Adjuvant treatment with Cordyceps sinensis for lung cancer: A systematic review and meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps sinensis (CS) is a fungus parasitic on lepidopteran larvae which is often used to treat lung diseases and regulate immune function. AIM OF THE STUDY: This review aimed to evaluate the efficacy of CS in the adjuvant treatment of lung cancer. MATERIALS AND METHODS: As of June 2022, the electronic database search was conducted in PubMed, EMBASE, Cochrane Library, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Database and China Science Journal Database (VIP database). Randomized clinical trials (RCTs) that evaluated the efficacy of CS as an adjuvant treatment for lung cancer were included. After the quality evaluation, meta-analysis was performed with Stata 16.0 software. RESULTS: A total of 12 RCTs with 928 patients were identified for this meta-analysis, which showed that as an adjuvant treatment, CS has the following advantages in the treatment of lung cancer: (1) Improved tumor response rate (TRR) (RR: 1.17， 95%CI: 1.05-1.29，P = 0.00); (2) improved immune function, including increased CD4 (MD: 4.98, 95%CI: 1.49-8.47, P = 0.01), CD8 (MD: 1.60, 95%CI: 0.40-2.81, P = 0.01, I2 = 0.00%), NK (MD: 4.17, 95%CI: 2.26-6.08, P = 0.00), IgA (MD: 1.29, 95%CI: 0.35-2.24, P = 0.01), IgG (MD: 3.95, 95%CI: 0.98-6.92, P = 0.01) and IgM (MD: 6.44, 95%CI: 0.63-12.26, P = 0.03); (3) improved patients' quality of life based on the mean ± SD of Karnofsky Performance Status (KPS) (MD: 8.20, 95%CI: 6.87-9.53, P = 0.00); (4) reduced the incidence of adverse drug reactions (ADRs), including the incidence of myelosuppression (RR: 0.38, 95%CI: 0.19-0.75, P = 0.01), leukopenia (RR: 0.76, 95%CI: 0.63-0.92, P = 0.00), and thrombocytopenia (RR: 0.52, 95%CI: 0.31-0.86, P = 0.01) (5) reduced the incidence of radiation pneumonitis (RR: 0.74, 95%CI: 0.62-0.88, P = 0.00). However, the number of improved patients based on KPS (RR: 1.47, 95%CI: 0.98-2.20, P = 0.06) were similar between two groups, liver and renal damage (RR: 0.32, 95%CI: 0.09-1.10, P = 0.07) and gastrointestinal adverse reactions (RR: 0.80, 95%CI: 0.47-1.37, P = 0.42) as well. Subgroup analysis showed that CS could increase the TRR in the treatment with 6 g/d and 21 days/3-4 cycles. CONCLUSION: Compared with conventional treatment, adjuvant treatment with CS of lung cancer not only improve TRR, QOL and immune function, but also reduce the incidence of ADRs and radiation pneumonitis. The optimal usage may be 6 g/d and 21 days/3 to 4 cycles. PROSPERO REGISTRATION NO: CRD42022333681.

Qijiao Shengbai Capsule alleviated leukopenia by interfering leukotriene pathway: Integrated network study of multi-omics.

BACKGROUND: Leukopenia could be induced by chemotherapy, which leads to bone marrow suppression and even affects the therapeutic progression of cancer. Qijiao Shengbai Capsule (QSC) has been used for the treatment of leukopenia in clinic, but its bioactive components and mechanisms have not yet been elucidated clearly. PURPOSE: This study aimed to elucidate the molecular mechanisms of QSC in treating leukopenia. STUDY DESIGN: Serum pharmacochemistry, multi-omics, network pharmacology, and validation experiment were combined to study the effect of QSC in murine leukopenia model. METHODS: First, UPLC-QTOF-MS was used to clarify the absorbed components of QSC. Then, cyclophosphamide (CTX) was used to induce mice model with leukopenia, and the therapeutic efficacy of QSC was assessed by an integrative approach of multi-omics and network pharmacology strategy. Finally, molecular mechanisms and potential therapeutic targets were identified by validated experiments. RESULTS: 121 compounds absorbed in vivo were identified. QSC significantly increase the count of white blood cells (WBCs) in peripheral blood of leukopenia mice with 15 days treatment. Multi-omics and network pharmacology revealed that leukotriene pathway and MAPK signaling pathway played crucial roles during the treatment of leukopenia with QSC. Six targets (ALOX5, LTB4R, CYSLTR1, FOS, JUN, IL-1ß) and 13 prototype compounds were supposed to be the key targets and potential active components, respectively. The validation experiment further confirmed that QSC could effectively inhibit the inflammatory response induced by leukopenia. The inhibitors of ALOX5 activity can significantly increase the number of WBCs in leukopenia mice. Molecular docking of ALOX5 suggested that calycosin, daidzein, and medicarpin were the potentially active compounds of QSC. CONCLUSION: Leukotriene pathway was found for the first time to be a key role in the development of leukopenia, and ALOX5 was conformed as the potential target. QSC may inhibit the inflammatory response and interfere the leukotriene pathway, it is able to improve hematopoiesis and achieve therapeutic effects in the mice with leukopenia.

