Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis.

BACKGROUND: Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear. METHODS: We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored. RESULTS: After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). CONCLUSIONS: Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).

The PI3K/AKT/mTOR signaling pathway is aberrantly activated in primary central nervous system lymphoma and correlated with a poor prognosis.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a specific subtype of non-Hodgkin lymphoma that is highly invasive and confined to the central nervous system (CNS). The vast majority of PCNSLs are diffuse large B-cell lymphomas (DLBCLs). PCNSL is a highly heterogeneous disease, and its pathogenesis has not yet been fully elucidated. Further studies are needed to guide individualized therapy and improve the prognosis. METHODS: In this study, we detected 1) the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 by immunohistochemistry (IHC) and Western blotting, 2) the mRNA expression by real-time qPCR and 3) the deletion of PTEN gene by immunofluorescence in situ hybridization (FISH) in order to investigate the activation status of the PI3K/AKT/mTOR signaling pathway in PCNSL. Samples of reactive hyperplasia lymphnods were used as the control group. The correlations between the clinical characteristics and prognosis of PCNSL patients and the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 and the deletion of PTEN were assessed. RESULTS: The IHC results showed that the positive expression rates of p-AKT, p-mTOR, p-S6 and p-4E-BP1 in PCNSL were significantly higher in the PCNSL group than in the control group (P < 0.05). The relative mRNA expression level of MTOR in PCNSL samples was significantly increased (P = 0.013). Correlation analysis revealed that the expression of p-mTOR was correlated with that of p-AKT, p-S6, p-4E-BP1. PTEN deletion was found in 18.9% of PCNSL samples and was correlated with the expression of p-AKT (P = 0.031). Correlation analysis revealed that the PCNSL relapse rate in the p-mTOR-positive group was 64.5%, significantly higher than that in the negative group (P = 0.001). Kaplan-Meier survival analysis showed inferior progression-free survival (PFS) in the p-mTOR- and p-S6-positive groups (P = 0.002 and 0.009, respectively), and PTEN deletion tended to be related to shorter overall survival (OS) (P = 0.072). Cox regression analysis revealed p-mTOR expression as an independent prognostic factor for a shorter PFS (hazard ratio (HR) =7.849, P = 0.046). CONCLUSIONS: Our results suggest that the PI3K/AKT/mTOR signaling pathway is aberrantly activated in PCNSL and associated with a poor prognosis, which might indicate new therapeutic targets and prognostic factors.

Parenchymal central nervous system involvement in aggressive B-cell lymphoma: retrospective analysis of clinical and MRI features in a Chinese population.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) is defined as secondary central nervous system (CNS) involvement in patients with systemic lymphoma. It is considered a profoundly adverse complication with inferior clinical outcome. Parenchymal involvement in the CNS in aggressive B-cell lymphoma is not frequently seen and remains a diagnostic dilemma. METHODS: In our study, we retrospectively analyzed the clinical and magnetic resonance imaging (MRI) features of 26 parenchymal SCNSL patients. In addition, we compared MRI features of SCNSL and primary CNS lymphoma (PCNSL) patients after 1:1 propensity score matching. Also we presented two SCNSL cases with atypical MRI appearance. RESULTS: Among SCNSL patients, the median CNS relapse time was 3 months, and multiple lesions were found in 76.9% of the cases. In PCNSL, this percentage was 42.3% (p = 0.011). None of the SCNSL patients and 23.1% of the PCNSL patients had solitary infratentorial lesions (p = 0.003). CONCLUSIONS: The majority of parenchymal involvement occurred within the first year of systemic lymphoma, in which mostly cases presenting with multiple and supratentorial locations, unlike what was found in PCNSL.

CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study.

