The role of proliferating stem-like plasma cells in relapsed or refractory multiple myeloma: Insights from single-cell RNA sequencing and proteomic analysis.

The management and comprehension of relapsed or refractory multiple myeloma (RRMM) continues to pose a significant challenge. By integrating single-cell RNA sequencing (scRNA-seq) data of 15 patients with plasma cell disorders (PCDs) and proteomic data obtained from mass spectrometry-based analysis of CD138+ plasma cells (PCs) from 144 PCDs patients, we identified a state of malignant PCs characterized by high stemness score and increased proliferation originating from RRMM. This state has been designated as proliferating stem-like plasma cells (PSPCs). NUCKS1 was identified as the gene marker representing the stemness of PSPCs. Comparison of differentially expressed genes among various PC states revealed a significant elevation in LGALS1 expression in PSPCs. Survival analysis on the MMRF CoMMpass dataset and GSE24080 dataset established LGALS1 as a gene associated with unfavourable prognostic implications for multiple myeloma. Ultimately, we discovered three specific ligand-receptor pairs within the midkine (MDK) signalling pathway network that play distinct roles in facilitating efficient cellular communication between PSPCs and the surrounding microenvironment cells. These insights have the potential to contribute to the understanding of molecular mechanism and the development of therapeutic strategies involving the application of stem-like cells in RRMM treatment.

Keyhole morphology monitoring of laser welding based on image processing and principal component analysis.

The keyhole is a specific phenomenon produced by the intense interaction between laser and material. Keyhole morphology can reflect welding stability and welding quality to a certain extent. Nowadays, the keyhole is observed and image processed by a high-speed camera and related algorithms, respectively. However, the binarization threshold is fixed in keyhole extraction, and conventional binarization methods are not adaptive. This will affect the feature extraction of keyhole morphology. In this paper, a dynamic threshold adjustment method is proposed, which can combine the quick positioning of the Otsu method and the weight balance of the average method. Furthermore, seven defined features of the keyhole region are divided into dynamic parameters and shape parameters. The dimension of these parameters is reduced by principal component analysis (PCA). The first three PCs occupy more than 92%, which covers most of the keyhole information. At last, the influence of dynamic parameters and shape parameters on keyhole morphology is presented. This research plays a positive role in monitoring the keyhole morphology of laser welding.

Radiotherapy Advances in Renal Disease-Focus on Renal Ischemic Preconditioning.

Ionizing irradiation is widely applied as a fundamental therapeutic treatment in several diseases. Acute kidney injury (AKI) represents a global public health problem with major morbidity and mortality. Renal ischemia/reperfusion (I/R) is the main cause of AKI. I/R injury occurs when blood flow to the kidney is transiently interrupted and then restored. Such an ischemic insult significantly impairs renal function in the short and long terms. Renal ischemic preconditioning (IPC) corresponds to the maneuvers intended to prevent or attenuate the ischemic damage. In murine models, irradiation-induced preconditioning (IP) renders the renal parenchyma resistant to subsequent damage by activating defense pathways involved in oxidative stress, angiogenesis, and inflammation. Before envisioning translational applications in patients, safe irradiation modalities, including timing, dosage, and fractionation, need to be defined.

A prognostic model incorporating inflammatory cells and cytokines for newly diagnosed multiple myeloma patients.

Peripheral blood cell counts and cytokines can be used as predictors of multiple myeloma (MM) patients' outcomes. 313 newly diagnosed MM patients treated with novel agents were divided into training and validation cohorts. We selected the common peripheral blood cell counts, including the lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR), systemic inflammation response index (SIRI), and serum cytokines which contained tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 receptor (IL-2R), interleukin-8 (IL-8), interleukin-6 (IL-6), and interleukin-10 (IL-10) as related variables. The least absolute shrinkage and selection operator (LASSO) regression was conducted to sort the predictor variables in the training cohort, and then the developed nomogram was assessed in the training and validation cohort. Our study showed that SIRI, PLR, and IL-8 were independent prognostic factors for the survival of MM patients. Patients with lower SIRI (≤ 0.87) had superior survival than patients with higher SIRI (> 0.87). Further, according to the LASSO regression, a nomogram embracing LMR (> 3.78), SIRI (> 0.87), PLR (≤ 106.44), and IL-8 was established. The nomogram demonstrated a better correlation with the outcomes of MM patients in the training cohort than International Staging System (ISS) and Revised-International Staging System (R-ISS). The same results were verified in the validation cohort. The nomogram incorporating inflammatory cells and cytokines could be a helpful tool to stratify MM patients in the era of novel agents.

