Multiple rechallenges with anti-PD-1 immunotherapy in patients with checkpoint inhibitor-related pneumonitis: A report of two cases.

INTRODUCTION: With the expanding use of immune checkpoint inhibitors (ICIs) in patients with various types of cancers, many more patients are experiencing checkpoint inhibitor-related pneumonitis (CIP). After recovery from CIP, some patients are rechallenged with ICI therapy. The CIP will recur in a considerable proportion of rechallenged patients. When severe or recurrent CIP (rCIP) occurs, ICI therapy is usually terminated, resulting to treatment failure and tumour progression. The feasibility of multiple rechallenges with immunotherapy in patients with rCIP is unknow. CASE PRESENTATION: Two patients with refractory classical Hodgkin lymphoma (cHL) were treated with anti-programmed cell death protein 1 (PD-1) immunotherapy. The lymphoma responded well to the ICI therapy, but both patients experienced CIP. The immunotherapy was suspended and steroid was introduced to treated the CIP. When the CIP resolved, however, the lymphoma progressed. MANAGEMENT AND OUTCOME: The patients were rechallenged with anti-PD-1 immunotherapy in the absence of alternative treatment options. The lymphoma responded again, but the CIP recurred. The immunotherapy was suspended again and steroid was reintroduced. These episodes repeated multiple times. At the time of submission of this manuscript, the tumour in both patients has been controlled for more than 4 years, and the immunotherapy is still continuing. CONCLUSION: Multiple rechallenges with immunotherapy is feasible in selected patients with rCIP.

An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL.

Diffuse large B-cell lymphomas (DLBCLs) contain 2 major molecular subtypes; namely, the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) DLBCLs. It is well documented that ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and the rituximab (R)-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL-specific resistance mechanism that is directed toward 1 of the CHOP components and is inadequately addressed by rituximab. Here, we report that the main cytotoxic ingredient in CHOP, doxorubicin (Dox), has subtype-specific mechanisms of cytotoxicity in DLBCLs resulting from differences in the subcellular distribution pattern. Specifically, in cell line models of ABC-DLBCL, Dox is often enriched in the cytoplasm away from the nuclear DNA. As a result, Dox-induced cytotoxicity in ABC-DLBCLs is often dependent on oxidative stress, rather than DNA damage response. These findings are corroborated by gene signature analysis, which demonstrates that basal oxidative stress status predicts treatment outcome among patients with ABC-DLBCL, but not patients with GCB-DLBCL. In terms of redox-related resistance mechanism, our results suggest that STAT3 confers Dox resistance in ABC-DLBCLs by reinforcing an antioxidant program featuring upregulation of the SOD2 gene. Furthermore, a small-molecule STAT3 inhibitor synergizes with CHOP to trigger oxidative stress and kill ABC-DLBCL cells in preclinical models. These results provide a mechanistic basis for development of novel therapies that target either STAT3 or redox homeostasis to improve treatment outcomes for ABC-DLBCLs.

MMP-2 together with MMP-9 overexpression correlated with lymph node metastasis and poor prognosis in early gastric carcinoma.

The aim of this study was to correlate matrix metalloproteinase-2 and matrix metalloproteinase-9 expression with the clinicopathological features and outcome of patients with early gastric cancer and to clinically elucidate more information on the role of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein overexpression with regard to lymph node metastasis of early gastric cancer. The levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein expression were assessed by immunohistochemistry. An association was observed between matrix metalloproteinase-2, matrix metalloproteinase-9, and matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression and clinicopathological factors, such as ulceration and lymph node metastasis. Furthermore, matrix metalloproteinase-9 and matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression both were strongly correlated with histological grade. In addition, matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression correlated with deep invasion. Multivariate Cox regression analysis revealed that matrix metalloproteinase-2 and matrix metalloproteinase-9 expression were both independent factors of overall survival in patients with early gastric cancer. In novelty, we found that matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression was an independent indicator of lymph node metastasis in early gastric cancer which will be helpful in clinic to select the appropriate treatment of these patients.

Extranodal involvement in young patients with diffuse large B-cell lymphoma: distribution, prognostic value and treatment options.