Chimeric antigen receptor modified T cells against CD19 (CART19s) have potent anti-leukemia activities in patients with refractory/relapsed acute lymphoblastic leukemia (R/R ALL). This study was designed to investigate the correlation between safety/efficacy and therapeutic modalities including chemotherapy and CART19 therapy. Total 23 and 69 patients were enrolled in the CART19 group and in the chemotherapy group, respectively. The safety and efficacy profiles of 66 and 22 patients in the 2 groups were evaluated. The complete remission (CR) rate was higher in the CART19 group than that in the chemotherapy group (90.9 vs 37.9%, P = 0.000). For patients relapsed after allo-HSCT and chemotherapy, CR rates were 100% (8/8) vs 48.0% (12/25) (P = 0.009) and 85.7% (12/14) vs 31.7% (13/41) (P = 0.000), respectively. Moreover, a higher percentage in the CART19 group had results below the threshold for minimal residual disease (100 vs 7.58%, P = 0.000). In survival analysis, the overall survival rate at 12 months was higher in the CART19 group than that in the chemotherapy group (60.9 vs 10.1%, P = 0.000). For post-transplant patients achieving CR, 25.0% (2/8) and 75.0% (9/12) complicated with GVHD (P = 0.04) in the CART19 group and chemotherapy group, respectively. For all CR patients, the median duration of absolute neutrophil count less than 500/µL and platelet count less than 20,000/µL were longer in the CART19 group than in the chemotherapy group (p = 0.0047 and 0.0003, respectively). Our data demonstrated that patients with CART19s therapy acquired higher rates of remission and longer survival, confirming the encouraging application of CART19 therapy in R/R ALL.

Reduction of Foxp3+ T cell subsets involved in incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Foxp3+ T cells (CD4+ Tregs and CD8+ Treg) have been demonstrated to play roles in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). We have found that Foxp3+ γδTCR+ Treg cells (γδTregs) exerted regulatory functions. In the current study, patients were recruited and divided as non-cGVHD, limited cGVHD and extensive cGVHD groups. Healthy volunteers were recruited as healthy group. Treg cells were evaluated by flow cytometry. Serum cytokine levels of IL-2, tumour necrosis factor-α, interferon-γ and transforming growth factor-ß1 (TGF-ß1) were evaluated by ELISA. The results showed that percentages of CD4+ Tregs, CD8+ Tregs and γδTregs were all significantly increased in non-cGVHD group compared with those in healthy group, limited cGVHD group and extensive cGVHD group. Moreover, compared with extensive cGVHD group, percentages of these three types of Tregs were significantly increased in limited cGVHD group. The levels of TGF-ß1 increased dramatically in non-cGVHD group compared with other groups. Spearman's correlation analysis revealed that the increased levels of TGF-ß1 and IL-2 were positively associated with increased Treg subsets, indicating that TGF-ß1 and IL-2 participated in the expansion process of Foxp3+ Tregs in vivo. Our findings support that increasing the number of Tregs following allo-HSCT would be a preferential strategy for controlling cGVHD. Copyright © 2015 John Wiley & Sons, Ltd.

Targeting the tumor microenvironment in primary central nervous system lymphoma: Implications for prognosis.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma, and there is limited research on its tumor microenvironment (TME). Nevertheless, more and more studies have evidence that TME has essential effects on tumor cell proliferation, immune escape, and drug resistance. Thus, it is critical to elucidate the role of TME in PCNSL. The understanding of the PCNSL TME is gradually unfolding, including factors that distinguish it from systemic diffuse large B-cell lymphoma (DLBCL). The TME in PCNSL exhibits both transcriptional and spatial intratumor heterogeneity. Cellular interactions between tumor cells and stroma cells reveal immune evasion signaling. The comparative analysis between PCNSL and DLBCL suggests that PCNSL is more likely to be an immunologically deficient tumor. In PCNSL, T cell exhaustion and downregulation of macrophage immune function are accompanied by suppressive microenvironmental factors such as M2 polarized macrophages, endothelin B receptor, HLA depletion, PD-L1, and TIM-3. MMP-9, Integrin-ß1, and ICAM-1/LFA-1 play crucial roles in transendothelial migration towards the CNS, while CXCL13/CXCR5, CD44, MAG, and IL-8 are essential for brain parenchymal invasion. Further, macrophages, YKL-40, CD31, CD105, PD-1/PD-L1 axis, osteopontin, galectin-3, aggregative perivascular tumor cells, and HLA deletion may contribute to poor outcomes in patients with PCNSL. This article reviews the effect of various components of TME on the progression and prognosis of PCNSL patients to identify novel therapeutic targets.

Impact of a tenofovir disoproxil fumarate plus ritonavir-boosted protease inhibitor-based regimen on renal function in HIV-infected individuals: a prospective, multicenter study.