Autologous Stem Cells Transplantation for No-Option Angiitis-Induced Critical Limb Ischemia: Recurrence and New Lesion.

Although satisfying outcomes have been demonstrated in terms of autologous stem cell transplantation in the treatment of angiitis-induced critical limb ischemia (AICLI), few studies have systematically reported the recurrence conditions. In the current study, we aimed to investigate recurrence conditions of a relatively large AICLI cohort in our center during a long-term follow-up period. From May 2009 to August 2020, 181 patients with AICLI received peripheral blood mononuclear cells (PBMNCs) or purified CD34+ cells (PCCs) transplantation. The main outcomes included recurrence and new lesions. Patient demographic data, ischemic limb characteristics, interventional characteristics, etc., were identified and analyzed. A logistic multivariable regression was performed to identify the independent risk factors for recurrence by a stepwise selection of variables. One hundred forty-eight patients were enrolled in this study. The mean follow-up period was 62.3 ± 37.4 months (range 12-144 months). The 5- and 10-year recurrence-free rates were 88.5% (95% confidence interval [CI] 3.1%-82.6%) and 71.7% (95% CI 7.6%-58.2%), respectively. The 5- and 10-year new lesion-free rates were 93.2% (95% CI 2.2%-89.0%) and 91.7% (95% CI 2.7%-86.6%), respectively. The finding of multiple limbs involved (OR 1.322 95% CI 1.123-12.549, P = .036) and ischemia relief period ≥5 months (OR 3.367 95% CI 1.112-10.192, P = .032) were demonstrated to be independent risk factors for recurrence in patients with AICLI who underwent cell transplantation. For patients with AICLI who responded to cell transplantation, the durability of this therapy was satisfactory, with 5- and 10-year recurrence-free rates of 88.5% and 71.7%, respectively. Multiple limbs involved at admission and ischemia relief period ≥5 months were demonstrated to be independent risk factors for recurrence after transplantation.

Return to work after cell transplantation in patients with angiitis-induced critical limb ischaemia and factors related: a single-centre retrospective cohort study.

BACKGROUND: Angiitis-induced critical limb ischaemia (AICLI) patients, who are usually young and have a high amputation rate, always lose their ability to return to the labour force. Return to work (RTW) not only indicates patients' physical health, showing that they could undertake the work, but also demonstrates their psychological well-being. While cell transplantation showed satisfactory efficacy in limb salvage, few studies of AICLI patients' RTW after transplantation have been reported. METHODS: From May 2009 to May 2021, AICLI patients who underwent cell transplantation and completed no less than 12 months of follow-up were retrospectively enrolled. The primary endpoint was RTW. Patient demographics and characteristics of the ischaemic limbs were reviewed to analyse independent risk factors for RTW. RESULTS: A total of 171 AICLI patients (170 males) were enrolled with a mean age of 41.9 ± 9.6 years (range: 20-57 years). The 12-month and 24-month RTW cumulative rates were 69.4% (95% confidence interval [CI] 61.6-75.6%) and 70.1% (95% CI 62.3-76.2%), respectively. Age < 40 years (odds ratio [OR] 2.659, 95% CI 1.138-6.719) and preoperative occupation as a mental worker (OR 8.930, 95% CI 2.665-42.847) were identified as independent protective factors for RTW. Perioperative limb infection with ulcer or gangrene (OR 0.250, 95% CI 0.075-0.779) was identified as an independent risk factor. CONCLUSION: AICLI patients who underwent cell transplantation usually had a satisfactory midterm RTW cumulative rate. AICLI patients < 40 years old with preoperative occupation as mental workers were more likely to return to work. Prevention of limb infection during the perioperative period is of great significance to RTW.

The peripheral blood mononuclear cells versus purified CD34+ cells transplantation in patients with angiitis-induced critical limb ischemia trial: 5-year outcomes and return to work analysis-a randomized single-blinded non-inferiority trial.

