International Staging System (ISS) II/III was the worst in all patients.