Gastrointestinal Reactions Research Articles

Therapeutic Potential of Natural Resources Against Endometriosis: Current Advances and Future Perspectives.

Endometriosis (EMS) is defined as the appearance, growth, infiltration, and repeated bleeding of endometrioid tissue (glands and stroma) outside the uterus cavity, which can form nodules and masses. Endometriosis is a chronic inflammatory estrogen-dependent disease and occurs in women of reproductive age. This disorder may significantly affect the quality of life of patients. The pathogenic processes involved in the development and maintenance of endometriosis remain unclear. Current treatment options for endometriosis mainly include drug therapy and surgery. Drug therapy mainly ties to the use of non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal drugs. However, these drugs may produce adverse effects when used for long-term treatment of endometriosis, such as nausea, vomiting gastrointestinal reactions, abnormal liver and kidney function, gastric ulcers, and thrombosis. Although endometriosis lesions can be surgically removed, the disease has a high recurrence rate after surgical resection, with a recurrence rate of 21.5% within 2 years and 40% to 50% within 5 years. Thus, there is an urgent need to develop alternative or additional therapies for the treatment of endometriosis. In this review, we give a systematic summary of therapeutic multiple component prescriptions (including traditional Chinese medicine and so on), bioactive crude extracts of plants/herbs and purified compounds and their newly found mechanisms reported in literature in recent years against endometriosis.

Clinical efficacy and adverse reactions analysis of PD-1/PD-L1 inhibitors in advanced esophageal squamous cell carcinoma.

The aim of this study was to investigate the clinical efficacy and associated adverse reactions of Programmed Death Receptor-1 (PD-1)/PD-L1 inhibitors in the management of patients with advanced esophageal squamous cell carcinoma (ESCC). In this retrospective study, 54 patients with advanced ESCC treated with PD-1/PD-L1 inhibitors in our hospital from January 2021 to January 2023 were identified as the research subjects. Using propensity score matching at a 1:1 ratio, patients only receiving chemotherapy were recruited as controls. The clinical effectiveness of PD-1/PD-L1 was evaluated by comparing the objective response rate (ORR) and disease control rate (DCR). Progression-free survival (PFS) and overall survival (OS) were analyzed for treatment outcome assessments. Adverse events (AEs) between the two groups were recorded and compared. Patients treated with PD-1/PD-L1 inhibitors had a higher rate of ORR (33.33%) and disease control (85.19%), compared to controls with an objective response rate of 20.37% and a disease control rate of 59.26%. The two groups showed similar ORR results, while the incorporation of PD-1/PD-L1 inhibitors resulted in significantly increased DCR when compared to the controls. The median OS was 22 months (95% CI: 1,629 months) for the control group and 31 months (95% CI: 28NA) for the study group, suggesting OS benefits offered by PD-1/PD-L1 inhibitor treatment (HR=0.479, 95% CI: 0.284, 0.809). The median PFS was 15 months (95% CI: 1,223 months) for the control group and 23 months (95% CI: 1,926) for the study group, indicating more PFS benefits provided by PD-1/PD-L1 inhibitors (HR=0.662, 95% CI: 0.436, 1.005). Adverse events and their severity were recorded during patient follow-up, and no grade 5 adverse events were reported in either group. The incidence of grade 3 or higher adverse events between the two groups was similar, while PD-1/PD-L1 inhibitors appeared to significantly reduce the incidence of gastrointestinal reactions in patients. PD-1/PD-L1 inhibitors integrated with chemotherapy provide significant benefits in the management of patients with advanced ESCC without increasing adverse events.

Efficacy and safety of rifampicin-based triple therapy for non-puerperal mastitis: A single-arm, open-label, prospective clinical trial

ObjectivesTo assess the efficacy and safety of rifampicin-based triple therapy (rifampicin, isoniazid, and ethambutol) for treating NPM. MethodsThis single-center, single-arm, prospective clinical trial was conducted at the Second Hospital of Shandong University (Jinan, China). Patients with pathologically diagnosed granulomatous lobular mastitis and periductal mastitis received triple drugs, i.e., rifampicin (450 mg/day), isoniazid (300 mg/day), and ethambutol (15 mg/kg/day), until complete response or the investigator decided to discontinue treatment. The primary endpoint was the complete response rate (CRR) assessed by the investigator. The secondary endpoints included the overall remission rate (ORR), recurrence rate (RR), and safety. ResultsA total of 218 patients were enrolled in the study between January 1, 2013 and October 31, 2020. With a median follow-up time of 48 months, the CRR and the ORR were 78.44% and 94.04%, respectively. While 13 patients (5.96%) demonstrated no response and 19 relapsed (8.72%). Adverse events (AEs) were not common. The most common AEs during treatment were liver dysfunction (1.83%), gastrointestinal reactions (1.83%), fatigue (1.83%), erythema (1.38%), and menstrual disorders (0.92%). ConclusionRifampicin, isoniazid, and ethambutol demonstrated promising response rates with acceptable safety profiles in patients with NPM. Further confirmatory trial is warranted in the future. Trial registrationThe study was approved by the Ethics Committee of the Second Hospital of Shandong University and retrospectively registered at the China Clinical Trial Registration Center (registration number: ChiCTR2100049591).