BACKGROUNDS: Patients with AICLI constitute a considerable proportion of NO-CLI patients and cannot be treated with surgical or endovascular treatment. Although cell therapy has shown satisfactory results in treating AICLI, research comparing the efficacy of treatment with the 2 kinds of cell products is rare. The aim of this study was to report the 5-year outcomes of a randomized single-blinded noninferiority trial (Number: NCT02089828) on peripheral blood mononuclear cells (PBMNCs) and purified CD34+ cells (PCCs) transplantation for treating angiitis-induced critical limb ischemia (AICLI). METHODS: A randomized single-blinded non-inferiority trial (Number: NCT02089828) was performed. Fifty patients were randomized 1:1 to the PBMNCs and PCCs groups. Efficacy outcomes, safety outcomes and patients' work conditions were analyzed. The primary efficacy outcomes included major amputation and total amputation over 60 months. RESULTS: During the 60-month follow-up, 1 patient was lost to follow-up, 1 died, and 2 underwent major amputation. The major amputation-free survival rate (MAFS) was 92.0% (95% confidence interval [CI] 82.0%-100.0%) in the PBMNCs group and 91.7% (95% CI 81.3%-100.0%) in the PCCs group (P = 0.980). Compared with the PCCs group, the PBMNCs group had a significantly higher 5-year new lesion-free survival rate (100.0% vs. 83.3% [95% CI 69.7-99.7%], P = 0.039). All patients lost their ability to work before transplantation, and the 5-year cumulative return to work (RTW) rates were 88.0% in the PBMNCs group and 76.0% in the PCCs group (P = 0.085). CONCLUSION: The long-term follow-up outcomes of this trial not only demonstrated similar efficacy and safety for the 2 types of autoimplants but also showed a satisfactory cumulative RTW rate in AICLI patients who underwent cell transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02089828. Registered 14 March 2014, https://clinicaltrials.gov/ct2/show/record/NCT02089828 .

Three-year outcomes of peripheral blood mononuclear cells vs purified CD34+ cells in the treatment of angiitis-induced no-option critical limb ischemia and a cost-effectiveness assessment: A randomized single-blinded noninferiority trial.

For patients with angiitis-induced critical limb ischemia (AICLI), cell transplantation, such as purified CD34+ cells (PCCs) and peripheral blood mononuclear cells (PBMNCs), is gradually being used as a promising treatment. This was the first randomized single-blinded noninferiority trial (number: NCT02089828) specifically designed to evaluate the therapeutic efficacies of the transplantation of PCCs vs those of PBMNCs for the treatment of AICLI. We aimed to compare the mid-term safety and efficacy between the two groups and determine their respective advantages. From April 2014 to September 2019, 50 patients with AICLI were equally allocated to the two groups, except for 1 lost patient, 1 amputee, and 1 patient who died of heart disease. The other 47 patients completed the 36-month follow-up. The endpoints were as follows: major amputation-free survival and total amputation-free survival at 6 months, which were 96.0% and 84.0% in the PBMNCs group and 96.0% and 72.0% in the PCCs group, respectively. These rates remained stable at 12, 24, and 36 months. The PCCs group had a significant higher probability of rest pain relief than the PBMNCs group, whereas earlier significant improvements in the Rutherford classification were observed in the PBMNCs group. Accordingly, PCCs would be preferred for patients with significant pain, whereas PBMNCs may be a good option for patients with two or more critically ischemic limbs. Concerning cost-effectiveness, PCCs are not more cost-effective than PBMNCs. These outcomes require verification from long-term trials involving larger numbers of patients.

Long-Term Outcomes of Peripheral Blood Mononuclear Cells in the Treatment of Angiitis-Induced No-Option Critical Limb-Threatening Ischemia.

Background: Peripheral blood mononuclear cells (PBMNCs) showed encouraging short outcomes in the treatment of angiitis-induced no-option critical limb-threatening ischemia (AICLTI) in the pilot study. This study aimed to demonstrate the long-term outcomes of this treatment. Methods: From May 2014 to December 2018, patients diagnosed with AICLTI and treated by autotransplantation of PBMNCs in our center were enrolled and analyzed. The primary endpoint was major amputation-free survival (MAFS), the secondary endpoints included peak pain-free walking time (PPFWT), Wong-Baker FACES pain rating scale score (WFPRSS), labor recovery, ankle-brachial index (ABI), transcutaneous partial oxygen pressure (TcpO2), and SF-36v2 scores. Results: A total of 58 patients were enrolled. During a minimal follow-up of 36 months, the MAFS was 93.1% and the labor competence restored rate was 62.1%. The WFPRSS was decreased from 8.7 ± 1.6 to 1.6 ± 3.2, and PPFWT was significantly improved from 2.9 ± 4.2 min to 16.6 ± 6.9 min. The quality of life was also significantly improved at each follow-up point. Perfusion evaluating parameters, such as ABI and TcPO2, were also significantly improved. No critical adverse event was observed during the treatment and follow-up period. Conclusions: The treatment of AICLTI by autotransplantation of PBMNCs demonstrated encouraging long-term results. It could not only restore labor competence, improve the quality of life, but also significantly reduce the major amputation rate.