BACKGROUND: The aim of this study was to investigate the impact of a tenofovir disoproxil fumarate (TDF) plus ritonavir-boosted protease inhibitor (PI/r) regimen on renal function in Chinese HIV-infected patients. METHODS: Seventy-five HIV-1 infected patients failing first-line antiretroviral therapy (ART) comprised the TDF+PI/r group. Seventy-five HIV-1 infected patients matched for gender, age, and renal function made up the control. All subjects completed follow-up visits over 48 weeks. CD4 cell count, plasma HIV-1 viral load, and urine protein level were assessed at the trial start (baseline, week 0) and at week 48. The serum creatinine and estimated glomerular filtration rate (eGFR) were monitored at each follow-up point. Change in eGFR from baseline to week 48 was also compared. RESULTS: Compared to control, the TDF+PI/r group exhibited higher levels of serum creatinine (79 vs. 69.7 µmol/L, P<0.001) and a lower rate of eGFR (93.0 vs. 101.6 ml/min/1.73 m², P=0.009) at the end of week 48. Patients treated with TDF+PI/r showed greater decline in eGFR than control (-8.8 vs. 6.4 ml/min/1.73 m², P<0.001). Compared to baseline renal function of the control group, the TDF+PI/r group exhibited a greater median decline in eGFR at the end of week 48 (P<0.001). CONCLUSIONS: We found that a TDF+PI/r based ART regimen resulted in greater renal function decline over 48 weeks. Therefore, renal function should be monitored especially when TDF is used in combination with PI/r. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00872417.

Challenges in the management of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma. Stereotactic biopsy remains the gold standard for the pathological diagnosis of PCNSL. However, certain new auxiliary diagnostic methods are considered to have good application prospects; these include cytokine and tumor circulating DNA, among others. Although new drugs such as immunomodulators, immune checkpoint inhibitors, chimeric antigen receptor T-cells, and Bruton tyrosine kinase inhibitors have brought hope owing to their improved efficacy, the high recurrence rate and subsequent high mortality remain barriers to long-term survival. Increasing emphasis is therefore being placed on consolidation treatments. Consolidation treatment strategies include whole brain radiotherapy, autologous hematopoietic stem cell transplantation, and non-myeloablative chemotherapy. As studies directly comparing the effectiveness and safety of different consolidation treatment schemes are lacking, the optimal consolidation strategy remains uncertain. This article will review the diagnosis and treatment of PCNSL, focusing on the progress in research pertaining to consolidation therapy.

Phytohemagglutinin-activated human T cells induce lethal graft-versus-host disease in cyclophosphamide and anti-CD122 conditioned NOD/SCID mice.

Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Much of our knowledge regarding GVHD comes from experiments on the mouse hematopoietic system due to ethical and technical constraints. Thus, in vivo GVHD models of the human immune system are required. In this study, we report an effective and reliable protocol for xenogeneic GVHD (xeno-GVHD) model induction using NOD/SCID mice, in which mice underwent a conditioning regimen consisting of intraperitoneal injection of cyclophosphamide and anti-CD122, followed by transfusion of phytohemagglutinin-activated human peripheral blood mononuclear cells containing 1 × 107 T cells, which has not been reported previously. The present model can be utilized to study human immune cell function in vivo and elucidate the mechanisms underlying the pathogenesis of human GVHD. In addition, this model system can help researchers to rapidly determine whether proposed therapeutic strategies for GVHD are efficient in vivo and will elucidate the underlying mechanisms of drugs and cells to be investigated. Furthermore, such a protocol will undoubtedly be very helpful to laboratories that have no available sources of irradiation.

Non-Myeloablative Chemotherapy as Consolidation Strategy After High-Dose Methotrexate-Based Chemoimmunotherapy in Patients With Primary CNS Lymphoma: A Retrospective Single Center Study in China.