OBJECTIVE: Extranodal involvement represents a peculiar presentation of diffuse large B-cell lymphoma (DLBCL). Previous studies have suggested that older patients are more prone to extranodal involvement. This study retrospectively addressed the distribution, prognostic value and treatment options of extranodal involvement in young patients with DLBCL. METHODS: A total of 329 patients were enrolled according to the inclusion requirements. The effects of gender, extranodal involvement, age-adjusted international prognostic index (aaIPI), rituximab infusion and radiotherapy on patient outcomes were evaluated. RESULTS: Among these patients, 59% presented extranodal involvement in 16 anatomic sites. More than one instance was linked to many poorer clinical characteristics and poorer survival compared with either nodal disease or one instance. In patients with one extranodal lesion, multivariate analysis revealed that the site of extranodal involvement, but not the aaIPI or rituximab infusion, was independently related to the outcome, and radiotherapy had a negative influence on survival. CONCLUSIONS: Extranodal involvement is common in younger patients and exhibits a ubiquitous distribution. The site of extranodal involvement is of strong prognostic significance. Radiotherapy for extranodal lesions does not improve patient outcomes.

Variant arterial supply to the lesser curvature of the stomach and duodenum from double inferior phrenic arteries.

A rare case of the left accessory inferior phrenic artery (IPA) supplying the lesser curvature of the stomach and the right accessory IPA supplying the duodenum was observed during interventional radiography. To our knowledge, variation arteries supplying the stomach and duodenum have never been reported in English literature; herein, we report the first case of variant arterial supply to the lesser curvature of the stomach and duodenum from double IPAs.

[Efficacy and safety of fixed dose rate gemcitabine infusion in combination with docetaxel in patients with relapsed/refractory soft tissue sarcoma].

OBJECTIVE: To evaluate the efficacy and safety of fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel in patients with relapsed/refractory soft tissue sarcoma. METHODS: Clinicopathological data of 28 patients with relapsed/refractory soft tissue sarcoma treated in our hospital from April 2008 to August 2013 were reviewed in this study. The patients received 900 mg/m² gemcitabine with a FDR infusion (10 mg/m²/min) in a total dose of 900 mg/m² on days 1 and 8, and 75 mg/m² docetaxel intravenously over 60 min on day 8 of a 21-day cycle. When irradiation was conducted before drug therapy, the dose of gemcitabine was reduced to 675 mg/m² on days 1 and 8. The clinicopathological characteristics, short-term response, long-term survival status and toxicity were analyzed retrospectively. RESULTS: The 28 patients received a total of 118 cycles of therapy (range 1-8 cycles, median 4 cycles per patient). No patient achieved complete response (CR), 4 partial responses (PR) and 11 stable diseases (SD), with an overall response rate (ORR) of 14.3% and clinical benefit rate (CBR) of 53.6%. The median progression-free survival (PFS) was 3.2 months and the median overall survival (OS) was 8.5 months. PFS and OS were correlated with the response to this treatment regimen (P < 0.0001). Patients with clinical benefit had significantly better PFS and OS than the patients with progressive disease (P < 0.05 for all). The ORR, CBR, PFS and OS were better in patients with leiomyosarcoma than in patients with other histological subtypes in this study, but the differences were not significant (P > 0.05 for all). Grade 3-4 neutropenia, anemia and thrombocytopenia were 50.0%, 17.9% and 14.3%, respectively. Only one patient (3.6%) had febrile neutropenia. Grade 3 non-hematologic toxicities were nausea/vomiting (3.6%) and mucositis (3.6%). No grade 4 non-hematologic toxicities were observed. Almost all non-hematologic toxicities were grade 1-2 and manageable. CONCLUSIONS: The fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel is an effective treatment regimen for patients with relapsed/refractory soft tissue sarcoma, and with tolerable adverse reactions.

ED50 and ED95 of Remimazolam Tosilate Combined with Different Doses of Fentanyl in Elderly Patients for Painless Gastroscopy.

