Assessment of nucleus accumbens impairment in a rat model of postoperative cognitive dysfunction using diffusion tensor imaging.

BACKGROUND: Postoperative cognitive dysfunction (POCD) often occurs in elderly patients, causing depression and other symptoms. Nucleus accumbens (NAc) is involved in depression. We investigate the diffusion tensor imaging (DTI) parameters of NAc in a POCD model of depression. METHODS: Twenty-month-old male Sprague-Dawley (SD) rats were randomly divided into the POCD and Sham groups. The POCD group underwent exploratory laparotomy to establish a POCD depression model, while the Sham group underwent a sham operation. The fractional anisotropy (FA) and mean diffusivity (MD) values of the bilateral NAc, behavioural changes of forced swimming test and sucrose preference rate, and pathological changes of glial fibrillary acidic protein (GFAP) fluorescent intensity were observed at 15 days (D15 ) and 30 days (D30 ) after the operation. RESULTS: The FA value of the bilateral NAc area in the POCD group was lower than that in the Sham group at the two time periods after the operation (P < 0.05). However, the MD value at D30 was higher in the POCD group than in the Sham group (P < 0.05). The FA value in the POCD group was lower at D30 than at D15 (P < 0.05). The floating time was prolonged while the sucrose preference rate was decreased in the POCD group compared with the Sham group (P < 0.05). The floating time in the POCD group was longer at D30 than at D15 . However, the sucrose preference rate in the POCD was lower at D30 than at D15 . The GFAP fluorescent intensity in the bilateral NAc region in the POCD group was higher than in the Sham group (P < 0.05). CONCLUSION: Microstructural changes of the NAc area are associated with POCD related depression. In addition, FA and MD were demonstrated to be effective in diagnosing and monitoring postoperative depression and its severity.

Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells.

The therapeutic effect of CAR-T is often accompanied by sCRS, which is the main obstacle to the promotion of CAR-T therapy. The JAK1/2 inhibitor ruxolitinib has recently been confirmed as clinically effective in maintaining control over sCRS, however, its mechanism remains unclear. In this study, we firstly revealed that ruxolitinib significantly inhibited the proliferation of CAR-T cells without damaging viability, and induced an efficacy-favored differentiation phenotype. Second, ruxolitinib reduced the level of cytokine release not only from CAR-T cells, but also from other cells in the immune system. Third, the cytolytic activity of CAR-T cells was restored once the ruxolitinib was removed; however, the cytokines released from the CAR-T cells maintained an inhibited state to some degree. Finally, ruxolitinib significantly reduced the proliferation rate of CAR-T cells in vivo without affecting the therapeutic efficacy after withdrawal at the appropriate dose. We demonstrated pre-clinically that ruxolitinib interferes with both CAR-T cells and the other immune cells that play an important role in triggering sCRS reactions. This work provides useful and important scientific data for clinicians on the question of whether ruxolitinib has an effect on CAR-T cell function loss causing CAR-T treatment failure when applied in the treatment of sCRS, the answer to which is of great clinical significance.

Diagnostic value of spiral CT energy spectrum imaging in lymph node metastasis of colorectal cancer.