Bojungikgi-tang for Chemotherapy-induced Leukopenia: A Systematic Review and Meta-Analysis.

Chemotherapy-induced leukopenia is a common side effect of cytotoxic anticancer drugs. It can deprive patients of treatment opportunities, resulting in the delay, reduction, or discontinuation of chemotherapy or other anticancer drug administration. Two researchers searched English, Chinese, Japanese, and Korean electronic databases, without limiting the time period and language, using search terms such as "Bojungikgi," "WBC," "leuko," and "neutrop." Among the human randomized controlled studies in which Bojungikgi-tang was administered to patients who underwent chemotherapy, studies reporting leukopenia-related outcomes were selected, and data extraction, bias risk assessment, and meta-analysis were performed on the selected papers. Ten studies were selected, and a systematic review with meta-analysis was conducted. Nine papers were published in China and the total number of participants was 715. As a result of administering Bojungikgi-tang to these patients, the number of patients with chemotherapy-induced leukopenia significantly decreased (OR: 0.41, 95% CI: 0.27-0.61, P = .0001, I2 = 35%). Further, white blood cell counts were compared with that of the control group, and it showed an effect on prevention (MD: 0.64, 95% CI: 0.46-0.83, P < .00001, I2 = 90%). A pronounced effect was observed, especially when administered after a diagnosis based on the pattern identification, such as Qi deficiency. (OR: 0.32, 95% CI: 0.18-0.58, P = .0002, I2 = 0%). However, all studies had a high risk of bias due to non-blinding, and most studies had a high or uncertain risk of bias in creating random assignment orders and concealing them. Bojungikgi-tang has an effect on the prevention and treatment of chemotherapy-induced leukopenia. The effect rate can be increased when administered after proper diagnosis, and the possibility of adverse reactions and side effects is lower than that of Granulocyte-Colony Stimulating Factor (G-CSF) injection. Bojungikgi-tang appears to be useful in the treatment and prevention of leukopenia caused by cytotoxic anticancer drugs. However, it is necessary to conduct high-quality clinical studies in the future, considering the possibility of local and language bias, heterogeneity of carcinoma and intervention, and the risk of bias.Registration: PROSPERO CRD4202341054.

Targeting CD38/ ADP-ribosyl cyclase as a novel therapeutic strategy for identification of three potent agonists for leukopenia treatment.

Leukopenia is the most common side effect of chemotherapy and radiotherapy. It potentially deteriorates into a life-threatening complication in cancer patients. Despite several agents being approved for clinical administration, there are still high incidences of pathogen-related disease due to a lack of functional immune cells. ADP-ribosyl cyclase of CD38 displays a regulatory effect on leukopoiesis and the immune system. To explore whether the ADP-ribosyl cyclase was a potential therapeutic target of leukopenia. We established a drug screening model based on an ADP-ribosyl cyclase-based pharmacophore generation algorithm and discovered three novel ADP-ribosyl cyclase agonists: ziyuglycoside II (ZGSII), brevifolincarboxylic acid (BA), and 3,4-dihydroxy-5-methoxybenzoic acid (DMA). Then, in vitro experiments demonstrated that these three natural compounds significantly promoted myeloid differentiation and antibacterial activity in NB4 cells. In vivo, experiments confirmed that the compounds also stimulated the recovery of leukocytes in irradiation-induced mice and zebrafish. The mechanism was investigated by network pharmacology, and the top 12 biological processes and the top 20 signaling pathways were obtained by intersecting target genes among ZGSII, BA, DMA, and leukopenia. The potential signaling molecules involved were further explored through experiments. Finally, the ADP-ribosyl cyclase agonists (ZGSII, BA, and DMA) has been found to regenerate microbicidal myeloid cells to effectively ameliorate leukopenia-associated infection by activating CD38/ADP-ribosyl cyclase-Ca2+-NFAT. In summary, this study constructs a drug screening model to discover active compounds against leukopenia, reveals the critical roles of ADP-ribosyl cyclase in promoting myeloid differentiation and the immune response, and provides a promising strategy for the treatment of radiation-induced leukopenia.