Background: The novel short-acting benzodiazepine drug, remimazolam tosilate, has been employed for sedation during endoscopic procedures. The optimal loading dosage of remimazolam tosilate in gastroscopy for elderly patients when co-administered with fentanyl remains unclear. Therefore, the primary objective of our research was to ascertain the median effective dose (ED50) and the 95% effective dose (ED95) of remimazolam tosilate in combination with various fentanyl dosages for elderly patients undergoing painless gastroscopy. Methods: Seventy-five patients aged ≥65 years and American Society of Anesthesiologists (ASA) class I-III were recruited to undergo elective painless gastroscopy. All patients were randomized assigned to group F1, group F2, and group F3, and were injected intravenously with different doses of fentanyl (0.5 ug/kg, 1 ug/kg, and 1.5 ug/kg) 3 minutes prior to the administration of remimazolam tosilate, respectively. The initial preset dose of remimazolam tosilate was 0.3 mg/kg in group F1, 0.2 mg/kg in group F2, 0.15 mg/kg in group F3. The dose gradient was 0.02 mg/kg per group according to the up-and-down sequential method. Probibt regression model was employed to determine the ED50 and ED95 of remimazolam tosilate. Results: The ED50 of remimazolam tosilate in group F3 was lower than that in group F1 and F2 (0.095 [0.088-0.108] mg/kg vs 0.162 [0.153-0.171] mg/kg; 0.258 [0.249-0.266] mg/kg, p < 0.05). The ED95 of remimazolam tosilate was 0.272 mg/kg (95% CI: 0.264-0.295 mg/kg) in group F1, 0.175 mg/kg (95% CI: 0.167-0.200 mg/kg) in group F2 and 0.109 mg/kg (95% CI: 0.101-0.135 mg/kg) in group F3. The total dosage of remimazolam tosilate decreased gradually with the increasing of fentanyl (p < 0.001). The frequency of injection pain was higher in group F1 compared to groups F2 and F3 (p < 0.05). The patients in group F3 had a lower incidence of hypotension than in groups F1 and F2 (p < 0.05). There was no respiratory depression, intraoperative consciousness, dizziness or delirium in the three groups. Conclusion: The concurrent use of fentanyl reduces the dosage of remimazolam tosilate required for sedative gastroscopy in elderly patients in a dose-dependent manner. Moreover, 1.5 ug/kg fentanyl combined with remimazolam tosilate may reduce the incidence of hypotension and injection pain. These findings should be confirmed in a large-scale study.

Severe inflammation in C57/BL6 mice leads to prolonged cognitive impairment by initiating the IL-1ß/TRPM2 pathway.

BACKGROUND: Sepsis could lead to chronic cognitive impairment by unclear molecular mechanisms. Transient receptor potential melastatin-2 (TRPM2) is essential against immunity-related activities and inflammation. Our study attempted to decipher the relationship between cognitive impairment caused by severe inflammation and TRPM2 expression levels. METHODS: Severe inflammation was induced by intraperitoneally injecting C57/BL6 mice with a high dosage (5 mg kg-1) of Lipopolysaccharide (LPS). Fear conditioning and a Morris water maze test were performed to examine the cognitive abilities of the mice. Moreover, the signaling and expression of pro-inflammatory cytokines and TRPM2 were measured using Western blotting and Reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry and immunofluorescence staining helped to determine the astrocyte apoptosis rate. RESULTS: Severe inflammation can lead to long-term cognitive impairment in C57/BL6 mice. The interleukin-1 beta (IL-1ß) levels intra-hippocampus were significantly elevated until P14 post-LPS introduction. At both P7 and P14, there is an up-regulation of TRPM2 expression within hippocampus. Administration of recombinant IL-1ß to astrocytes results in a significant up-regulation of TRPM2 expression. IL-1ß or TRPM2 level knockdown helped counter the cognitive impairment caused by significant inflammation. CONCLUSIONS: A continuous increase in IL-1ß levels within the hippocampus can lead to cognitive impairment by enhancing TRPM2 levels caused by severe inflammation.

[Inhibitory effects of celecoxib combined with capecitabine on H22 hepatoma mice and its mechanism].