Systematic review and meta-analysis on the efficacy and safety of Injectable Lentinan combined with chemotherapy in the treatment of gastric cancer

BackgroundThis study employed a meta-analysis to evaluate the efficacy and safety of adjunctive treatment with injectable Lentinan (LNT) in combination with chemotherapy for gastric cancer (GC). MethodsComputer-based searches of 6 databases were performed to identify randomized controlled trials (RCTs) relevant to the treatment of GC with LNT through mid-March 2023. Two independent researchers performed risk of bias assessment and trial sequential analysis(TSA), extracted the data and used Revman 5.3 software for data analysis. The certainty of evidence was graded based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. ResultsA total of 31 RCTs with 2729 patients were included in the analysis. The results revealed that adjunctive therapy with LNT was associated with improved treatment efficacy (RR = 1.48, 95%CI: 1.36 ∼ 1.61, p < 0.00001), improvement in clusters of differentiation (CD3+, CD4+, and CD4+/CD8+), natural killer (NK) cells, and quality of life assessment (RR = 1.32, 95%CI: 1.20 ∼ 1.45, p < 0.00001) compared to using chemotherapy alone. In addition, there was a reduction in CD8+ levels, incidence of white blood cell decline, gastrointestinal reactions, and platelet decline. TSA results indicated that there was sufficient evidence to draw firm conclusions about these outcomes, and the GRADE scores showed ‘high’ or ‘moderate’ quality of evidence for these outcomes. ConclusionThe efficacy of treatment of GC with LNT in combination with chemotherapy was found to be better than chemotherapy alone. And no serious adverse effects were observed. However, further RCTs are needed to further validate the results of this study.

Fecal calprotectin level is nonlinearly associated with GI pathogen detection in patients with and without inflammatory bowel disease.

Fecal calprotectin (FCP) is used to monitor inflammatory bowel disease (IBD) activity and can also be elevated in gastrointestinal infections. Our study's objective was to quantify the relationship between FCP levels and lab-confirmed infections in people with and without IBD. We performed a cross-sectional study at a tertiary-care center of all encounters during which FCP and gastrointestinal pathogen polymerase-chain reaction (GI PCR) panel testings were conducted. Using non-parametric tests and quantile regression, we compared the FCP levels by IBD status and pathogen detection. There were 3,347 encounters with FCP and GI PCR testings from 2,780 unique individuals between 1 August 2016 and 17 February 2022. Overall, 54.4% had IBD (n = 1,819). Pathogens were detected in 744 encounters (22.2%), and the detection rate did not differ by IBD status. Median FCP without IBD was significantly elevated when a pathogen was detected (64 vs 41 mg/kg, P = 0.0003, normal ≤50.0 mg/kg), but FCP with IBD was not significantly elevated when a pathogen was detected (299 vs 255 mg/kg, P = 0.207). In quantile regression adjusted for age and IBD, pathogen detection was only significantly associated with higher FCP in the lower two quartiles, though IBD remained significantly associated with higher FCP at all levels (P > 0.001). Pathogen detection by GI PCR is associated with elevated FCP, though this relationship is nonlinear and varies by IBD status. Our findings indicate that FCP may be an adjunct to, but not a substitute for, stool pathogen testing.

ВСТРЕЧАЕМОСТЬ АЛЛЕЛЕЙ И ГЕНОТИПОВ ПО АЛЛЕЛЬНЫМ ВАРИАНТАМ CYP2С9*2 И CYP2С9*3 СРЕДИ БОЛЬНЫХ С БОЛЕВЫМ СИНДРОМОМ, ПРИНИМАВШИХ НЕСТЕРОИДНЫЕ ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА

Abstract. Introduction. The most clinically significant polymorphic markers of the CYP2C9 gene are the amino acid substitutions of CYP2C9*2. One of the human cytochrome P450 types, i.e., cytochrome CYP2C19, is essential to the metabolism of some drugs, including proton pump inhibitors. Genetic polymorphism of СУР2С19 has some pronounced interindividual differences. Significance of genetic polymorphism is detected where the occurrence of variant alleles exceeds 1% in the population. Aim of the study was to improve the principles of pharmacotherapy with nonsteroidal anti-inflammatory drugs, as related to the frequency of alleles and genotypes on the allelic variants of CYP2С9*2 and CYP2С9*3 in pain syndrome patients taking nonsteroidal anti-inflammatory drugs. Materials and Methods. The study included 69 patients with pain syndrome. Association between being the carrier of genotypes on the CYP2С9*2 and CYP2С9*3 alleles and developing gastropathies as reactions to administering anti-inflammatory drugs was investigated by conducting a prospective case-control study. Molecular genetic testing was performed based on the Laboratory of Medical Genetics of the Research Institute of Hematology and Blood Transfusion at the Ministry of Health of the Republic of Uzbekistan. Results and Discussion. No statistically significant differences were found in the frequencies of the CYP2C9 and CYP2C19 alleles between the groups of patients with and without adverse gastrointestinal reactions to administering nonsteroidal anti-inflammatory drugs or proton pump inhibitors. Conclusions. Our findings allow us to suggest that being a carrier of the allelic CYP2C9*2 and CYP2C9*3 variants should be considered as a gastropathy risk factor of using nonsteroidal anti-inflammatory drugs. It can be assumed that, to reduce the risk of adverse reactions developed in the patients of this category to nonsteroidal anti-inflammatory drugs, the latter ones need a concomitant administration with proton pump inhibitors. It is necessary to continue studying the frequencies of the alleles and genotypes on allelic CYP2С9*2 and CYP2С9*3 variant sin pain syndrome patients taking nonsteroidal anti-inflammatory drugs.

Preferences and Willingness to Pay for Medication in Patients with Renal Cell Carcinoma in China: A Discrete-Choice Experiment.