Long-Term Safety and Efficacy of Eltrombopag for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia: Results of the ASPIRE Extension Study.

ASPIRE, a three-part, international, phase 2 trial (ClinicalTrials.gov identifier: NCT01440374), investigated eltrombopag efficacy and safety in patients with advanced myelodysplastic syndrome or acute myeloid leukemia and grade 4 thrombocytopenia (<25 × 109 platelets/L). Approximately 30-65% of patients in this open-label extension phase experienced clinically relevant thrombocytopenic events; no conclusions could be made regarding long-term efficacy (non-randomized design, no placebo control), and survival rates may simply reflect advanced disease. Long-term safety was consistent with the double-blind phase and contrasted with earlier SUPPORT study findings in higher-risk patients, suggesting that eltrombopag may have a role in treating thrombocytopenia in patients with low-/intermediate-risk myelodysplastic syndrome.

Sex differences in systemic lupus erythematosus (SLE): an inception cohort of the Chinese SLE Treatment and Research Group (CSTAR) registry XVII.

BACKGROUND: The onset and clinical presentation of systemic lupus erythematosus (SLE) are sex-related. Few studies have investigated the distinctions in clinical characteristics and treatment preferences in male and female SLE patients in the initial cohort. This study aimed to improve the understanding of Chinese SLE patients by characterizing the different sexes of SLE patients in the inception cohort. METHODS: Based on the initial patient cohort established by the Chinese SLE Treatment and Research Group, a total of 8713 patients (795 men and 7918 women) with newly diagnosed SLE were enrolled between April 2009 and March 2021. Of these, 2900 patients (347 men and 2553 women) were eligible for lupus nephritis (LN). A cross-sectional analysis of the baseline demographic characteristics, clinical manifestations, laboratory parameters, organ damage, initial treatment regimens, and renal pathology classification was performed according to sex. RESULTS: In the SLE group, as compared to female patients, male patients had a later age of onset (male vs. female: 37.0 ±â€Š15.8 years vs. 35.1 ±â€Š13.7 years, P  = 0.006) and a higher SLE International Collaborative Clinic/American College of Rheumatology damage index score (male vs. female: 0.47 ±â€Š1.13 vs. 0.34 ±â€Š0.81, P  = 0.015), LN (male vs. female: 43.6% vs. 32.2%, P < 0.001), fever (male vs. female: 18.0% vs. 14.6%, P  = 0.010), thrombocytopenia (male vs. female: 21.4% vs. 18.5%, P  = 0.050), serositis (male vs. female: 14.7% vs. 11.7%, P  = 0.013), renal damage (male vs. female: 11.1% vs. 7.4%, P < 0.001), and treatment with cyclophosphamide (CYC) (P < 0.001). The frequency of leukopenia (male vs. female: 20.5% vs. 25.4%, P  = 0.002) and arthritis (male vs. female: 22.0% vs. 29.9%, P < 0.001) was less in male patients with SLE. In LN, no differences were observed in disease duration, SLE Disease Activity Index score, renal biopsy pathological typing, or 24-h urine protein quantification among the sexes. In comparisons with female patients with LN, male patients had later onset ages (P  = 0.026), high serum creatinine (P < 0.001), higher end-stage renal failure rates (P  = 0.002), musculoskeletal damage (P  = 0.023), cardiovascular impairment (P  = 0.009), and CYC use (P  = 0.001); while leukopenia (P  = 0.017), arthritis (P  = 0.014), and mycophenolate usage (P  = 0.013) rates were lower. CONCLUSIONS: Male SLE patients had more severe organ damage and a higher LN incidence compared with female SLE patients; therefore, they may require more aggressive initial treatment compared to female patients.

Comparison of Efficacy and Safety of Taxanes Plus Platinum and Fluorouracil Plus Platinum in the First-Line Treatment of Esophageal Cancer: A Systematic Review and Meta-Analysis.