OBJECTIVE: To evaluate the inhibitory effect and its mechanism of celecoxib combined with capecitabine on the growth of implanted H22 hepatoma in mice. METHODS: Tumor model was established by hypodermical injection of H22 cells in BALB/c nude mice. Forty mice were equally randomly divided into 4 groups: control group, celecoxib group (receiving 100 mg/kg celecoxib), capecitabine group (receiving 755 mg/kg capecitabine), and combined treatment group (receiving 100 mg/kg of celecoxib and 755 mg/kg of capecitabine). From the third post-implantation day, each mouse was given relevant drug (or normal saline) by oral gavage. Fifteen days later, all mice were sacrificed and the tumor tissues were measured. The mRNA and protein levels of nuclear factor kappa-B (NF-ΚB) p65 and cyclooxygenase (COX)-2 in tumor tissues were detected by the quantitative polymerase chain reaction (qPCR)and Western blotting, respectively. RESULTS: The tumor inhibition rate was 30.2% in celecoxib group and 49.9% in capecitabine group, which was significantly lower than that (75.4%) in the combined treatment group (P<0.01,P<0.05, respectively). qPCR showed a significant decrease of the mRNA expression of COX-2 in celecoxib group and combined treatment group when compared with control group (P<0.001), but no significant change in NF-ΚB p65.Capecitabine had no significant effects on the mRNA expression of COX-2 and NF-ΚB p65. Western blotting showed that celecoxib and combined treatment significantly inhibited the protein expression of COX-2 and NF-ΚB p65(P<0.05), but not capecitabine. CONCLUSION: Celecoxib can enhance the antitumor effect of capecitabine by inhibiting the expressions of COX-2 and NF-ΚB p65 in mice bearing H22 implanted tumor.

[Study on antagonistic effect of liangxue huayu recipe on endoplasmic reticulum stress-induced L02 hepatocyte apoptosis and its mechanism].

Endoplasmic reticulum stress (ERS) is a new pathway inducing cell apoptosis that has been discovered in recent years. This study focused on the protective effect of Liangxue Huayu recipe (LHR) on tumor necrosis factor-alpha (TNF-alpha) and D-GalN-induced hepatocyte apoptosis. It found that TNF-alpha and D-GalN could obviously inhibit hepatocyte proliferation, induce cell apoptosis, and significantly increase free calcium ions in cytoplasms, as well as protein expressions of ERS apoptosis-related signal molecules phosphorylated PERK, phosphorylated elF2alpha, cleaved Caspase-12, GRP78 and CHOP. After the administration of LHR of different concentrations, compared with the TNF-alpha/GalN injury group, LHR could significantly alleviated L02 hepatocyte proliferation, decreased cell apoptosis, inhibited growth of intracytoplasmic free calcium content, and gradually reduced the protein expressions of phosphorylated PERK, phosphorylated elF2alpha, cleaved Caspase-12, GRP78 and CHOP. These findings indicated that LHR has the inhibitory effect on TNF-alpha and D-GalN-induced hepatocyte apoptosis. Its mechanism may be related to down-regulation of ERS apoptosis-related signal molecules phosphorylated PERK, phosphorylated elF2alpha, cleaved Caspase-12, GRP78 and CHOP that maintain calcium homeostasis in endoplasmic reticulum.

Treatment of extranodal NK/T-cell lymphoma: From past to future.

Extranodal NK/T-cell lymphoma (ENKTCL) is the most common subtype of T/NK-cell lymphoma in Asia and Latin America, but very rare in North American and Europe. Patient survival has improved significantly over the past two decades. However, standard treatment has not yet been established, although dozens of prospective trials have been conducted. To help understand how the treatment of ENKTCL has evolved in the past and what trends lie ahead, we have comprehensively reviewed the treatment of this aggressive malignancy, with a particular focus on neglected or unanswered issues, such as the optimal staging method, the best partner of asparaginase (Asp), the individualized administration of Asp, the preferred sequence of CT and RT and so on. Overall, the 5-year overall survival (OS) of patients with Ann Arbor stage I/II disease increased from < 50% in the early 20th century to > 80% in recent years, and the median OS of patients with Ann Arbor stage III/IV disease increased from < 1 year to more than 3 years. The improvement in patient survival is largely attributable to advances in radiation technology and the introduction of Asp and anti-PD-1/PD-L1 immunotherapy into practice. Radiotherapy is essential for patients with early-stage disease, while Asp-based chemotherapy (CT) and PD-1/PD-L1 inhibitors significantly improved the prognosis of patients with advanced-stage disease. ENKTCL management is trending toward simpler regimens, less toxicity, and higher efficacy. Novel drugs, such as manufactured T cells, monoclonal antibodies, and small molecule inhibitors, are being intensively investigated. Based on the fact that ENKTCL is highly resistant to cytotoxic drugs except Asp, and aggressive CT leads to higher toxicity rather than better outcomes, we recommend it is unnecessary to expend additional resources to compare different combinations of Asp with cytotoxic agents. Instead, more efforts should be made to optimize the use of Asp and immunotherapy to maximize efficacy and minimize toxicity, explore ways to overcome resistance to Asp and immunotherapy, identify novel treatment targets, and define subpopulations who may benefit more from specific treatments.