Single-Cell Transcriptomes Combining with Consecutive Genomics Reveal Clonal Evolution and Gene Regulatory Networks in Relapsed and Refractory Multiple Myeloma.

This study attempted to investigate how clonal structure evolves, along with potential regulatory networks, as a result of multiline therapies in relapsed/refractory multiple myeloma (RRMM). Eight whole exome sequencing (WES) and one single cell RNA sequencing (scRNA-seq) were performed in order to assess dynamic genomic changes in temporal consecutive samples of one RRMM patient from the time of diagnosis to death (about 37 months). The 63-year-old female patient who suffered from MM (P1) had disease progression (PD) nine times from July 2017 [newly diagnosed (ND)] to Aug 2020 (death), and the force to drive branching-pattern evolution of malignant PCs was found to be sustained. The mutant-allele tumor heterogeneity (MATH) and tumor mutation burden (TMB) initially exhibited a downward trend, which was then upward throughout the course of the disease. Various somatic single nucleotide variants (SNVs) that had disappeared after the previous treatment were observed to reappear in later stages. Chromosomal instability (CIN) and homologous recombination deficiency (HRD) scores were observed to be increased during periods of all progression, especially in the period of extramedullary plasmacytoma. Finally, in combination with WES and scRNA-seq of P1-PD9 (the nineth PD), the intro-heterogeneity and gene regulatory networks of MM cells were deciphered. As verified by the overall survival of MM patients in the MMRF CoMMpass and GSE24080 datasets, RUNX3 was identified as a potential driver for RRMM.

[Clinical analysis of primary gastric diffuse large B-cell lymphoma].

OBJECTIVE: To analyze the clinical features and prognostic factors of primary gastric diffuse large B-cell lymphoma (PG-DLBCL) and to evaluate the staging system and treatment modality of PG-DLBCL. METHODS: The clinicopathological data of 69 patients with PG-DLBCL were retrospectively analyzed. Event-free survival (EFS) and overall survival (OS) were the primary endpoints. RESULTS: The EFS rates at 1, 3, and 5 years were 83.8%, 71.1%, and 69.0%, respectively, with a mean EFS of 91.3 months. The 1-, 3-, and 5-year OS rates were 91.3%, 80.3%, and 72.4%, respectively, with a mean OS of 98.8 months. Univariate analysis revealed that either EFS or OS was significantly prolonged by the following factors (P < 0.05): modified Ann Arbor stage I(E) or II(E1) disease; normal lactate dehydrogenase (LDH) level; normal hemoglobin level; normal albumin level; International Prognostic Index (IPI) of 0 or 1; tumor size < 5 cm; and less depth of invasion. While gender, age, B symptoms at presentation, performance status and treatment modality were not significantly associated with the prognosis (P > 0.05). Cox regression model revealed that only modified Ann Arbor stage and albumin level were independent prognostic factors for EFS and OS. CONCLUSION: The most accurate staging system and the exact role of different therapeutic options for PG-DLBCL are still debated. Further randomized prospective studies with a large number of patients are still needed to establish an optimal management for this disease.

Autologous peripheral blood-derived stem cells transplantation for treatment of no-option angiitis-induced critical limb ischemia: 10-year management experience.