OBJECTIVES: To evaluate the value of preoperative CT energy spectrum imaging in detecting lymph node metastasis of colorectal cancer. METHODS: From September 2019 to November 2021, a retrospective study was performed for the eighty-two patients with colorectal cancer through preoperative colonoscopy or surgical pathology confirmed in our hospital. Based on the lymph node metastasis status, these cases were divided into the metastasis and non-metastasis groups. GE Revolution CT scanner was used to scan the patients with energy spectrum imaging, it measured and recorded the single-energy CT values from 40 to 140 keV and various energy spectrum parameters of lymph nodes around the lesions in the arterial and venous phases, and statistically analyze the above indices. RESULTS: In the arterial and venous phases: the single-energy CT values of 40-140 keV in the non-metastatic group were higher than those in the metastatic group (all P < 0.05); the parameter values of IC (iodine concentration), NIC (normalized iodine concentration), λ (the slope of the energy spectrum curve), and Eff-Z (effective-Z) in the non-metastatic group were higher than those in the metastatic group (all P < 0.05). Further evaluation of ROC curve showed that the higher AUC (area under curve) of the single-energy CT value of 50 keV in the arterial phase was 0.889, among the energy spectrum parameters of IC, NIC, λ, and Eff-Z, the NIC had the better diagnostic efficiency and the AUC of the NIC was 0.873, the highest AUC of the combination of NIC and λ was 0.885 when the energy spectrum parameters were combined. The higher AUC of the single-energy CT value of 60 keV in the venous phase was 0.853, among the energy spectrum parameters of IC, NIC, λ, and Eff-Z, the λ had the better diagnostic efficiency and the AUC of the λ was 0.822, the higher AUC of the combination of NIC, λ, and Eff-Z was 0.840 when the energy spectra were combined. CONCLUSIONS: Parameters of energy spectrum CT imaging can effectively evaluate whether lymph nodes have metastases, and provide favorable imaging diagnosis basis for the range and the number of lymph nodes to be cleaned during clinical operation and can evaluate the prognosis of patients. It is worthy of clinical recommendation.

CT differentiation of malignant peritoneal mesothelioma and tuberculous peritonitis.

OBJECTIVE: The aim of this study was to determine which computed tomography (CT) findings were useful in differentiating malignant peritoneal mesothelioma (MPM) and tuberculous peritonitis (TBP). METHODS: CT scans performed in 53 patients with MPM and 27 patients with TBP confirmed by pathology were retrospectively reviewed. The CT findings were evaluated for the morphologic appearance of ascites, peritoneum, mesenterium and omentum involvement, enlarged lymph nodes, solid abdominal viscera infiltration and metastases, and thoracic changes. The Pearson χ (2) test was used to compare differences between groups. RESULTS: Patients in both groups displayed a high proportion of peritoneum and mesenterium thickening. However, there were no obvious differences observed for ascites or swollen lymph nodes. There were significant differences in the following aspects between the two groups: (1) smooth peritoneal thickening was more frequent in patients with TBP, while irregular thickening was more frequently observed in patients with MPM; (2) caked omentum stratification was more common in patients with MPM; (3) mesentery involvement was less commonly observed in patients with TBP; (4) abdominal viscera infiltration and pleural plaques were more common in patients with MPM (46/53 and 48/53, respectively) than in those with TBP (0/27 and 0/27); and (5) more patients in the TBP group (14/27) displayed pleural effusion, and extraperitoneal tuberculosis was more common in patients with TBP (20/27). CONCLUSION: Although most CT findings analyzed are observed in both diseases, each disease has its own several unique characteristics. Therefore, using a combination of CT findings may increase our ability to distinguish TBP from MPM.

Radiomics based on preoperative rectal cancer MRI to predict the metachronous liver metastasis.

PURPOSE: At present, there are few effective method to predict metachronous liver metastasis (MLM) from rectal cancer. We aim to investigate the efficacy of radiomics based on multiparametric MRI of first diagnosed rectal cancer in predicting MLM from rectal cancer. METHODS: From 301 consecutive histopathologically confirmed rectal cancer patients, 130 patients who have no distant metastasis detected at the time of diagnosis were enrolled and divided into MLM group (n = 49) and non-MLM group (n = 81) according to whether liver metastasis be detected later than 6 month after the first diagnosis of rectal cancer within 3 years' follow-up. The 130 patients were divided into a training set (n = 91) and a testing set (n = 39) at a ratio of 7:3 by stratified sampling using SPSS 24.0 software. The DWI model, HD T2WI model, and DWI + HD T2WI model were constructed respectively. The best performing model was selected and combined with the screened clinical features (including non-radiomics MRI features) to construct a fusion model. The testing set was used to evaluate the performance of the models, and the area under the curve (AUC) of receiver operating characteristics (ROC) was calculated for both the training set and the testing set. RESULTS: The AUC of the DWI + HD T2WI model in the testing set was higher than that of the DWI or the HD T2 model alone with statistically significance (P < 0.05). The screened clinical features were extramural vascular invasion (EMVI), T and N stages in MRI (mrT, mrN), and the distance from the lower edge of the tumor to the anal verge. The AUC of the fusion model in the testing set was 0.911. Decision curves and nomogram also showed that the fusion model had excellent clinical performance. CONCLUSION: The fusion model of primary rectal cancer MRI based radiomics combing clinical features can effectively predict MLM from rectal cancer, which may assist clinicians in formulating individualized monitoring and treatment plans.