A retrospective study of autologous hematopoietic stem cell transplantation for peripheral T-cell lymphoma: pre-transplant patients with partial remission benefit from post-transplant maintenance therapy.

Background: Whether autologous hematopoietic stem cell transplantation (ASCT) improves the survival of patients with peripheral T-cell lymphoma (PTCL) remains controversial. Some studies have demonstrated that the efficacy of ASCT is superior in patients with complete remission (CR), whereas patients with partial remission (PR) remain vulnerable to relapse after ASCT, resulting in decreased survival rates. Maintenance therapy after chemotherapy may reduce the relapse rate of PTCL and improve survival; however, the role of maintenance therapy after ASCT in PTCL remains unclear. In this study, we aimed to analyze the efficacy of ASCT and post-transplant maintenance therapy in PTCL. Methods: We retrospectively analyzed the clinical data of 69 patients with PTCL who underwent ASCT at our center between November 2001 and November 2021. According to the patients' intention, thirty patients received post-transplant maintenance treatment, whereas 39 did not. The overall survival (OS) and progression-free survival (PFS) between the groups were compared using the log-rank test. Results: At a median follow-up of 36 months, the entire cohort's 3-year OS and PFS were 67.8% and 53.0%, respectively. The 3-year OS and PFS of patients with CR1, CR2, and PR were 85.3% and 65.4%, 80.0% and 60.0%, and 38.4% and 32.0%, respectively (OS: P=0.001; PFS: P=0.003). The relapse rates between the groups with or without maintenance therapy were 26.7% vs. 52.2%, the 3-year OS was 86.0% vs. 54.2% (P=0.004), and the 3-year PFS was 73.3% vs. 37.5% (P=0.004). Further analysis revealed that the efficacy of maintenance therapy was not significant in patients with CR1 and CR2, whereas patients with PR benefited from maintenance therapy. The relapse rate of patients with PR who received or did not receive maintenance therapy was 33.3% vs. 78.7%, 3-year OS was 66.7% vs. 21.9% (P=0.007), and 3-year PFS was 66.7% vs. 12.5% (P=0.004). Conclusions: Patients with CR in PTCL benefit from ASCT, and post-transplant maintenance therapy reduces the relapse rate and significantly improves OS and PFS in patients with PR.

Low incidence of hepatitis B virus reactivation in patients with hematological malignancies receiving novel anticancer drugs: A report from a high epidemic area and literature review.

BACKGROUND: More and more novel anticancer drugs have been approved for patients with hematological malignancies in recent years, but HBV reactivation (HBV-R) data in this population is very scarce. This study aimed to evaluated HBV-R risk in patients with hematological malignancies receiving novel anticancer drugs. METHODS: HBV markers and serum HBV DNA levels of patients with hematological malignancies receiving novel anticancer drugs in a tertiary cancer hospital were retrospectively collected. HBV-R risk in the whole cohort and subgroups was described. The relevant literature was reviewed to make a pooled analysis. RESULTS: Of 845 patients receiving novel anticancer drugs, 258 (30.5%) were considered at risk for HBV-R. The median duration of exposure to novel drugs was 5.6 (0.1-67.6) months. The incidence of HBV-R was 2.1% in patients with past HBV infection without prophylactic antiviral treatment (PAT) and 1.2% in all patients at risk of HBV-R. In a pooled analysis of 11 studies with 464 patients, the incidence of HBV-R was 2.4% (95% CI: 1.3-4.2) in all at-risk patients receiving novel anticancer drugs and 0.6% (95% CI: 0.03-3.5) in patients with anticancer drugs plus PAT. The incidence of death due to HBV-R was 0.4% (95% CI: 0.1-1.6) in all at-risk patients and 18.2% (95% CI: 3.2-47.7) in patients with HBV-R. CONCLUSION: Most episodes of HBV-R are preventable, and most cases with HBV-R are manageable. We recommend that novel anticancer drugs should not be intentionally avoided when treating cancer patients with HBV infection.