We aimed to assess the relative importance of attributes and the willingness to pay for pharmacological therapies among patients with renal cell carcinoma in China. Patients with renal cell carcinoma completed a D-efficient-designed, discrete-choice experiment online survey that presented a series of ten trade-off questions and one examining scenario. Based on the literature review and consultations with patients with renal cell carcinoma and clinicians, each question included a pair of hypothetical renal cell carcinoma medication profiles characterized by seven attributes including progression-free survival, objective response rate, medication regimen, fatigue, gastrointestinal reaction, hand-foot syndrome, and monthly out-of-pocket costs. Relative importance and willingness to pay were calculated using coefficients estimated by mixed logit regression in the main analysis. Subgroup analyses were conducted considering the heterogeneity of the participants, based on sex, education level, and income level, using conditional logit regression. The analysis incorporated responses from 182 Chinese respondents. Except for the medication regimen, all attributes were statistically significant. Progression-free survival was the most important attribute, followed by objective response rate, monthly out-of-pocket costs, fatigue, gastrointestinal reaction, and hand-foot syndrome. Patients were willing to pay ￥2010.51 ($298.30), ￥494.93 ($73.43) for 1 unit improvement of progression-free survival, and objective response rate, and￥7558.93 ($1121.50), ￥6927.24 ($1027.78) to avoid experiencing fatigue and gastrointestinal reaction, respectively. Differences in preferences and willingness to pay were found according to patients' gender, income, and education level. In China, patients with renal cell carcinoma preferred medications with better efficacy (objective response rate and progression-free survival) and lower out-of-pocket costs. Heterogeneity can be found in preferences and willingness to pay based on patients' gender, income, and education levels.

Comparison of Long-Term Outcome between Imatinib and Dasatinib Prophylaxis after Allogeneic Stem Cell Transplantation in Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia-a Multi-Center Retrospective Study

Background: Though the prognosis of Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has been improved since the introduction of tyrosine kinase inhibitors (TKIs) and combined with allogeneic stem cell transplantation (allo-HSCT), relapse after HSCT remains a concern. Prophylactic TKIs after allo-HSCT seemed a promising strategy to prevent relapse. But the optimal choice of the agent is still obscure.Methods: We retrospectively analyzed the clinical data of Ph-positive ALL patients who underwent allo-HSCT in CR1 from 6 medical centers in China between September 2010 and October 2021. Patients were divided into two cohorts according to different choice of TKI after allo-HSCT, namely Ima cohort with imatinib prophylaxis and Das cohort with dasatinib prophylaxis. Survival and safety outcomes of two cohorts were compared, and prognostic factors were determined by univariate and multivariate analyses.Results: One hundred and forty-one patients, with median age of 37 years (range, 14-61 years), were included, of whom 91 were in Ima cohort and 50 were in Das cohort. After median follow-up of 50.6 months, 5-year cumulative relapse rate (CIR), non-relapse mortality rate (NMR), leukemia-free time (LFS) and overall survival (OS) in Ima and Das cohort were 16.1% and 12.5%; 5.2% and 9.8%; 78.8% and 77.6%; 86.5% and 77.6%, respectively, with no significant difference. Mild cGVHD was higher in Das cohort compared to Ima cohort, while the total, moderate or severe cGVHD were similar. The most common adverse event was neutropenia (66.4%). Das cohort owned higher incidence of gastrointestinal bleeding and gastrointestinal reaction than Ima cohort. The proportion of patients treated on schedule was 30% in Das cohort, lower than that of in Ima cohort (p&amp;lt;0.001). Drug intolerance was the main reason for not completed treatment as intended.Conclusions: For patients with Ph-positive ALL receiving allo-HSCT in CR1, imatinib prophylaxis after transplantation could obtain the same long-term outcome compared to dasatinib, showing better tolerance.

Chidamide-Based Pre-Emptive Treatment for High-Risk AML Patients after Hematopoietic Stem Cell Transplantation: A Real-World Experience from Chinese Single-Center

Background: The treatment of relapsed or refractory acute myeloid leukemia ( AML) remains challenging. Measurable residual disease (MRD) persistence at transplantation or post-transplantation has been identified as the strongest risk factor for relapse and poor outcomes for patients with hematological malignancies (HMs). Chidamide, a novel oral histone deacetylase inhibitor, has shown potential therapeutic effects in various types of HMs by inducing cell apoptosis and regulating immunity. This study aimed to evaluate the efficacy and safety of Chidamide-based prophylactic or pre-emptive treatment for patients who are MRD positive before or who have sustained MRD positive after transplantation. Aim: The rate of 6 months of conversion to MRD- and relapse-free survival of high-risk AML after Chidamide-based treatment. Methods: From December 2020 to July 2023, 50 patients with high-risk HMs received chidamide-based therapy after allo-HSCT. 39 patients were diagnosed with AML ( 4 secondary AML), 2 with myelodysplastic syndromes, 6 with acute lymphoid leukemia, and 3 with mixed-phenotype acute leukemia. 46 patients (92%) with relapsed/refractory status or detectable MRD (MRD+) at transplantation or after allo-HSCT received chidamide as pre-emptive, and the remaining 4 high-risk patients with MRD− conducted as prophylactic intervention. Patients with detectable MRD before transplantation and those who remained positive for MRD after transplantation were defined as very high-risk AML (VHR-AML). Chidamide was administered at a dose of 5 mg per day orally, 6 times per week, lasting at least 1 year after engraftment. Additional agents included hypomethylating agents (HMAs), donor lymphocyte infusion (DLI) or tyrosine kinase inhibitor (TKI) in patients with Philadelphia chromosome-positive. In this study, 28 patients received chidamide monotherapy, 13 received chidamide combined with HMAs, and 9 cases with other therapy. Results: The median age of all patients was 38 years old (range 17-67), comprising 24 males and 26 females. Up to 1st July 2023, with a median follow-up period of 376 days (25-984d), the overall rate of MRD negative showed 64%. The rate of MRD- survival, Relapse-free survival (RFS) and overall survival (OS) were 56%, 66% and 76%, respectively. The 6 months MRD negative rate, RFS and OS rate were 86%, 82%, 86% and 88%, which maintained at 82%, 82% and 86% with 12 months follow-up, respectively. In 46 cases of the pre-emptive intervention arm, the overall MRD- rate was 61.7%. Among them, 83.3% of patients (20/24) who received chidamide monotherapy exhibited a much higher conversion to MRD− than those combined with HMAs (7/13, 53.8%) or other drugs (2/9, 22.2%) (P=0.004). In 4 cases who received chidamide monotherapy as prophylactic intervention, 3 patients sustained MRD negativity up to the last follow-up, except for one patient diagnosed with MPAL(B+M) relapsed after 1 year of HSCT with taking chidamide for 6 months. A total of 30 patients (including 25 AML) with VHR diseases remained in a status of MRD+ or non-remission after transplantation. Eighteen patients (60%) achieved MRD− and sustained for a median of 251 days (range 31-531 d). VHR-AML patients account for 94.4% (17/18) of MRD- responders(Figure 1A). Similarly, the results showed a higher rate of conversion from MRD+ to MRD− in chidamide monotherapy than the combination groups (Chidamide monotherapy, 81.8%; Chidamide + HMA, 63.6% and Chidamide + others, 25%, P=0.042,Figure 1B). It highlighted that treatment with chidamide resulted in increased MRD− response, especially for AML. On the contrary, of 7 patients with B-cell malignancy, including 5 B-ALL and 2 MPAL (B + M) patients, only 2 (28.6%) patients converted to MRD−. Reversible grade 3/4 neutropenia occurred in 38% of patients, and thrombocytopenia was observed in 24% during the first four treatment cycles. Five patients experienced grade 1/2 non-hematological adverse events, such as fatigue, gastrointestinal reaction, pneumonia and infection. No new-onset GvHD was reported in patients without a prior history of GvHD during chidamide treatment. Conclusion: The chidamide-based regimen is safe and effective in pre-emptive treatment for patients with high-risk relapsed AML after transplantation. Whether as a monotherapy or combined with HMA, chidamide shows significant efficacy in eliminating MRD, warranting further clinical research.