Fluoropyrimidine plus platinum (FP) and taxanes plus platinum (TP) are standard treatments for esophageal cancer (EC). This systematic review and meta-analysis aim to explore the difference in the therapeutic effect and toxicity of FP and TP regimens in EC patients. PubMed, Embase, and Cochrane were fully searched and analyzed to find relevant articles on EC patients treated with FP and TP regimens up to 22 March 2022. Thirty-one studies, with a total of 3432 participants, were included in this review. The primary outcomes showed that the prognosis and therapeutic efficacy of TP groups were better than those of FP groups for the EC patients treated with definitive chemoradiotherapy treatment (3-year OS: RR: 1.25, 95% CI: 1.08−1.44, p = 0.003; 3-year PFS: RR: 1.43, 95% CI: 1.17−1.75, p = 0.0006; ORR: RR: 1.17, 95% CI: 1.06−1.29, p = 0.001). However, TP therapy was significantly correlated with a higher incidence of leukopenia and thrombocytopenia (p < 0.05). In the preoperative neoadjuvant chemoradiotherapy group, these two groups had a similar survival time (p > 0.05). The FP regimen corresponded to a higher incidence of thrombocytopenia, while the TP regimen was associated with an increased incidence of febrile leukopenia (p < 0.05). Therefore, TP regimens could generate both superior clinical response and survival benefits when compared with FP regimens in EC patients undergoing definitive chemoradiotherapy.

Age-Dependent Hematologic Toxicity Profiles and Prognostic Serologic Markers in Postoperative Radiochemotherapy Treatment for Uterine Cervical Cancer.

Introduction: In the adjuvant setting for cervical cancer, classical risk factors for postoperative radiochemotherapy have been established. However, data on laboratory changes during therapy and the prognostic value of serological markers are limited and further knowledge is needed to optimize the toxic trimodal regimen. Methods: We retrospectively identified 69 women who underwent weekly postoperative radiochemotherapy with 40 mg/m2 of cisplatin for cervical cancer between 2010 and 2021 at a single center. Laboratory parameters were recorded before, at each cycle and after radiochemotherapy. Kaplan-Meier and log-rank analyses were used to calculate and compare survival, groups were compared using the Mann-Whitney U, χ2, and variance tests. Results: With a median follow-up of 17.7 months, the 1- and 5-year local control rates were 94.0% and 73.7%, respectively, with significantly better rates for more chemotherapy cycles and negative resection margins. Only 68.1% of patients completed all cycles. The most common reasons for early discontinuation were persistent asymptomatic leukopenia in women aged ≤ 50 years, and limiting infections in women aged > 50 years. Leukopenia was more likely to occur after the third cycle. Significantly worse survival was observed for post-radiochemotherapy elevated C-reactive-protein and lactate dehydrogenase levels, low pre-radiochemotherapy nutritional index, and raised C-reactive-protein-levels; the latter were also predictable for local control. The Glasgow prognostic score did not reliably predict survival. Conclusion: Incomplete application of simultaneous chemotherapy leads to inferior local control, and age-dependent limiting factors should be identified at an early stage. In addition to classical risk factors, serological markers (C-reactive-protein, lactate dehydrogenase, nutritional index) show prognostic significance.

Visceral Leishmaniasis: A Case Report of a Challenging Diagnosis After Orthotopic Liver Transplantation.

Leishmaniasis is a disease caused by a protozoan and transmitted by sandfly species in several emerging countries. Visceral leishmaniasis is a serious complication, especially in immunosuppressed patients, and is uncommon after liver transplantation. We report the case of a 48-year-old female patient who underwent liver transplantation owing to polycystic liver disease. Six months after the procedure, she was hospitalized with diarrhea, acute kidney failure, and leukopenia. She had been off steroids for 3 months and was taking mycophenolate and tacrolimus. She had already been treated for cytomegalovirus, which was negative on admission. During hospitalization, fever, splenomegaly, ascites, and pancytopenia appeared. Serology for Leishmania by indirect immunofluorescence was negative. Then, bone biopsy and molecular testing for Leishmania diagnosed it as visceral leishmaniasis. Amphotericin therapy was initiated with resolution of fever after 4 days of treatment and gradual recovery from pancytopenia. This case highlights the challenge of early diagnosis of visceral leishmaniasis in liver transplant recipients with diarrhea and leukopenia, which can be caused by immunosuppression or more prevalent viral diseases. Late onset of fever, splenomegaly, and a first negative serologic test also made early diagnosis difficult. The aim of the report is to emphasize the suspicion of visceral leishmaniasis in symptomatic patients from emerging countries and to question the benefit of including protozoan screening in liver transplant donors and recipients in endemic areas.