Treatment of upper eyelid third-degree burns by dispersed implantation of very small autologous columnar skin grafts: A pilot study of a new method.

OBJECTIVE: This retrospective study compared the effectiveness of dispersed implantation of very small autologous columnar skin (SCS) grafts and full-thickness skin grafts (FTSGs) for treating upper eyelid third-degree burns. METHODS: Fourteen patients and 26 eyes with granulation tissue formed by third-degree upper eyelid burns were enrolled in the study from August 2017 to June 2020. The experimental group of 6 patients with 11 eyes was treated with SCS grafts. The control group of 8 patients with 15 eyes was treated with FTSGs. The survival rate of the grafts, healing time, SCS diameter, upper eyelid movement distance (ULMD), visual analogue scale (VAS) score for patient satisfaction, and Vancouver Scar Scale (VSS) score were evaluated. RESULTS: The difference in the survival rate between the two groups was not statistically significant (P = 0.06). The ULMD and VAS scores in the experimental group were higher than those in the control group (P < 0.05). The healing time was longer in the experimental group than in the control group (P < 0.05). The VSS scores of the donor site and the skin grafting site in the experimental group were lower than those in the control group (P < 0.05). CONCLUSION: Unlike classical skin grafts, SCS implantation surgery can restore the appearance of the upper eyelid, and there is no obvious scar at the donor site. This can be a viable alternative to traditional FTSGs with potential benefits.

Influence mechanism of structure on shear mechanical deformation characteristics of loess-steel interface.

The mechanical properties of loess-steel interface are of great significance for understanding the residual strength and deformation of loess. However, the undisturbed loess has significant structural properties, while the remolded loess has weak structural properties. There are few reports on the mechanical properties of loess-steel interface from the structural point of view. This paper focused on the ring shear test between undisturbed loess as well as its remolded loess and steel interface under the same physical mechanics and test conditions (water content, shear rate and vertical pressure), and explored the influence mechanism of structure on the mechanical deformation characteristics of steel-loess interface. The results show that the shear rate has little effect on the residual strength of the undisturbed and remolded loess-steel interface. However, the water content has a significant influence on the residual strength of the loess-steel interface, moreover, the residual internal friction angle is the dominant factor supporting the residual strength of the loess-steel interface. In general, the residual strength of the undisturbed loess-steel interface is greater than that of the remolded loess specimen (for example, the maximum percentage of residual strength difference between undisturbed and remolded loess specimens under the same moisture content is 6.8%), which is because that compared with the mosaic arrangement structure of the remolded loess, the overhead arrangement structure of the undisturbed loess skeleton particles makes the loess particles on the loess-steel interface re-adjust the arrangement direction earlier and reach a stable speed relatively faster. The loess particles with angular angles in the undisturbed loess make the residual internal friction between the particles greater than the smoother particles of the remolded loess (for example, the maximum percentage of residual cohesion difference between undisturbed and remolded loess specimens under the same vertical pressure is 4.29%), and the intact cement between undisturbed loess particles brings stronger cohesion than the remolded loess particles with destroyed cement (for example, the maximum difference percentage of residual cohesion between undisturbed and remolded soil specimens under the same vertical pressure is 33.80%). The test results provide experimental basis for further revealing the influence mechanism of structure, and parameter basis for similar engineering construction.

A retrospective cohort study of polatuzumab vedotin combined with immunochemotherapy in Chinese patients with relapse/refractory diffuse large B cell lymphoma.