Primary central nervous system lymphoma (PCNSL) remains a disease with poor outcome and high recurrence rate. We retrospectively analyzed the clinical data of 243 immunocompetent patients with PCNSL in Beijing Tiantan Hospital. The median age of PCNSL patients was 57 years (range 10-95 years). For induction therapy, 94.7% of patients received high-dose methotrexate (HD-MTX) containing regimens, and 59.3% received rituximab, which increased over time. The overall response rate was 72.8%, with 58.8% achieving complete response. With a median follow-up of 27.0 months (95% confidence interval 23.6-30.4), the median progression-free survival (PFS) time was 14.0 months (95% CI 9.45-18.55), and the 2-year PFS rate was 33.2%. The median overall survival (OS) was not reached (NR), with an estimated overall survival rate at 4 years of 61.6%. Among 95 patients who completed sequential consolidation chemotherapy with either pemetrexed or etoposide plus cytarabine, the median PFS was 28 months (95% CI 17.11-38.89), and the estimated overall survival at 4 years was 78.7%. In conclusion, HD-MTX based induction chemotherapy with non-myeloablative sequential consolidation chemotherapy is an alternative feasible treatment option.

Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study.

Chimeric antigen receptor (CAR)-T cell therapy against T cell malignancies faces major challenges including fratricide between CAR-T cells and product contamination from the blasts. Allogeneic CAR-T cells, generated from healthy donor T cells, can provide ready-to-use, blast-free therapeutic products, but their application could be complicated by graft-versus-host disease (GvHD) and host rejection. Here we developed healthy donor-derived, CD7-targeting CAR-T cells (RD13-01) with genetic modifications to resist fratricide, GvHD and allogeneic rejection, as well as to potentiate antitumor function. A phase I clinical trial (NCT04538599) was conducted with twelve patients recruited (eleven with T cell leukemia/lymphoma, and one with CD7-expressing acute myeloid leukemia). All patients achieved pre-set end points and eleven proceeded to efficacy evaluation. No dose-limiting toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade ≥ 3) were observed. 28 days post infusion, 81.8% of patients (9/11) showed objective responses and the complete response rate was 63.6% (7/11, including the patient with AML). 3 of the responding patients were bridged to allogeneic hematopoietic stem cell transplantation. With a median follow-up of 10.5 months, 4 patients remained in complete remission. Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) reactivation was observed in several patients, and one died from EBV-associated diffuse large B-cell lymphoma (DLBCL). Expansion of CD7-negative normal T cells was detected post infusion. In summary, we present the first report of a Phase I clinical trial using healthy donor-derived CD7-targeting allogeneic CAR-T cells to treat CD7+ hematological malignancies. Our results demonstrated the encouraging safety and efficacy profiles of the RD13-01 allogeneic CAR-T cells for CD7+ tumors.

Relapsing hematologic malignancies after haploidentical hematopoietic stem cell transplantation.

Haploidentical hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic regimen that could increase donor availability to nearly 100%. Rapid advances in medical technology and the application of novel drugs mean that most haploidentical HSCT-associated complications can now be prevented or remarkably well controlled, even cured. However, relapsing hematologic malignancy remains a major cause of death in haploidentical HSCT recipients. Haploidentical HSCT should theoretically trigger a more potent graft-versus-tumor effect compared with human leukocyte antigen-identical transplantation, due mainly to the major histocompatibility complex and minor histocompatibility anitigen disparities on donors' immune cells and recipients' tumor cells. The underlying mechanisms of such relapsing hematologic malignancies remain elusive. In this review, we suggest correlating factors and potential mechanisms and examine feasible therapeutic and preventive strategies for relapsing hematologic malignancies after haploidentical HSCT.

KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts.

The spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)-Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time- and dose-dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra-bone injection of INA-6 cells to subcutaneously implanted rabbit bones (SCID-rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID-rab model. These results suggest that KRN5500 exerts anti-MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.

Efficacy and Safety of Ibrutinib in Central Nervous System Lymphoma: A PRISMA-Compliant Single-Arm Meta-Analysis.