Advanced MRI to assess hippocampal injury after incomplete cerebral ischemia-reperfusion in rats.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate advanced MRI findings in the bilateral hippocampus CA1 region of rats with hemorrhagic shock reperfusion (HSR) and their correlation with histopathological results. Additionally, this study aimed to identify effective MRI examination methods and detection indexes for assessing HSR. METHODS: Rats were randomized into the HSR and the Sham groups with 24 rats in each group. MRI examination included diffusion kurtosis imaging (DKI) and 3-dimensional arterial spin labeling (3D-ASL). Apoptosis and pyroptosis were evaluated directly from tissue. RESULTS: In the HSR group, cerebral blood flow (CBF) was significantly lower than that of the Sham group, while radial kurtosis (Kr), axial kurtosis (Ka), and mean kurtosis (MK) were all higher. In the HSR group, fractional anisotropy (FA) at 12 and 24 hours and radial diffusivity, axial diffusivity (Da), and mean diffusivity (MD) at 3 and 6 hours were lower than in the Sham group. MD and Da at 24 hours in the HSR group were significantly higher. The apoptosis rate and pyroptosis rate were also enhanced in the HSR group. CBF, FA, MK, Ka, and Kr values in the early stage were strongly correlated with apoptosis rate and pyroptosis rate. The metrics were obtained from DKI and 3D-ASL. CONCLUSIONS: Advanced MRI metrics from DKI and 3D-ASL, including CBF, FA, Ka, Kr, and MK values, are useful to evaluate abnormal blood perfusion and microstructural changes in the hippocampus CA1 area in the setting of incomplete cerebral ischemia-reperfusion in rats induced by HSR.

Abdominal surgery plus sevoflurane exposure induces abnormal emotional changes and cognitive dysfunction in aged rats.

BACKGROUND: Cognitive impairment, which includes perioperative psychological distress and cognitive dysfunction, can be determined by preoperative and post-operative neuropsychological tests. Several mechanisms have been proposed regarding the two-way communication between the immune system and the brain after surgery. We aimed to understand the mechanisms underlying perioperative neurocognitive disorders (PND) in elderly rats using an experimental abdominal surgery model. METHODS: 24-month-old SD rats were exposed to the abdominal surgery model (AEL) under 3% anesthesia. On day 15 and day 30 post-surgery, fractional anisotropy (FA) using diffusion kurtosis imaging (DKI) was measured. From day 25 to day 30 post-surgery, behavioral tests, including open field test (OFT), Morris water maze (MWM), novel object recognition (NOR), force swimming test (FST), and elevated plus maze (EPM), were performed. Then, the rats were euthanized to perform pathological analysis and western blot measurement. RESULTS: The rats exposed to AEL surgical treatment demonstrated significantly decreased time crossing the platform in the MWM, decreased recognition index in the NOR, reduced time in the open arm in the EPM, increased immobility time in the FST, and increased number of crossings in the OFT. Aged rats, after AEL exposure, further demonstrated decreased FA in the mPFC, nucleus accumbens (NAc), and hippocampus, together with reduced MAP2 intensity, attenuation of GAD65, VGlut2, CHAT, and phosphorylated P38MAPK expression, and increased reactive astrocytes and microglia. CONCLUSIONS: In this study, the aged rats exposed to abdominal surgery demonstrated both emotional changes and cognitive dysfunction, which may be associated with neuronal degeneration and reduced phosphorylated P38MAPK.

CAR-T cell therapy followed by allogenic hematopoietic stem cell transplantation yielded comparable outcome between Ph like ALL and other high-risk ALL.