Background: There are no standard therapies for patients with relapse/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for transplantation. Recently, polatuzumab vedotin (pola) combined with rituximab and bendamustine (pola-BR) has been validated in clinical trials. However, pola is not approved in China and clinical data in Chinese population is still lacking. This study is intended to preliminarily evaluate the clinical effectiveness of this regimen in China. Methods: This study retrospectively evaluated the efficacy and tolerability of pola-BR regimen in Chinese R/R DLBCL patients treated in a compassionate use program (CUP; pola CUP) after failing ≥2 prior regimens. Patients participated in CUP at 4 Chinese centers from December 2019 to July 2020 were enrolled. The outcomes were the overall response rate (ORR), complete response (CR) rate, and progression-free survival (PFS). Adverse events (AEs) were collected. Results: A total of 28 patients enrolled in the pola CUP were included. At data analysis cut-off (30 September 2020), the best overall response (BOR) rate was 71.4%, and a CR rate of 25.0% was obtained. The estimated median PFS of all patients was 200 [95% confidence interval (CI): 97 to not evaluable (NE)] days. The most common AEs were thrombocytopenia (32.1%), neutropenia (28.6%), and fever (14.3%). High-grade (grade ≥2) peripheral neuropathy (PN) was not observed. Conclusions: These preliminary data suggested that the pola-BR regimen has promising efficacy and tolerable safety in Chinese transplantation ineligible R/R DLBCL patients. Hence, pola-BR may be an optional regimen. Considering the limited sample size and short follow-up, larger sample and long-term survival outcome studies are warranted.

Microstructure of unsaturated loess and its influence on strength characteristics.

Previous studies have shown that structure has a significant influence on the mechanical deformation of unsaturated loess, but there is little published information focused on the influence mechanism of microstructure and mesostructure on the mechanical properties of loess. In this paper, the unsaturated undisturbed loess and its remolded loess under the same physical condition were taken as the research objects. The unsaturated triaxial shear tests with constant suction and net confining pressure were carried out, and the microstructure differences between the two are compared by using SEM and CT scanning to reveal the influence of structure on strength characteristics. The test results show that the cohesion and internal friction angle of undisturbed loess are greater than those of remolded loess. The angle of undisturbed soil particles is obvious, and the particles are bracket contact with good cementation. The remolded loess particles are close to round shape, and the particles are inlaid contact with destroyed cementation. The average radius of undisturbed soil is higher than that of remolded soil, indicating that there are bracket pores in undisturbed soil, but the bracket structure and macropores are deformed during shear deformation, and good structural and cementation ensure the strength of loess specimens.

MiRNA-363-3p/DUSP10/JNK axis mediates chemoresistance by enhancing DNA damage repair in diffuse large B-cell lymphoma.

Anthracycline-based chemotherapy resistance represents a major challenge in diffuse large B-cell lymphoma (DLBCL). MiRNA and gene expression profiles (n = 47) were determined to uncover potential chemoresistance mechanisms and therapeutic approaches. An independent correlation between high expression of miRNA-363-3p and chemoresistance was observed and validated in a larger cohort (n = 106). MiRNA-363-3p was shown to reduce doxorubicin-induced apoptosis and tumor shrinkage in in vitro and in vivo experiments by ectopic expression and CRISPR/Cas9-mediated knockout in DLBCL cell lines. DNA methylation was found to participate in transcriptional regulation of miRNA-363-3p. Further investigation revealed that dual specificity phosphatase 10 (DUSP10) is a target of miRNA-363-3p and its suppression promotes the phosphorylation of c-Jun N-terminal kinase (JNK). The miRNA-363-3p/DUSP10/JNK axis was predominantly associated with negative regulation of homologous recombination (HR) and DNA repair pathways. Ectopic expression of miRNA-363-3p more effectively repaired doxorubicin-induced double-strand break (DSB) while enhancing non-homologous end joining repair and reducing HR repair. Targeting JNK and poly (ADP-ribose) polymerase 1 significantly inhibited doxorubicin-induced DSB repair, increased doxorubicin-induced cell apoptosis and tumor shrinkage, and improved the survival of tumor-bearing mice. In conclusion, the miRNA-363-3p/DUSP10/JNK axis is a novel chemoresistance mechanism in DLBCL that may be reversed by targeted therapy.