Selinexor in Combination with Hypomethylating Agent (HMA) in Patients with Refractory/Relapsed Acute Myeloid Leukemia (AML) Previously Exposed to Venetoclax: A Retrospective Study

Background Acute myeloid leukemia (AML) is a heterogeneous hematologic tumor with varied clinical manifestations. Venetoclax combination regimens have shown promising results as a first-line treatment for AML. However, for patients who fail venetoclax treatment, the prognosis remains poor, necessitating the exploration of new therapeutic approaches. Selinexor, a selective inhibitor of XPO1, has shown potential as a therapeutic strategy to overcome resistance to conventional chemotherapy for AML. Here, we report the safety and efficacy data from a real-world study of selinexor + HMA in patients with refractory/relapsed (R/R) AML previously exposed to venetoclax. Methods We conducted a monocentric retrospective analysis on adult patients with unfit R/R AML or those with comorbidities preventing the use of intensive induction chemotherapy. The patients received selinexor-based combinations between May 2021 and December 2022. AML genetic risk stratification and response criteria were assessed according to the 2022 European Leukemia Net (ELN) consensus. The selinexor + HMA regimen consisted of selinexor 40 mg twice weekly for 3 weeks orally, and either decitabine (DAC, 10 mg/dfor 7-10 days intravenously) or azacytidine (AZA, 75 mg/m 2/d for 7 days subcutaneously, halved for patients over 60 years). Supportive treatments and dose adjustments were administered based on individual clinical indications. Some patients underwent allogeneic hematopoietic stem-cell transplantation. Results A total of 12 patients with R/R AML treated with selinexor-based combinations were considered in this study, including 7 patients with refractory AML and 5 patients with relapsed AML (one with post-transplant recurrence). The median age of the patients was 36 years (range 18-68 years). All patients had intermediate or adverse ELN genetic risk. All patients had previously received venetoclax-based combinations, and 58% (7/12) had been treated with HMAs. The overall response rate (ORR) was 66.7% (8/12) with a combined CR rate (CRc) of 50% (6/12). Among the 6 patients with CRc, 3 (50%) achieved negative minimal residual disease (MRD,≤1*10 -3). CRc was 42.9% (3/7) in patients previously exposed to HMA-based therapy and 100% in patients without exposure history. The most common grade 3 or 4 adverse events were neutropenia (83.3%) and thrombocytopenia (58%), with the median recovery time of 14 (8-21) and 16 (8-24) days, respectively. Common non-hematologic toxicities included infection (66.7%) and gastrointestinal reactions (66.7%). As of Jun 20, 2023, with a median follow-up of 11.3 months (range 0.7-19.5 months), 50% (6/12) of the patients died due to disease progression or severe infections. 66.7% (8/12) of the patients received transplants after achieving remission. The median overall survival (OS) was significantly longer in the transplantation group compared to the non-transplantation group (p=0.009) (Figure.1a). Patients without previous HMA exposure seemed to have a better efficacy benefit from the X+HMA combination regimen, although the difference was not statistically significant due to the llimited sample size (Figure.1b). Conclusion The real-life study demonstrated that the combination of selinexor and HMAs is a viable and safe option for patients with unfit R/R AML who were previously exposed to venetoclax. X+HMA salvage therapy followed by transplantation showed durable survival benefits in R/R AML patients, especially those without prior HMA exposure, suggesting a potential efficacy advantage.