It was previously believed that patients with Ph-like ALL had poorer prognosis compared with other B-ALL subgroups due to resistance to conventional chemotherapy and lack of targeted drugs. CAR-T therapy has been successfully applied in the treatment of relapsed and refractory B-ALL. Currently, there are few data on whether CAR-T therapy can alter the outcome of Ph-like ALL. Here we included 17 Ph-like, 23 Ph+ and 51 other B-ALL patients, who received autologous CAR T-cell therapy and subsequently allogenic stem cell transplantation. Patients in the Ph-like group and B-ALL-others group were younger that those in the Ph+ group (P=0.001). Ph-like and Ph+ ALL patients showed higher white blood cell counts at diagnosis (P=0.025). The percentage of patients with active disease before receiving CAR T-cells infusion was 64.7%, 39.1% and 62.7% in the Ph-like, Ph+ and B-ALL-others groups. The response rates to CAR-T therapy were 94.1% (16/17), 95.6% (22/23) and 98.0% (50/51) in the Ph-like, Ph+ and B-ALL-others groups. Measurable residual disease negative CR was achieved in 64.7% (11/17), 60.9% (14/23) and 54.9% (28/51) in the Ph-like, Ph+ and B-ALL-others groups, respectively. The estimated rates of 3-year overall survival (65.9%±16.5%, 59.7%±10.5% and 61.6%±7.3%, P=0.758) and 3-year relapse-free survival (59.8%±14.8%, 63.1%±10.5% and 56.3%±7.1%, P=0.764) were comparable among the Ph-like, Ph+ and B-ALL-others groups. Estimated 3-year cumulative relapse rate was 7.8%±0.6%, 23.4%±0.9% and 29.0%±0.4% (P=0.241). Our findings suggest that CART followed by allo-HSCT results in a comparable prognosis in Ph-like ALL and other high-risk B-ALL.Trial registration ClinicalTrials. gov, NCT03275493, Registered on September 7, 2017, prospectively registered and NCT03614858, Registered on August 3, 2018, prospectively registered.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

Correlation of CT Perfusion Parameters and Vascular Endothelial Growth Factor (VEGF) and Basic Fibroblast Growth Factor (BFGF) in Patients with Primary Liver Cancer.

Objective: To investigate the correlation of CT perfusion-related parameters with serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF) in patients with primary liver cancer. Methods: A total of 100 patients with primary liver cancer who were treated in our hospital from June 2019 to June 2021 were selected as the observation group, and 90 patients with benign liver lesions during the same period were selected as the control group. The CT perfusion-related parameters (perfusion volume and perfusion index) and serum VEGF and BFGF levels were compared between the two groups. Pearson correlation was used to analyze the correlation between CT perfusion-related parameters and serum VEGF and BFGF levels. Results: Compared to the control group, significantly higher HAP and lower HPP and TLP were observed in the observation group. The perfusion volume indexes of patients with different stages of liver cancer in the observation group were statistically different (P < 0.05). Compared to the control group, the observation group witnessed significantly higher HAPI and lower HPPI. There were statistically significant differences in the perfusion index of patients with different stages of primary liver cancer in the observation group (P < 0.05). The serum VEGF and BFGF levels in the observation group were significantly higher than those in the control group, and the serum VEGF and BFGF levels in patients with different stages of primary liver cancer in the observation group were statistically different (P < 0.05). Pearson correlation analysis showed that HAP and HAPI were positively correlated with VEGF and BFGF (r = 0.986, P ≤ 0.001; r = 0.983, P ≤ 0.001), and HPP, TLP, and HPPI were negatively correlated with VEGF and BFGF (r = -0.992, P ≤ 0.001; r = -0.993, P ≤ 0.001; r = -0.995, P ≤ 0.001). Conclusion: CT perfusion-related parameters and serum VEGF and BFGF levels in patients with primary liver cancer are abnormally expressed, and there is a strong correlation between the two, which might aid clinical diagnosis and treatment.

Investigation of the risk factors to predict cytokine release syndrome in relapsed or refractory B-cell acute lymphoblastic leukemia patients receiving IL-6 knocking down anti-CD19 chimeric antigen receptor T-cell therapy.