Plasma EBV-DNA and peripheral blood mononuclear cell EBV-DNA have disparate clinical relevance in patients with extranodal NK/T-cell lymphoma.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related hematological malignancy. The presence of EBV-DNA in peripheral blood is a widely used ENKTCL tumor marker. However, there is no consensus on the preferred blood specimen type for EBV testing. Furthermore, discordance between EBV-based and imaging-based disease assessments is common, and how to interpret this discordance is important. METHOD: We retrospectively analyzed the data of ENKTCL patients in the Affiliated Cancer Hospital of Zhengzhou university and Sun Yat-sen University Cancer Center. All EBV-DNA and imaging-based disease assessment data were collected at diagnosis, during treatment, at the end of treatment, and during follow-up. We compared matched plasma EBV-DNA and peripheral blood mononuclear cell (PBMC) EBV-DNA and matched EBV-based and imaging-based assessments to uncover their clinical relevance. RESULT: A total of 450 patients with adequate data were included, of whom 278 had plasma EBV-DNA data, 250 had PBMC EBV-DNA data, and 78 had matched plasma and PBMC EBV-DNA data. No significant correlations were found between PBMC and plasma EBV-DNA and between PBMC EBV-DNA and imaging-based assessment, but patients with positive PBMC EBV-DNA at diagnosis or intermittently/persistently positive PBMC EBV-DNA during follow-up had poorer survival. In contrast, plasma EBV-DNA strongly correlated with lymphoma status. Detectable pre- and post-treatment plasma EBV-DNA was associated with significantly worse survival. Patients with early-stage disease who had detectable plasma EBV-DNA at the end of treatment shared similar survival to those with advanced-stage disease, even if their imaging-based assessments were negative. For disease relapse monitoring, 78 (55.7%) episodes of relapse were detected by both imaging and plasma EBV-DNA; 58 (41.4%) detected by plasma EBV-DNA earlier than imaging, with a median time of 9.3 (0.3 - 37.8) months; and only 4 (2.9%) detected by plasma EBV-DNA later than imaging. The sensitivities of plasma EBV-DNA, PET/CT, and CT/MRI were 97.1%, 76.8%, and 45.1%, respectively, and their specificities were 91.7%, 84.2%, and 96.7%, respectively. Analysis of EBV kinetic patterns in EBV+/imaging- episodes revealed that relapse occurred only in patients with intermittently/persistently positive plasma EBV-DNA. Persistent plasma EBV+ was also seen in patients after autologous hematopoietic stem cell transplantation. Occasional EBV+ was not associated with relapse. CONCLUSION: Plasma and PBMC EBV-DNA have different clinical relevance in ENKTCL patients. PBMC EBV-DNA does not correlate with imaging-based disease assessment. PBMC or even whole blood should not be used for response evaluation and relapse monitoring. However, PBMC EBV-DNA still has prognostic value. Plasma EBV-DNA is strongly related to tumor status and is not only a prognosticator at diagnosis and end of treatment, but also a sensitive marker in relapse monitoring compared to PET/CT and CT/MRI. The specificity of plasma EBV-DNA is relatively low, but when EBV-DNA kinetic patterns are considered, it can identify at-risk patients.

Primary Testicular Lymphoma with Central Nervous System Relapse Was Successfully Treated by a Chemo-Free Regimen: A Case Report and Literature Review.

Primary testicular lymphoma (PTL) is a rare malignancy of testis. Although the multimodality treatment (including orchiectomy, systemic chemotherapy, scrotal radiotherapy, and preventive central nervous system (CNS)-targeted treatment) is widely used to treat PTL, recurrence, especially CNS recurrence, occurred frequently. Patients with relapsed PTL have a dismal prognosis and limited treatment options. In this report, we described the case of a 63-year-old man with early-stage PTL. The patient received the multimodality treatment, but CNS relapse occurred 3 months following the front-line therapy. We gave him a combined chemo-free regimen treatment, including rituximab, ibrutinib, and lenalidomide (RIL), based on the tumor's gene mutation profile and the patient's preference. A complete response was achieved after the first cycle of treatment. Whole-brain radiotherapy was delivered as consolidative treatment following three more cycles of RIL. Thereafter, ibrutinib and lenalidomide continued as maintenance treatment. As of the submission of this manuscript, the response has lasted for more than 16 months. Based on the case, we believe chemo-free regimen RIL might be a favorable approach for PTL patients with CNS relapse, especially those frail elderly patients, when alternative treatments are not available.