Selective PI3Kδ Inhibitor Parsaclisib Combined with HDAC Inhibitor Chidamide in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma: Preliminary Results of a Phase Ib/Ⅱ Study

Background: Peripheral T-cell lymphoma (PTCL) is a highly heterogenous non-Hodgkin lymphoma with poor survival. Pts with relapsed/refractory PTCL (r/r PTCL) have extremely poor prognosis and limited treatment options. Conventional salvage treatments have a median progression-free survival (PFS) of only 3-4 months. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor has shown encouraging efficacy and favorable safety profile in B-cell malignancies. We developed a phase Ib/II study to evaluate the safety and efficacy of parsaclisib with HDAC inhibitor (HDACi) chidamide in r/r PTCL (NCT05083208). Here, we report the preliminary results of this study. Method: Eligible pts were ≤ 75 years old adults with histologically confirmed PTCL who received ≥ prior line of systemic therapy. Phase Ib dose-escalation study determined the maximum tolerated dose (MTD) of parsaclisib with chidamide using a 3 + 3 design. Parsaclisib was administered once daily at 3 dose levels (dose-level (DL) 1: 10 mg; DL2: 15 mg; DL3: 20mg) in the first 8 weeks followed by 2.5 mg QD in the subsequent treatment. Chidamide was administered at a fixed dose of 20 mg twice a week throughout the study. Once the MTD was established, pts were enrolled into phase 2 study to further characterize safety and efficacy. MTD of parsaclisib and objective response rate (ORR) were the primary endpoints; complete response rate (CRR), PFS, overall survival (OS) and tolerability were secondary endpoints. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) infection in the first 8 weeks were required. Results: From March 2022 to July 27, 2023 (date cut-off), 11 pts were recruited with a median age of 52 (39-74) years old. The median number of prior systemic therapies was 2 (1-5). Of 6 pts treated at DL1, 1 had dose-limiting toxicity (DLT) (grade 3 elevation of ALT/AST). No DLT was observed in 3 pts at DL2 and 2 at DL3. The DLT was resolved subsequently but the patient died from lymphoma progression. Treatment-emergent adverse events (TEAEs) were observed in all pts. The TEAEs were mainly hematologic toxicities and gastrointestinal reactions, most of which were grade 1/2. Grade 3/4 TEAEs were neutropenia (n=4), leukopenia (n=1), elevation of ALT/AST (n=1), and diarrhea (n=1) (Table 1). TEAE led to dose interruption in one patient. In 9 pts evaluable for responses (1 withdrew from this study and 1 was unevaluable), 5 (55.6%) pts achieved complete response (CR) and one (11.1%) partial response at the first efficacy assessment. In 7 pts previously exposed to chidamide, 4 pts achieved CR and 2 of them had a PFS &amp;gt; 16 months (Table 2 and Figure 1). Conclusion: Preliminary data demonstrated that selective PI3Kδ Inhibitor parsaclisib with HDACi chidamide was tolerable and produced promising responses in r/r PTCL, including patients previously exposed to chidamide. This trial is currently ongoing.

Anti-PD-1 Antibody (Tislelizumab) Combined with R-CHOP for the Treatment of Previously Untreated Primary Mediastinal B-Cell Lymphoma: A Prospective Phase II Study

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a rare aggressive B-cell lymphoma of thymic origin. Due to the low incidence rate of PMBCL, there is currently no internationally accepted standard first-line treatment regimen. Dose-adjusted (DA) EPOCH-R which is the more commonly used first-line therapy plan is not so effective because patients usually cannot tolerate it. The R-CHOP regimen is comparable to the R-DA-EPOCH for the first-line treatment of PMBCL in terms of survival and has a better safety profile (Bhatt, V.R. et al, Cancer Treat Rev 2015; Iwanicka el al., Curr Hematol Malig Rep 2014). Meanwhile, patients with PMBCL usually have alterations of 9p24.1, leading to overexpression of PDL-1/2. Previous studies have found that PD-1 monoclonal antibody shows good efficacy in recurrent and refractory PMBCL (Steidl et al., Blood 2011; Zinzani et al., Blood 2017). Tislelizumab, a humanized IgG4 antibody that binds PD-1 with high affinity, minimizes binding to Fcγ receptor 1 (FcγRI) on macrophages by the genetic engineering of Fc segment, abrogating antibody-dependent phagocytosis (ADCP)-induced T-cell clearance. The efficacy and safety of its combination with R-CHOP in previously untreated PMBCL is not yet clear. We speculate that the combination of both may be a new option for the first-line therapy for PMBCL patients with good efficacy and low toxicity. Methods: This is a single-arm, multi-center, phase II clinical study (ChiCTR2100044313). Patients aged 18 years or older with a diagnosis of PMBCL and previously untreated were eligible. Eligible patients received 6 cycles of Tislelizumab (200 mg D1), Rituximab (375 mg/m 2 D1), Cyclophosphamide (750 mg/m 2 D2), Pirarubicin (50 mg/m 2 D2), Vincristine (1.4 mg/m 2, maximum dose 2 mg, D2), Prednisone (100 mg/d D2-6), every 21 days for 1 cycle. Disease response assessments were performed by positron emission tomography and computed tomography (PET-CT) or enhanced CT every two cycles, meanwhile peripheral blood ctDNA was monitored, and treatment-related adverse effects were assessed and recorded. The primary endpoint was objective remission rate (ORR). The secondary endpoints included treatment safety, progression-free survival (PFS) and overall survival (OS), and the exploratory analyses of the correlation between PD-L1 expression in tumor tissues, tumor-associated macrophages (TAM) phenotype in tumor microenvironment and efficacy. Results: From June 2020 to June 2023, 12 patients were enrolled and 9 patients had evaluable efficacy with the median age of 34 years, 3 males and 6 females, all patients had large mediastinal mass at initial diagnosis. 7 patients had PD-L1 expression (VENTANA SP263) above 80% and 2 cases could not be further tested due to insufficient tissue specimens. The ORR was 100%, and the CR rate was 77.8% (7/9) after 6 cycles of treatment. The 5 th and 9 th patient reached PR after 6 cycles of treatment due to irregular hospitalization. And CR was achieved after 2 cycles of regular treatment for the 5 th patient. NGS from formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) evaluation from blood were performed across all patients before treatment. 5 patients underwent end of treatment-ctDNA test. Median follow-up 15m (6.8m-26.3m), the third patient was lost to follow-up at 9m. The other patients who achieved CR are still at complete remission. Moreover, we found SOCS1, TNFAIP3 are the most frequently mutated genes in biopsies of PMBCL and only the 5th patient had RHOA mutation which is highly related to PMBCL. The PET-CT and ctDNA assessments were negative in three patients at the end of 6 cycles with 60% concordance, and the 5 th and 9 th patient achieved PR on PET-CT, but the ctDNA assessments were negative. The most common adverse events (AEs) were gastrointestinal reactions, 2 patients experienced grade IV myelosuppression and 1 patient had grade I hyperthyroidism. No treatment-related deaths occurred. Conclusion: Tislelizumab combined with R-CHOP for the treatment of previously untreated PMBCL had good efficacy and sustained response with low toxicity. Longer follow-up is required to access the survival benefit of this regimen. Figure 1: Disease Remission in the Included Patients