CD19 chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable results in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the cytokine release syndrome (CRS) was presented in most patients as common toxicity and severe CRS (sCRS) characterized by the sharp increase in interleukin-6 (IL-6) could be life-threatening. We conducted a phase II clinical trial of ssCAR-T-19 cells, anti-CD19 CAR-T cells with shRNA targeting IL-6, in 61 patients with r/r B-ALL. This trial was registered at www.clinicaltrials.gov as #NCT03275493. Fifty-two patients achieved CR while nine patients were considered NR. The median duration of response (DOR) and overall survival (OS) were not reached (>50 months). CRS developed in 81.97% of patients, including 54.10% with grades 1 to 2 (grade 1, 31.15%; grade 2, 22.95%) and 27.87% with grades 3 to 4 (grade 3, 26.23%; grade 4, 1.64%). sCRS occurs earlier than mild CRS (mCRS). A multivariable analysis of baseline characteristics identified high bone marrow disease burden and poor genetic risk before infusion as independent risk factors for sCRS. After infusion, patients with sCRS exhibited larger expansion of ssCAR-T-19 cells, higher peak levels of IL-6, IL-10, and IFN-γ, and suffered more severe hematological and non-hematological toxicities compared with those with mCRS.

Successful application of PD-1 knockdown CLL-1 CAR-T therapy in two AML patients with post-transplant relapse and failure of anti-CD38 CAR-T cell treatment.

Patients with relapsed/refractory acute myeloid leukemia (R/R AML) often show resistance to chemotherapy and have dismal outcomes. Therefore, it is urgent to develop new treatment strategies to address this problem. With tremendous achievement of chimeric antigen receptor T cells (CAR-T) therapy against B-cell malignancies, many efforts have been devoted to developing CAR-T therapy for R/R AML but with limited success, in part owing to a lack of specific targets. C-type lectin-like molecule-1 (CLL-1) is highly expressed on AML blasts with no expression on normal hematopoietic stem cells, which makes it an ideal target of immunotherapy for AML. Here, we report 2 R/R AML patients who relapsed after allogeneic stem cell transplantation and failed multiline salvage therapies including anti-CD38 CAR-T therapy, but were successfully treated with PD-1 silenced anti-CLL-1 CAR-T therapy. Both patients achieved molecular complete remission with incomplete hematologic recovery at 28 days of evaluation after CLL-1 CAR-T cell infusion. Cytokine release syndrome in cases 1 and 2 were grade 1 and 2, respectively. At the last follow-up, cases 1 and 2 had maintained continuous remission for 8 and 3 months, respectively. Our results demonstrated that CLL-1 CAR-T cells might be an effective and safe salvage therapy for AML patients with posttransplant relapse.

[Construction and Identification of Leukemia Cell Line Stably Expressing CD123 and CLL-1].

OBJECTIVE: To construct an acute myeloid leukemia cell line stably expressing CD123-CLL1 so as to provide an "in vitro" model for studying the role of CD123 and CLL-1 in leukemia and the treatment targeting CD123 and CLL-1. METHODS: The recombinant plasmid of lentivirus was constructed by synthesizing CD123 and CLL-1 sequences and PCR homologous recombination. The lentivirus vector was packaged by three-plasmid packaging system. After collecting the supernatant of lentivirus, the virus titer was determined by quantitative PCR. K562 leukemia cells were collected and transtected with virus supernatant. Leukemia cell line stably expressing the target gene were screened by purinomycin. The expression levels of CD123 and CLL-1 were detected by RT-PCR and flow cytometry. RESULTS: The lentiviral vector was successfully constructed, and identified by agarose gel electrophoresis and gene sequencing, then the virus titer of the supernatant was up to 5.81×108 after quantitative PCR assay. The K562 leukemia cell line obtained positive expression cells after being infected by puromycin. The high expression of CD123 and CLL-1 was confirmed by RT-PCR, while the significantly high expression of CD123 and CLL-1 was confirmed by flow cytometry. CONCLUSION: Lentiviral vector expressing CD123-CLL1 has been successfully constructed, and K562 leukemia cell line stably expressing CD123 and CLL-1 has been successfully obtained.