BACKGROUND: Central nervous system lymphoma (CNSL) is an aggressive lymphoma. Studies investigating primary CNSL determined that the Bruton tyrosine kinase (BTK) played an important role in pathogenesis. Ibrutinib, an oral BTK inhibitor, is a new treatment strategy for CNSL. The purpose of this meta-analysis was to clarify the effectiveness and safety of ibrutinib in the treatment of CNSL. METHODS: A systematic search of PubMed, Embase, Cochrane library, Wanfang Data Knowledge Service Platform, and China National Knowledge Infrastructure databases was conducted through to 31 October 2019. Studies involving patients with CNSL who received ibrutinib that reported the overall response (OR), complete remission (CR), and partial response (PR) were included. The random-effects or fixed-effects model with double arcsine transformation was used for the pooled rates and 95% confidence intervals (CI) were determined for all outcomes. RESULTS: Eight studies including 162 patients were identified and included in the meta-analysis. The pooled OR rate after treatment with ibrutinib was 69% (95% CI, 61-79%, I2 = 47.57%, p = 0.06), while the pooled CR and PR was 52% (95% CI, 35-68%, I2 = 74.95%, p = 0.00) and 17% (95% CI, 7-30%, I2 = 67.85%, p = 0.00), respectively. Among PCNSL patients, including new diagnoses PCNSL and R/R PCNSL, the pooled OR rate was 72% (95% CI, 63-80%, I2 = 49.20%, p = 0.06) while the pooled CR and PR rates were 53% (95% CI, 33-73%, I2 = 75.04%, p = 0.00) and 22% (95% CI, 14-30%, I2 = 46.30%, p = 0.07), respectively. Common adverse events above grade 3 included cytopenia and infections. CONCLUSIONS: The ibrutinib-containing therapy was well tolerated and offered incremental benefit to patients with CNSL. However, randomized-controlled studies that directly compare efficacy and adverse events of ibrutinib are still needed. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42020218974.

Treatment of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center study.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) is defined as lymphoma involvement within the central nervous system (CNS) that originated elsewhere, or a CNS relapse of systemic lymphoma. Prognosis of SCNSL is poor and the most appropriate treatment is still undetermined. METHODS: We conducted a retrospective study to assess the feasibility of an R-MIADD (rituximab, high-dose methotrexate, ifosfamide, cytarabine, liposomal formulation of doxorubicin, and dexamethasone) regimen for SCNSL patients. RESULTS: Nineteen patients with newly diagnosed CNS lesions were selected, with a median age of 58 (range 20 to 72) years. Out of 19 patients, 11 (57.9%) achieved complete remission (CR) and 2 (10.5%) achieved partial remission (PR); the overall response rate was 68.4%. The median progression-free survival after CNS involvement was 28.0 months (95% confidence interval 11.0-44.9), and the median overall survival after CNS involvement was 34.5 months. Treatment-related death occurred in one patient (5.3%). CONCLUSIONS: These single-centered data underscore the feasibility of an R-MIADD regimen as the induction therapy of SCNSL, further investigation is warranted.

Effect of smoking on lung function, respiratory symptoms and respiratory diseases amongst HIV-positive subjects: a cross-sectional study.

BACKGROUND: Smoking prevalence in human immunodeficiency virus (HIV) positive subjects is about three times of that in the general population. However, whether the extremely high smoking prevalence in HIV-positive subjects affects their lung function is unclear, particularly whether smoking decreases lung function more in HIV-positive subjects, compared to the general population. We conducted this study to determine the association between smoking and lung function, respiratory symptoms and diseases amongst HIV-positive subjects. RESULTS: Of 120 enrolled HIV-positive subjects, 119 had an acceptable spirogram. Ninety-four (79%) subjects were men, and 96 (81%) were white. Mean (standard deviation [SD]) age was 43.4 (8.4) years. Mean (SD) of forced expiratory volume in one second (FEV1) percent of age, gender, race and height predicted value (%FEV1) was 93.1% (15.7%). Seventy-five (63%) subjects had smoked 24.0 (18.0) pack-years. For every ten pack-years of smoking increment, %FEV1 decreased by 2.1% (95% confidence interval [CI]: -3.6%, -0.6%), after controlling for gender, race and restrictive lung function (R2 = 0.210). The loss of %FEV1 in our subjects was comparable to the general population. Compared to non-smokers, current smokers had higher odds of cough, sputum or breathlessness, after adjusting for highly active anti-retroviral therapy (HAART) use, odds ratio OR = 4.9 (95% CI: 2.0, 11.8). However respiratory symptom presence was similar between non-smokers and former smokers, OR = 1.0 (95% CI: 0.3, 2.8). All four cases of COPD (chronic obstructive pulmonary disease) had smoked. Four of ten cases of restrictive lung disease had smoked (p = 0.170), and three of five asthmatic subjects had smoked (p = 1.000). CONCLUSIONS: Cumulative cigarette consumption was associated with worse lung function; however the loss of %FEV1 did not accelerate in HIV-positive population compared to the general population. Current smokers had higher odds of respiratory symptoms than non-smokers, while former smokers had the same odds of respiratory symptoms as non-smokers. Cigarette consumption was likely associated with more COPD cases in HIV-positive population; however more participants and longer follow up would be needed to estimate the effect of smoking on COPD development. Effective smoking cessation strategies are required for HIV-positive subjects.