Real-World Safety and Clinical Response of Flumatinib in the Treatment of Chronic Myeloid Leukemia: A Retrospective Study

Objective: The objective of this retrospective study was to assess the effectiveness and safety of flumatinib in the treatment of chronic phase chronic myeloid leukemia (CML) in real-world settings. Methods: A total of 61 patients who received flumatinib as first-line therapy were compared with 92 patients who received first-line imatinib therapy. Furthermore, the 58 patients who received flumatinib as post-line therapy were divided into two groups based on the timing of switching to flumatinib: an early conversion group (n=18) and a late conversion group (n=40). The molecular responses and outcomes were assessed at multiple time points (3, 6, 9, and 12 months) during the treatment of flumatinib, along with the observation of adverse reactions. Results: In comparison to imatinib, the use of flumatinib as a first-line therapy demonstrated statistically significant increases in early molecular response (EMR), major molecular response (MMR), and deep molecular response (DMR) at various milestones (p&amp;lt;0.05). Additionally, the incidence of adverse events was lower in the flumatinib group, as evidenced by higher event-free survival (EFS) rates (83.6% vs. 39.1%, P=0.01) and a lower medication switching rate (90.2% vs. 31.5%, P&amp;lt;0.001). However, there were no significant differences observed in overall survival (OS) and progression-free survival (PFS) rates between the two groups (P&amp;gt;0.05). In the context of post-line therapy, a significant proportion of patients (72.2%) achieved EMR at 3 months, while 71.9% achieved MMR at 12 months when treated with flumatinib. Notably, the early conversion group exhibited higher rates of molecular response and demonstrated superior OS, PFS, and EFS at the 12-month mark compared to the late conversion group (P&amp;gt;0.05). Adverse events (AEs) commonly associated with flumatinib encompassed limb discomfort, gastrointestinal reactions, and elevated transaminase levels, with thrombocytopenia being the most frequently observed hematologic AE. Conclusion: Flumatinib exhibited notable efficacy and safety as a therapeutic option for patients with chronic phase CML, whether utilized as a first-line or post-line treatment. In comparison to imatinib, initial administration of flumatinib resulted in more profound and expeditious molecular responses. The utilization of flumatinib as a post-line therapeutic approach during the early stage of treatment exhibits a favorable influence on patient prognosis. However, no statistically significant disparity was noted when compared to the group receiving switch therapy during the late stage.

Venetoclax, Cladribine and Cytarabine for the Treatment of Relapse/Refractory Acute Lymphoblastic Leukemia: Interim Analysis of a Phase 2 Trial

Venetoclax, cladribine and cytarabine for the treatment of relapse/refractory acute lymphoblastic leukemia: interim analysis of a phase 2 trial Background: Philadelphia chromosome-negative acute B lymphoblastic leukemia (Ph- B-ALL) accounts for approximately 60-70% of adult B-ALL. Patients with relapse/refractory (R/R) Ph- B-ALL was reported to have a poor prognosis. Immunotherapies such as blinatumomab, CAR T-cell therapy achieved high response rate for Ph- B-ALL. However, salvage chemotherapies are also worth of investigation because many patients can't afford immunotherapies. We found that venetoclax, cladribine and low-dose cytarabine had synergistic cell toxicity against B-ALL cell line RS4;11 in our previously in vitro studies. Based on these findings, we designed a multicenter, phase 2 study utilizing the venetoclax, cladribine and cytarabine (CAV) regimen for the treatment of R/R B-ALL (NCT05657652). Methods: The CAV regimen consisted of cladribine 5 mg/m 2/day from day 1 to day 3 or day 5, cytarabine 20mg/m 2, q12h, for 7-10 days and venetoclax 100mg d1, 200 mg d2, 400 mg/day from day 3 to day 28. Bone aspiration evaluation was performed at 14-28 days after the completion of CAV regimen. Treatment responses were evaluated according to the NCCN guidelines. The threshold of MRD negativity was defined as less than 0.01% as detected by multiparameter flow cytometry. Results: Since February 2021, a total of 16 patients with R/R Ph- B-ALL were enrolled in this study. Baseline characteristics of these patients were summarized in Table 1. The median age was 36 years (range, 13-66 years), and 12/16 (75%) patients were male. Among them, 12 patients (75%) had relapsed Ph- B-ALL and 4 patients (25%) had refractory Ph- B-ALL. One patient had concurrent active central nervous system leukemia. One patient had a complex karyotype, and two patients had TP53 mutations. Treatment responses were shown in Table 2. 12/16 (75%) patients responded to CAV regimen after one cycle of CAV regimen, with 3/16 (18.75%) with complete remission (CR), 8/16 (50%) with CRi, and 1/16 (6.25%) with morphology leukemia-free state (MLFS). Among patients who achieved treatment response, 9/12 (75%) patients attained MRD negativity. During the treatment with the CAV regimen, one patient (1/16, 6.3%) developed grade 4 tumor lysis syndrome. 4/16 (25%) patients suffered grade 3 to 4 infections. Grade 1 to 2 gastrointestinal reactions and liver dysfunction were observed in 8/16 (50%) and 5/16 (31.3%) patients, respectively. The 60-day mortality rate was 6.3%. Two patients who relapsed after CAV treatment re-achieved remission after CART therapy. Nine patients received allo-HSCT after CAV regimen. With a median follow-up of 11 months (range, 0.3-28 months), the estimated 1-year overall survival rate was 76.2% and 1-year event-free survival rate was 38.4%. The survival swimming plot was shown in Figure 1. The median OS was not reached and the median EFS was 13 months. The cumulative relapse rate was 31.3% (5/16). At the last follow-up, two patients died of relapse, one patient died of cerebral hemorrhage and one patient died of sepsis. Conclusion: In summary, our results demonstrated that CAV regimen showed encouraging efficacy and safety in treating R/R Ph- B-ALL patients.

Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial.

To explore the safety and efficacy of subcutaneous semaglutide 2.4 mg, administered once a week in non-diabetic overweight or obese individuals. A thorough search was performed of various databases including PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrials.gov, CNKI and Wanfang from their inception up to April 11, 2023. Our aim was to identify randomized controlled trials (RCTs) that compared the efficacy of semaglutide administered once weekly with placebo in overweight or obese adults. Through a review of the literature, data were extracted from relevant studies and assessed for quality, and a meta-analysis was conducted using RevMan 5.4.1 software. Six RCTs comprising 3962 overweight or obese individuals were identified. The findings indicated that, in comparison to the placebo group, semaglutide caused a significant and sustainable reduction in the percentage of body weight (BW; mean difference [MD]: -11.80% [95% confidence interval {CI} -12.93, -10.68]; P < 0.00001) as well as a decrease in absolute BW (MD: -12.2 kg [95% CI -13.3, -11.1]; P < 0.00001), body mass index (MD: -4.5 kg/m2 [95% CI -4.9, -4.1]; P < 0.00001) and waist circumference (MD:-9.4 cm [95% CI -10.1, -8.8]; P < 0.00001). Moreover, it achieved a higher proportion of patients who experienced weight loss exceeding 5%, 10%, 15% and 20%. Furthermore, semaglutide showed significant efficacy in controlling blood pressure, blood sugar levels, C-reactive protein levels, and lipid profiles. In terms of safety, the most common adverse effects following semaglutide treatment were gastrointestinal adverse reactions (risk ratio: 1.49 [95% CI 1.38, 1.60]; P < 0.00001), which were generally mild to moderate in severity and temporary. In overweight or obese non-diabetic individuals, semaglutide had a remarkable and sustained weight loss effect that was well tolerated and safe.

Study of the Effect of Preoperative Dietary Intervention on Gastrointestinal Reaction of Microparticle TACE

Objective: To evaluate the effect of preoperative dietary intervention on the gastrointestinal reaction of microparticle transcatheter arterial chemoembolization (TACE). Methods: A total of 60 patients with primary liver cancer who were treated in our hospital from January 2018 to October 2018 were selected for this study. The random sampling method was used to divide the patients into an intervention group (30 cases) and a control group (30 cases). The control group received routine intervention, whereas the intervention group received optimized nursing intervention. The incidence of gastrointestinal reactions, the vomiting frequency, the average vomiting volume, the incidence of stomach discomfort, the quality of life, and the anxiety and depression indicators of both groups were compared. Results: The results of all indicators of the intervention group were better than those of the control group. The incidence of gastrointestinal reactions in the intervention group was 13.9%, which was lower than 43.3% of the control group. The scores of QLQ-C30 of the intervention group were higher than those of the control group; the SAS and SDS scores in the intervention group were lower than those of the control group. Conclusion: Preoperative dietary intervention can reduce the incidence of gastrointestinal reactions of microparticle TACE and improve the symptoms of gastric discomfort among patients.

The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

Safety and effectiveness of tigecycline combination therapy in renal transplant patients with infection due to carbapenem-resistant gram-negative bacteria.

Carbapenem-resistant gram-negative bacterial (CRGNB) infections are increasing among kidney transplant recipients, and effective therapeutic options are limited. This study aimed to investigate the efficacy and adverse events associated with combination therapy tigecycline in renal transplant patients with CRGNB infections. This study retrospectively analyzed 40 Chinese patients with confirmed or suspected CRGNB infections who received tigecycline therapy. The patients' case features and clinical and microbiological data were analyzed. A total of 40 renal transplant recipients received tigecycline therapy for a median duration of 9 (range, 3-25) days. CRGNB isolates were obtained from the organ preservation solution of the donor kidney in 28 patients, with confirmed transmission in 4 patients. Infections were detected in the bloodstream, urinary tract, sputum, and wound. The most prevalent isolates were Klebsiella pneumoniae (75%, 30/40), Acinetobacter baumannii (15%, 6/40), and Escherichia coli (10%, 4/40). A clinical response was observed in 32 (80%) patients. The 28-day all-cause mortality rate was 7.5% (3/40), while the one-year all-cause mortality rate was 2.5% (1/40). While one patient died owing to severe pancreatitis, no serious adverse events related to tigecycline therapy were reported. However, multiple indices of liver function and pancreatitis precursors increased after treatment with tigecycline compared to before treatment. Tigecycline therapy appears to be well tolerated in renal transplant recipients with multidrug-resistant bacterial infections. Nevertheless, attention should be paid to adverse reactions related to tigecycline therapy, especially gastrointestinal reactions, and the related laboratory tests should be closely monitored.