Secondary donor-derived humanized CD19-modified CAR-T cells induce remission in relapsed/refractory mixed phenotype acute leukemia after allogeneic hematopoietic stem cell transplantation: a case report.

BACKGROUND: Mixed phenotype acute leukemia (MPAL) is a rare leukemia and is regarded as a high-risk entity with a poor prognosis. Induction therapy of an acute lymphoblastic leukemia type or hybrid regimen and hematopoietic stem cell transplantation has been recommended for MPAL. However, the optimal therapies for relapsed or refractory MPAL remain unclear, especially for relapse after stem cell transplantation. Donor-derived chimeric antigen receptor T (CAR-T) cell therapy may be a promising therapeutic option for patients with MPAL who express target antigens and have relapsed after stem cell transplantation. However, recurrence remains a challenge, and reinfusion of CAR-T cells is not always effective. An infusion of secondary donor-derived humanized CD19-modified CAR-T cells may be effective in inducing remission. CASE PRESENTATION: We report a case of MPAL with CD19 expression. The patient was treated with acute lymphoblastic leukemia-like induction and consolidation therapies but remained positive for SET-NUP214 fusion gene transcript. He subsequently underwent a haploidentical stem cell transplantation but relapsed within 6 months. He then underwent donor-derived CD19-targeted CAR-T cell therapy and achieved a sustained, complete molecular remission. Unfortunately, he developed a CD19-positive relapse after 2 years. Donor-derived humanized CD19-directed CAR-T cells induced a second complete molecular remission without severe cytokine release syndrome or acute graft-versus-host disease. CONCLUSION: This case demonstrated the efficacy and safety of humanized donor-derived CD19-modified CAR-T cell infusion for treating the recurrence of MPAL previously exposed to murine-derived CD19-directed CAR-T cells.

Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia.

Few studies have described chimeric antigen receptor-modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial (ClinicalTrials.gov number, NCT03064269). Three patients with relapsed CNS B-ALL were enrolled, conditioned with the fludarabine and cyclophosphamide for lymphocyte depletion and infused with ssCART-19s for three consecutive days. Clinical symptoms and laboratory examinations were monitored. After ssCART-19 treatment, three patients' symptoms resolved almost entirely. Brain leukemic infiltration reduced significantly based on magnetic resonance imaging (MRI), and there were no leukemic blasts in cerebrospinal fluid (CSF), which was confirmed by cytological and molecular examinations. Additionally, increases in the levels of cytokines and immune cells were observed in the CSF of all patients. Only grade 1 cytokine release syndrome (CRS) manifesting as fever was noted in patients. In conclusion, CAR-Ts with shRNA-IL-6 gene knockdown migrated into the CNS, eradicated leukemic cells and elevated cytokines in CSF with mild, acceptable side effects.

Successful treatment of acute B lymphoblastic leukemia relapse in the skin and testicle by anti-CD19 CAR-T with IL-6 knocking down: a case report.

BACKGROUND: Extramedullary relapse is an important cause of treatment failure among patients with acute lymphoblastic leukemia (ALL). This type of relapse is commonly observed in the central nervous system, while it is rare in the testicles and skin. Chimeric antigen receptor-modified T cell (CAR-T) therapy targeting CD19 has shown to be a beneficial treatment approach for relapsed/refractory B cell acute lymphoblasticleukemia (r/r B-ALL). Yet, few studies have reported data regarding the treatment of extramedullary B-ALL relapse, especially both in skin and testicle, with CAR-T therapy. CASE PRESENTATION: Here we reported a single case of a patient with relapsed B-ALL in skin and testicle who was successfully treated by the shRNA-IL6-modified anti-CD19 CAR-T(ssCAR-T-19) therapy. A 29-year-old man with relapsed B-ALL in skin and testicle was enrolled in clinal trial involving the shRNA-IL6-modified anti-CD19 CAR-T(ssCAR-T-19) therapy (ClinicalTrials.gov number, NCT03919240). The patient had toxicity consistent with the grade 1 cytokine release syndrome. CONCLUSIONS: ssCART-19 therapy may be used to effectively eliminate infiltrating leukemia cells in the skin and testicle with mild toxicity, which could be a much safer approach to bridge allo-HSCT, thus further improving the patient's outcome. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03919240, Registered 18 April 2019, retrospectively registered.