Donor-derived solid malignancies after hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation is considered to be a potentially therapeutic strategy for various hematopoietic benign diseases and malignancies. The growing number of reports on long-term survivors after hematopoietic stem cell transplantation reveals the major merits of this strategy. However, such cohorts remain at high risk of potential late complications, including the development of secondary solid malignancies. An increasing number of cases of secondary malignancies originated from recipients, donors, or unknown sources has been reported. In this review, we focus on latest clinical evidence of donor-derived solid malignancies after allogeneic hematopoietic stem cell transplantation, postulate related potential mechanisms, and further address novel indications as well as feasible therapeutic and preventive perspectives.

Concentrations and accumulation rates of polychlorinated biphenyls in soil along an urban-rural gradient in Shanghai.

This study proposed an in situ soil experimental system to quantify concentration and accumulation rates of polychlorinated biphenyl (PCB) congeners in the soil in a rural-urban fringe and correlated them with multiple variables in the area. Variables, including road density, normalized difference vegetation index (NDVI), distance to the nearest highway and industrial area from the soil experimental sites, land-use impact index, population density, population change index (PCI), total population, and percentage of water area, were used to explain the concentration of different PCB congeners in soil during the experimental period. A proportion of 40.1%, 22.6%, 56.9%, and 34.3% accumulation rates of PCB8, PCB18, PCB28, and PCB118, respectively was explained by industrial developments, using stepwise linear regression analysis. NDVI was used to explain 33.6%, 61.5%, 49.1%, and 53.2% accumulation rates of PCB44, PCB101, PCB187, and PCB180, respectively. Filtering and transferring of airborne organic pollutants from atmosphere to soil by forests or tree stands and farmlands were all NDVI-related factors that affected the concentrations and accumulation rates of PCB congeners in soil. The traffic-related particle deposition might be the reason why the concentrations and accumulation rates of PCB congeners in soil were affected by road density. The findings can help quantitatively understand urbanization and the associated environmental effects. Graphic abstract.

Lymphodepletion chemotherapy revitalizes chimeric antigen receptor T cells contributing to regression of relapsed B-cell lymphoma: A case report.

INTRODUCTION: Chimeric antigen receptor T cells (CAR-T) targeting CD19 have shown great potential for treatment of B-cell malignancies. For those patients who can not achieve complete remission (CR) or suffer from relapse after CAR-T therapy, further therapeutic strategies still remain elusive. Whether existing CAR-T cells can revitalize in vivo and eradicate tumor cells is still unknown. PATIENT CONCERNS: We report a case of diffused large B-cell lymphoma patient who had achieved CR after CD19 targeted CAR-T therapy but relapsed after 5 months. DIAGNOSIS: Five months after CAR-T cell infusion, the patient was confirmed a relapse by follow-up PET/CT scan and a mass biopsy. Flow cytometry showed a dramatically decreased percentage of CAR-T cells in peripheral blood (PB). INTERVENTIONS: A second anti-CD19 CAR-T therapy was planned with deliberation. Firstly, the patient received lymphodepletion chemotherapy with fludarabine (25 mg/m, d1-d3) and cyclophosphamide (500 mg/m d2-d3). OUTCOMES: After fludarabine and cyclophosphamide (FC) lymphodepletion chemotherapy, pre-existing CAR-T cells were revitalized and the patient developed grade 2 cytokine release syndrome (CRS) contributing to the regression of relapsed B-cell lymphoma. CONCLUSIONS: This case suggested that FC chemotherapy could revitalize CAR-T cells contributing to the regression of relapsed B-cell lymphoma. Nevertheless, further researches are required in the future as this report described only a single case.