Venetoclax Plus Azacitidine, Low Dose Cytarabine, Aclarubicin and G-CSF (VA-CAG Regimen) for Newly Diagnosed Young Patients with Acute Myeloid Leukemia: A Prospective, Multicenter, Single-Arm Phase 2 Clinical Trial

Background: Venetoclax, in combination with hypomethylating agents or low-dose cytarabine, is approved for newly diagnosed acute myeloid leukemia (AML) patients who are over 75 years of age or not eligible for intensive chemotherapy, while the efficacy of venetoclax-based regimens in young fit AML patients still needs to be further explored. Although the combination of anthracycline and cytarabine has achieved a remission rate of about 70% in these patients, the low complete response rate in adverse-risk patients, strong adverse reactions, and long duration of myelosuppression limited the clinical benefit. We presumed that venetoclax plus azacitidine in combination with low-intensity regimens CAG (G-CSF priming, low dose cytarabine, and aclarubicin) could have a better composite complete remission with an acceptable safety profile. Methods: Patients who were newly diagnosed with AML aged from 18 to 65 years without active infection, bleeding and severe cardiopulmonary insufficiency were enrolled. Participants received induction as azacitidine 75 mg/m 2 subcutaneously once daily on days 1-7, cytarabine 10mg/m 2 subcutaneously q12h on days 1-7, aclacinomycin 12 mg/m 2 on days 1,3,5,7, granulocyte colony-stimulating factor 5µg/kg on days 1-7, and venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-21). Venetoclax dose was adjusted based on concomitant CYP3A inhibitors. The efficacy were evaluated by bone marrow morphology and flow cytometry on day 28 cycle 1. The primary endpoints were safety and the composite complete remission rate. This study was approved for ethical review and registered with ClinicalTrials.gov (NCT05662956). Results: Twenty-six patients from eight sites were enrolled between January 1, 2023, and June 20, 2023. The median age was 52 years (range, 18-63years). Thirteen patients (50.0%) had adverse risk, 7 patients (26.9%) had intermediate risk, and 6 patients (23.1%) had favorable risk. All 26 patients (100%) achieved complete remission after cycle 1, and 21 patients (80.8%) was MRD negative by flow cytometry. Two patients (7.7%) were treated with venetoclax for 14 days due to ineffective platelet transfusion and severe infection during treatment. Twenty-two patients (84%) used azole drugs to prevent fungal infection. The median myelosuppression time was 13 days (range, 5-22days), and the median red blood cell and platelet transfusions were 5.5u (range, 0-11.5u) and 30u (range, 0-170u), respectively. Eleven patients (42.3%) experienced infection (including pulmonary fungal infection, oral cold herpes, novel coronavirus infection, etc.), and two of them (7.7%) had a breakthrough invasive fungal infection, but with good management. The most common grade 3/4 adverse events included bone marrow suppression (92.3%), liver injury (19.2%), gastrointestinal reaction (11.5%) and coagulation dysfunction (3.8%).No treatment-related death occurred. Conclusion: VA-CAG regimen achieved high rates of complete remission and MRD negative in young adult fit patients with newly diagnosed AML. This combined regimen has an acceptable safety profile, with low incidence of infection and transfusion dependence.

Maintenance Therapy with Chidamide Plus Azacitidine after Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Acute Myeloid Leukemia Patients

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is theoretically the only curative option for high-risk acute myeloid leukemia (AML) patients. However, many patients relapse after allo-HSCT, and treatment options are very limited. Azacitidine, a DNA methyltransferase inhibitor exhibits anti-leukemia activity in myeloid diseases. Chidamide, a selective histone deacetylase inhibitor, effectively induces apoptosis of AML cells. They have synergistic inhibitory effect on AML cells when combined together. Therefore, we conducted a multicentre, prospective study (ChiCTR2300067593) to examine the tolerability and efficacy of a combination of both chidamide and azacitidine as a maintenance therapy for high-risk AML patients after allo-HSCT. Patients and methods： Patients ≤ 60 years of age with high-risk AML post- allo-HSCT were enrolled. The high-risk characteristics of AML were defined as one or more of the following criteria: a) Patients with poor prognosis according to the genetic risk stratification assessment of European Leukmia Net (ELN) in 2022; b) Primary refractory or recurrent AML; c) Secondary AML (secondary to MDS or treatment-related AML). All patients received Chidamide 5 mg/d combined with azacitidine 75 mg/m2/d for 5 days. The cycle interval was 6-8 weeks. A total of 6 cycles was recommended. Treatment started as early as 3 months after transplantation. The primary endpoint of this study was cumulative incidence of relapse (CIR). The secondary endpoints included rates of overall survival (OS) and event-free survival (EFS). Survival outcomes were estimated using Kaplan-Meier analysis. Results： Thirty-six patients have been recruited. The median age was 42 years (range, 16-59). Baseline characteristics are shown in Table 1. With a median follow-up time of 412（185-762）days, the 1-year CIR was 12.3 (6.5-18.1) %, the 1-year OS and EFS rates were 100.0% and 87.7 (81.9-93.5) %, respectively. The median OS and EFS time were not reached. Four patients relapsed, two died, and two are still alive and ready for the second transplantation. The most common adverse events (AEs) were thrombocytopenia reaction and gastrointestinal tract reaction. Grade 2 or 3 AEs were observed in 16.7% (6/36) and 25.0% (9/36) of the patients, respectively. No grade &amp;gt;3 AEs were noted. 9 patients (6/36,16.7%) developed grade 3-4 thrombocytopenia, without active hemorrhage. All of them received blood transfusion and thrombopoietin receptor agonist. The median persistence of thrombocytopenia was 3 (2-5) d. Chronic graft-versus-host-disease (cGVHD) occurred in 25.0% (9/36) of patients. Four cases (4/36, 11.1%) were complicated with infection. They were one case of intestinal infection, one case of pulmonary and EBV infections, one case of hepatitis B virus activation and one case of herpes zoster. And all infected patients recovered safely after anti-infection and symptom-oriented treatment. CMV activation was not observed. Non relapse mortality (NRM) was zero. Conclusions： We conclude that chidamide plus azacitidine can be administered safely after allo- HSCT with no evidence of an increased incidence of GVHD, and this combination may decrease the relapse rate in high-risk AML patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML patients.