Exogenous carbon monoxide protects against mitochondrial DNA­induced hippocampal pyroptosis in a model of hemorrhagic shock and resuscitation.

Carbon monoxide­releasing molecule­3 (CORM­3), which is an exogenous carbon monoxide (CO) compound, slowly releases CO under physiological conditions; this exerts neuroprotective effects against incomplete ischemia/reperfusion injury. The objective of the present study was to investigate whether the administration of CORM­3 protects against nucleotide­binding oligomerization domain­like receptor pyrin domain­3 (NLRP3) inflammasome formation and neuronal pyroptosis in the hippocampus following hemorrhagic shock and resuscitation (HSR). To establish this, an HSR model was created. Hemorrhagic shock was induced in adult male Sprague­Dawley rats under sevoflurane anesthesia by bleeding using a heparinized syringe to maintain a mean arterial pressure of 30±5 mmHg for 60 min. Resuscitation was performed by reperfusion of the blood and, if necessary, administering sterile saline to achieve the baseline arterial pressure. Following resuscitation, CORM­3 (4 mg/kg) was injected via the femoral vein. Neuronal pyroptosis in the hippocampus, mitochondrial morphology, mitochondrial DNA (mtDNA), brain magnetic resonance imaging, expression levels of NLRP3 and the interaction of pro­caspase­1 and apoptosis­associated speck­like protein containing a CARD domain (ASC) were examined 12 h after HSR; locomotor activity was assessed 7 days after HSR. Compared with HSR­treated rats, CORM­3 administration resulted in a lower level of neuronal pyroptosis in the hippocampus, improved mitochondrial morphology, a lower mtDNA level, steadier levels of metabolites, decreased expression levels of NLRP3 and pro­caspase­1 interacting with ASC and enhanced locomotor activity. In conclusion, treatment with CORM­3 ameliorated impairments of locomotor and exploratory activities in a rat model of HSR. The mechanism may be associated with the inhibition of mitochondrial DNA­induced pyroptosis via improvements in cell metabolism.

Diagnosis of intravenous leiomyomatosis extending to heart with emphasis on magnetic resonance imaging.

BACKGROUND: Intravenous leiomyomatosis is a rare neoplasm, and its cardiac extension is often overlooked or misdiagnosed. The purpose of this study was to explore the imaging features of intravenous leiomyomatosis with cardiac extension, especially the value of magnetic resonance imaging in differential diagnosis. METHODS: Between July 2005 and August 2008, 4 cases of intravenous leiomyomatosis with cardiac extension were resected in Cangzhou Central Hospital. Three cases had echocardiography performed, two had post contrast scans of CT performed, and two had MRI performed. Between July 2005 and May 2010, 25 cases of histopathologically proven other kinds of tumors involving the inferior vena cava and right atrium were compared for discussion of differential diagnosis. RESULTS: Intravenous leiomyomatosis with cardiac extension demonstrated a hyperechoic elongated mobile mass extending from the inferior vena cava to the right atrium with or without evidence of protruding into the right ventricle on echocardiography. The lesion was enhanced heterogeneously on post contrast scans of CT and was of relatively lower density compared to the enhanced blood in the inferior vena cava and right atrium, with common iliac vein and the ipsilateral internal iliac and ovarian veins involved in some cases. The untreated uterus myoma demonstrated enlargement of the uterus with heterogeneous contrast enhancement. On MRI, the lesion looked like a luffa vegetable sponge on FIESTA coronal images and a sieve pore on T2-weighted axial images. All four tumors were removed successfully, and follow up of one to four years revealed no recurrence. The 25 cases of histopathologically proven other kinds of tumors involving inferior vena cava and right atrium had their own imaging features different from those seen on intravenous leiomyomatosis with cardiac extension. With reference to their medical history, differential diagnosis can often be made. CONCLUSION: The imaging appearance of intravenous leiomyomatosis has some unique features, and the luffa vegetable sponge and sieve pore like appearance on MRI may be helpful for differential diagnosis.