The efficacy and safety of Xihuang Pill/capsule in adjuvant treatment of breast cancer: A systematic review and meta-analysis of 26 randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Xihuang Pill is a traditional Chinese medicine prescription for the treatment of breast cancer. There are many randomized controlled trials (RCTs) of Xihuang Pill in the treatment of breast cancer that have been published. Hence, a comprehensive systematic review and meta-analysis is needed. AIM: To evaluate the safety of Xihuang pill/capsule and its effect on the improvement of tumor progression, quality of life, immunity and prognosis in adjuvant treatment of breast cancer. METHODS: Chinese and English databases such as Sinomed, PubMed, Embase were searched to collect the RCTs of Xihuang pill/capsule in adjuvant treatment of breast cancer. Then the researchers extracted data from the RCTs that met the inclusion criteria, and used Cochrane standard risk bias to assess the quality of the data, and used Rev Man 5.3 statistical software for statistical analysis. RESULTS: A total of 26 RCTs with 2272 participants were included. The primary outcomes showed that Xihuang pill combined with chemotherapy and with endocrine therapy may suppress of tumor progression {Chemotherapy: risk ratio (RR) = 0.59, 95%Confidence interval (CI) [0.48,0.73], P < 0.00001; Endocrine therapy: RR = 0.56, 95%CI [0.33,0.96], P = 0.04}. Xihuang pill combined with chemotherapy, with endocrine therapy and with radiotherapy may improve the quality of life (chemotherapy: RR = 1.73, 95%CI[1.11, 2.70], P = 0.02; Endocrine therapy: RR = 1.18, 95%CI [1.01,1.38], P = 0.03; radiotherapy:RR = 1.51, 95%CI [1.01,2.27], P = 0.05). Xihuang pill combined with TCM + chemotherapy may decrease the inefficiency rate for clinical symptom improvement (RR = 0.50, 95%CI [0.28, 0.88], P = 0.02). Xihuang pill combined with chemotherapy may increase the Karnofsky Performance Scale (KPS) {Weighted Mean Difference (WMD) = 15.40, 95%CI [8.18, 22.62], P < 0.0001}. For adverse events, Xihuang pill combined with chemotherapy may alleviate adverse digestive events and leukopenia; Xihuang pill combined with endocrine therapy will not increase adverse events; Xihuang pill combined with non-antitumor therapy may reduce the incidence of leukopenia and red blood cell or hemoglobin reduction. CONCLUSION: The addition of Xihuang pill/capsule to breast cancer in conventional anti-tumor therapy may inhibit tumor progression, improve patient quality of life, reduce toxic reactions, regulate immunity, and reduce tumor markers. However, due to the overall low quality of RCTs, the research results need more high-quality RCTs to further test the conclusions.

Nomogram predicting leukopenia in osteosarcoma after high-dose methotrexate chemotherapy.

PURPOSE: To explore the trends of plasma drug concentration changes after high-dose methotrexate (MTX) treatment of osteosarcoma (OS), analyse the risk factors for leukopenia (LP) after MTX treatment, and establish a LP prediction nomogram. METHODS: A total of 35 OS patients at Tianjin Medical University Cancer Institute and Hospital between 2017 and 2021 were collected (the construction cohort). Another 12 OS patients between 2019 and 2021 in P.A. Hertsen Moscow Oncology Research Center were involved (the external validation cohort). Peripheral venous blood MTX concentration (CMTX) was monitored at 0h, 6h, 24h, 48h and 72h after MTX administration. The characteristics were collected: age, sex, body surface area, lesion site, pathological subtype, pathological fractures, American Joint Committee on Cancer (AJCC) clinical stage, MTX dose, tumour necrosis, Ki-67 index, erythrocyte count, haemoglobin count, white blood cell count, platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin concentration, creatinine, alkaline phosphatase, and lactate dehydrogenase. Logistic regression analysis was used to determine the risk factors for LP occurrence. Significant factors were used to construct the prediction nomogram. RESULTS: A total of 128 MTX chemotherapy cycles from 35 OS patients were included. Female, Ki-67>20%, CMTX>112µmol/L at 6h, PLT, and AST were risk factors for post-chemotherapy LP occurrence. The LP prediction nomogram was created and validated. CONCLUSIONS: Female, CMTX at 6h, Ki-67 index, AST and PLT before MTX treatment were risk factors for LP in OS patients who received MTX treatment. The established nomogram can guide personalized LP prediction in OS patients receiving MTX chemotherapy.

Effects of 225Ac-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis.

Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, has become a popular target for radionuclide-based theranostic applications in the advanced stages of prostate cancer. We conducted a meta-analysis of the therapeutic effects of PSMA-targeting α-therapy (225Ac-PSMA radioligand therapy [RLT]) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A systematic search was performed using the keywords "mCRPC," "225Ac-PSMA," and "alpha therapy." Therapeutic responses were analyzed as the pooled proportions of patients with more than a 50% prostate-specific antigen (PSA) decline and any PSA decline. Survival outcomes were analyzed by estimating summary survival curves for progression-free survival and overall survival. Adverse events were analyzed as the pooled proportions of patients with xerostomia and severe hematotoxicity (anemia, leukocytopenia, and thrombocytopenia). Results: Nine studies with 263 patients were included in our meta-analysis. The pooled proportions of patients with more than a 50% PSA decline and any PSA decline were 60.99% (95% CI, 54.92%-66.83%) and 83.57% (95% CI, 78.62%-87.77%), respectively. The estimated mean progression-free survival and mean overall survival were 9.15 mo (95% CI, 6.69-11.03 mo) and 11.77 mo (95% CI, 9.51-13.49 mo), respectively. The pooled proportions of patients with adverse events were 62.81% (95% CI, 39.34%-83.46%) for xerostomia, 14.39% (95% CI, 7.76%-22.63%) for anemia, 4.12% (95% CI, 0.97%-9.31%) for leukocytopenia, and 7.18% (95% CI, 2.70%-13.57%) for thrombocytopenia. Conclusion: In our study, around 61% of patients had more than a 50% PSA decline and 84% of patients had any PSA decline after 225Ac-PSMA RLT. The common adverse events in 225Ac-PSMA RLT were xerostomia in 63% of patients and severe hematotoxicity in 4%-14% of patients.

Efficacy of Aidi Injection and Brucea javanica Oil Emulsion Injection in Rectal Cancer during CapeOX Adjuvant Chemotherapy.

BACKGROUND: Adjuvant chemotherapy with CapeOX regimen is widely used in resected rectal cancer, which brings benefits to patients. But drug-related toxicities are severe during this process; thus, survival outcomes may potentially be affected. This study explored the efficacy of two Chinese herbal injections, Aidi injection (ADI) and Brucea javanica oil emulsion injection (BJOEI), as adjuvant drugs in CapeOX adjuvant chemotherapy on rectal cancer patients. METHODS: A total of 240 cases were enrolled in this retrospective study. 80 cases received CapeOX with ADI (the ADI group), 80 cases received CapeOX with BJOEI (the BJOEI group), and the rest 80 cases received CapeOX alone (the control group). After four cycles' chemotherapy, adverse reactions (ADRs) and quality of life (QOL) were analyzed. Then, patients received follow-up for at least one year, and the endpoint was disease-free survival (DFS). RESULTS: All patients completed at least four cycles' adjuvant chemotherapy. The incidence of leukopenia and thrombocytopenia was significantly lower in the ADI group; the incidence of nausea was significantly lower in the BJOEI group; the incidence of hand-foot syndrome was significantly lower in both the ADI group and BJOEI group. Significant difference was found in the control group regarding the Karnofsky Performance Status (KPS) scores prior and posttreatment. No difference was found among three groups regarding one-year DFS. CONCLUSION: As adjuvant drugs for rectal cancer during CapeOX chemotherapy, ADI shows advantages in decreasing leukopenia and thrombocytopenia, while BJOEI results better in remitting nausea. Both two CHIs had positive impacts on decreasing hand-foot syndrome and the maintenance of patients' QOL. It is worthy of further study and promotion for CHIs.

Characterizing the BCR repertoire during lymphocyte reduction and recovery mediated by cyclophosphamide and granulocyte-macrophage colony-stimulating factor.

Leukopenia is a common manifestation of many diseases, including global outbreak SAS-CoV-2 infection. Granulocyte-macrophage colony-stimulating factor (GM -CSF) has been proved to be effective in promoting lymphocyte regeneration, but adverse immunological effects have also emerged. This study aim to investigate the effect of GM -CSF on BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration. Cyclophosphamide (CTX) and GM -CSF were used to inhibit and stimulate bone marrow hematopoiesis, respectively. High throughput sequencing was applied to detect the characteristics of BCR CDR3 repertoire in controls, CTX group and GM -CSF group. The white blood cells (WBCs) were quickly reduced (P < 0.05) with lymphocytes decreasing causing by CTX, and the WBCs and lymphocytes returned to the level of controls after GM -CSF treatment. The diversity of BCR heavy chain CDR3 repertoire was also significantly decreased in CTX group. Although there is still a big gap from the controls, the diversity was picked up after GM -CSF treatment. The expression of IGHD01-01, IGHD02-14 and IGHJ04-01 with high-frequency usage regularly and significantly changed in three groups, and many genes with low-frequency usage lost in CTX group and did not reappear in GM -CSF group. Moreover, two shared sequences and accounted for the highest proportion in GM -CSF group have been detected in animal model of chronic lymphocytic leukemia. These results revealed that GM -CSF can partially restore changes in the BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration, but it may also lead to rearrangement, proliferation and activation of abnormal B cells, which can provide a basis for further study on the adverse immunological effects and mechanism of GM -CSF treatment.

Effect of leukopenia induced by cyclophosphamide on the initial stage of arterial thrombosis in mice.

INTRODUCTION: Leukocytes are found in organizing thrombi and are associated with thrombus growth. However, their role in the initial stage of thrombus formation is not well known. We investigated the role of leukocytes in the early stage of arterial thrombosis by inducing leukopenia. METHODS: In this double-blind, randomized, placebo-controlled study, 72 Institute of Cancer Research mice were randomly treated with intraperitoneal 100 mg/kg cyclophosphamide or normal saline. The primary outcome was time to occlusion after FeCl3 treatment. We also compared thrombus size, histological composition, and association with peripheral blood cell counts between cyclophosphamide and control groups. RESULTS: Cyclophosphamide treatment significantly decreased leukocyte counts by 82.8% compared to placebo (P < 0.001). The time to occlusion was significantly longer in the cyclophosphamide group (3.31 ± 1.59 min) than in the control group (2.30 ± 1.14 min; P = 0.003). The immunoreactivity for Ly6G-positive cells, intracellular histone H3, and released histone H3 in thrombi was significantly reduced in the cyclophosphamide group by 92.8%, 50.2%, and 34.3%, respectively. Time to occlusion had a moderate negative correlation with leukocyte count in peripheral blood (r = -0.326, P = 0.022) in the entire group. CONCLUSIONS: Cyclophosphamide-induced leukopenia attenuated thrombus formation during the early stage of arterial thrombosis. Our findings suggest the potential role of leukocytes in the initial stage of arterial thrombosis.

[Therapeutic Effect of Spleen Low Molecular Weight Extracts on Leukopenia Caused by Epirubicin in Mice and Its Mechanism].

OBJECTIVE: To investigate the therapeutic effect of spleen low molecular weight extracts on epileptics hydrochloride-induced leukopenia in mice and explore its mechanism. METHODS: The model of leukopenia in mice was established by the injection of epirubicin hydrochloride (10 mg/kg). After the injection of chemotherapeutic drugs, leukocytopenia mice were treated with different doses of spleen low molecular weight extract, Ganoderma oral solution and recombinant granulocyte colony stimulating factor (rhG-CSF). The general survival status indicators such as body weight, coat color and athletic ability of mice in each group were recorded; the tail vein blood of mice in each group was collected and the white blood cell count in them was calculated; bone marrow of mice was taken and bone marrow smears were observed. RESULTS: In the model group, the weight of the mice gradually decreased in the later period, their coat became dark and rough, and the ability to exercise decreased, while the mice in the treatment groups showed different degrees of improvement in their survival status except for the mice treated by rhG-CSF. There was no significant fluctuation in the white blood cell count of the blank control mice. After injection of epirubicin, the white blood cell count of peripheral blood in the model mice and treated mice were decreased. The white blood cell count was lower in the mice treated with high-dose low molecular weight extract and rhG-CSF than that in other experimental groups. Bone marrow smear showed that the proportion of bone marrow nucleated cells in the mice treated with the low molecular weight extract of the spleen was significantly higher than that of model mice (P<0.05). CONCLUSION: The low molecular weight spleen extracts can significantly improve the hematopoietic state of mouse bone marrow, promote the proliferation of inhibited bone marrow cells, and thus has the effect of treating leukopenia in mice.

Sanguisorba parviflora (Maxim) Takeda alleviates cyclophosphamide-induced leukopenia via regulating the hematopoietic cell-specific protein 1-associated protein X-1 gene.

WHAT IS KNOWN AND THE OBJECTIVE: Our previous studies have shown that saponins of Sanguisorba parviflora (Maxim) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in mice with leukopenia. The hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. This study aimed to comprehensively identify the role of HAX-1 in Sp. T to alleviate leukopenia. METHODS: HAX-1 expression was examined in the peripheral blood neutrophils using real-time polymerase chain reaction (PCR), Western blot analysis and immunohistochemical staining. Neutrophil apoptosis was measured by flow cytometry. Mitochondrial function was evaluated via reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity. RESULTS AND DISCUSSION: Our study indicated that the expression of the HAX-1 gene was significantly decreased in the peripheral blood neutrophils of leukopenia patients compared with healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability, while overexpression of HAX-1 reduced the production of reactive oxygen species (ROS) and maintained the integrity of the mitochondrial membrane potential. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or the addition of metformin. WHAT IS NEW AND OUR CONCLUSION: Our data support a mechanism where Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.

Sanguisorba parviflora (Maxim.) Takeda alleviates cyclophosphamide-induced leukopenia by regulating haematopoietic cell-specific protein 1-associated protein X-1 gene expression.

WHAT IS KNOWN AND OBJECTIVE: We have previously shown that the saponins of Sanguisorba parviflora (Maxim.) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in leukopenic mice. Haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. The aim of the present study was to comprehensively identify the role of HAX-1 in the mechanism of leukopenia alleviation by Sp. T. METHODS: HAX-1 gene and protein expression levels in peripheral blood neutrophils were examined using real-time quantitative reverse transcription-polymerase chain reaction, western blot and immunohistochemical assays. Neutrophil apoptosis was measured using flow cytometry. Mitochondrial function was determined via assessments of the reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity levels. RESULTS AND DISCUSSION: The HAX-1 gene expression level in the peripheral blood neutrophils was significantly lower in patients with leukopenia than in healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability. HAX-1 overexpression reduced the production of ROS and maintained ΔΨm integrity. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or metformin. WHAT IS NEW AND CONCLUSION: Our data suggest a mechanism through which Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.

Disseminated nontuberculous mycobacteriosis and fungemia after second delivery in a patient with MonoMAC syndrome/GATA2 mutation: a case report.

BACKGROUND: Heterozygous mutations in the transcription factor GATA2 result in a wide spectrum of clinical phenotypes, including monocytopenia and Mycobacterium avium complex (MAC) infection (MonoMAC) syndrome. Patients with MonoMAC syndrome typically are infected by disseminated nontuberculous mycobacteria, fungi, and human papillomavirus, exhibit pulmonary alveolar proteinosis during late adolescence or early adulthood, and manifest with decreased content of dendritic cells (DCs), monocytes, and B and natural killer (NK) cells. CASE PRESENTATION: A 39-year-old woman was diagnosed with MonoMAC syndrome postmortem. Although she was followed up based on the symptoms associated with leukocytopenia that was disguised as sarcoidosis with bone marrow involvement, she developed disseminated nontuberculous mycobacterial infection, fungemia, and MonoMAC syndrome after childbirth. Genetic testing revealed a heterozygous missense mutation in GATA2 (c.1114G > A, p.A372T). Immunohistochemistry and flow cytometry showed the disappearance of DCs and decreased frequency of NK cells in the bone marrow, respectively, after childbirth. CONCLUSIONS: To the best of our knowledge, this is the first study reporting that MonoMAC syndrome can be exacerbated after childbirth, and that immunohistochemistry of bone marrow sections to detect decreased DC content is useful to suspect MonoMAC syndrome.

Structural characterization and effect on leukopenia of fucoidan from Durvillaea antarctica.

Fucoidans from brown seaweed shows various bioactive properties and promising prospects in biomedical field. Here, a novel fucoidan (F-4) was extracted and purified from Durvillaea antarctica. The structure of F-4 was characterized by HPLC, HPGPC, GC-MS, together with IR and NMR spectral analysis. F-4 is a sulfated polysaccharide mainly composed of fucose (Fuc), galactose (Gal), and glucose (Glc) in a molar ratio of 26.4: 7.1: 1.0. The backbone of F-4 is composed of (1→3) and (1→4)-linked-α-L-Fucp residues, which sulfated at C-4 or C-2 positions and branched with α-L-Fuc, ß-D-Gal, and ß-D-Glc residues. Furthermore, F-4 can effectively promote the growth of leukocyte in a mouse model induced by cyclophosphamide, possibly by activating hematopoietic progenitor cells and regulating the hematopoietic microenvironment of bone marrow. Our data provide useful information for further investigation of fucoidan in the treatment of chemotherapy-induced leukopenia.