BACKGROUND: Previous studies have demonstrated that no-option angiitis-induced critical limb ischemia (NO-AICLI) could be significantly improved by transplantation of peripheral blood-derived stem cells (PBDSCs). Additionally, a randomized controlled trial (RCT) recently conducted by us suggested that peripheral blood-derived purified CD34+ cells (PCCs) were not inferior to non-purified peripheral blood mononuclear cells (PBMNCs) at limb salvage in treatment of NO-AICLI. However, most of these clinical trials whether RCT or single-arm studies were characterized with a small sample size and absence of long-term outcomes. METHODS: To analyze long-term clinical outcomes of PBDSCs transplantation for NO-AICLI, we reviewed clinical data of patients with NO-AICLI receiving PBDSCs transplantation at our center during the past decade. Meanwhile, we first compared the long-term safety and efficacy of intramuscular transplantation of PCCs versus PBMNCs in a sizable number of patients with NO-AICLI. RESULTS: From May 2009 to December 2019, a total of 160 patients with NO-AICLI patients were treated by PBDSCs transplantation (82 with PCCs, 78 with PBMNCs) at our center. Baseline characteristics between two groups were similar. Up to June 2020, the mean follow-up period was 46.6 ± 35.3 months. No critical adverse events were observed in either group. There was one death during the follow-up period. A total of eight major amputations occurred. The cumulative major amputation-free survival (MAFS) rate at 5 years after PBDSCs transplantation was 94.4%, without difference between two groups (P = .855). Wound healing, rest pain, pain-free walking time, ankle-brachial index, transcutaneous oxygen pressure, and quality of life (QoL) also significantly improved after PBDSCs transplantation. CONCLUSIONS: Autologous PBDSCs intramuscular transplantation could significantly decrease the major amputation rates and improve the QoL in patients with NO-AICLI. Long-term observation of a large sample of patients confirmed that the clinical benefits of PBDSCs transplantation were durable, without difference between the PCCs and PBMNCs groups.

The paradoxical prognostic role of 1q21 Gain/Amplification in multiple myeloma: every coin has two sides.

The prognostic value of 1q21 Gain/Amplification (1q21 Gain/Amp) in multiple myeloma (MM) has always been controversial. A total of 419 newly diagnosed MM patients were included in this retrospective study. The positive rate of 1q21 Gain/Amp was 48.6%. MM patients with 1q21 Gain/Amp were characterized as being in more advanced clinical stages and were more likely to be accompanied by del(13q14), t(4;14) or complex karyotypes (CKs) as well as with more severe anemia and worse renal function. In these patients, the percentage of complete remission (CR) or very good partial response (VGPR) was higher, however, in the early treatment period, the probability of progressive disease (PD) was also higher. No significant difference on progression free survival (PFS) and overall survival (OS) was showed between the group of 1q21Amp and 1q21Gain. The prognostic impact of 1q21 Gain/Amp on PFS of MM patients was heterogeneous and was in accordance with the accompanying parameters.

Predictors of responders to mononuclear stem cell-based therapeutic angiogenesis for no-option critical limb ischemia.

BACKGROUND: Although the mononuclear cell (MNC) transplantation could theoretically induce therapeutic angiogenesis in the patients with no-option critical limb ischemia (NO-CLI), the clinical responses to this approach are inconsistent among different clinical trials. The purpose of this study was to identify the prognostic factors of responders and develop a predictive nomogram to guide patient selection. METHODS: We retrospectively reviewed a consecutive NO-CLI cohort who received peripheral blood-derived transplantation in our center. The patients who survived and achieved complete remission of CLI at 6 months post-transplantation were defined as responders. Logistic regression models were used to screen and identify the prognostic factors based on which predictive nomogram was developed. A receiver operating characteristic (ROC) curve and a calibration curve were drawn to determine the discrimination level and predictive accuracy. RESULTS: The study ultimately enrolled 103 patients, including 58 responders and 45 non-responders. Based on the multivariate regression analysis, age ≥ 50 years (odds ratio [OR] 0.201, P = 0.004), blood fibrinogen > 4 g/L (OR 0.176, P = 0.003), arterial occlusion above the knee/elbow (OR 0.232, P = 0.010), the transcutaneous pressure of oxygen (TcPO2) (OR 1.062, P = 0.006), and the Log total transplanted CD34+ cell count (OR 3.506, P = 0.046) were identified as independent prognostic factors of the responders in the nomogram. An area under the ROC curve of 0.851 indicated good discrimination, and the calibration curve of the predicted probability showed optimal agreement with that of the observed probability. CONCLUSIONS: Age, blood fibrinogen, arterial occlusion level, TcPO2, and the total transplanted CD34+ cell count were independent prognostic factors of the responders. A nomogram with high discrimination and accuracy was developed to provide individualized predictions. TRAIL REGISTRATION: ChiCTR, ChiCTR1800019401 . Registered 9 November 2018-Retrospectively registered.

A Five-Year Study of the Efficacy of Purified CD34+ Cell Therapy for Angiitis-Induced No-Option Critical Limb Ischemia.

Angiitis-induced critical limb ischemia (AICLI) patients constitute a remarkable proportion of no-option critical limb ischemia (CLI) patients. Stem cell therapy has become an innovative and promising option for no-option CLI patients. As one of these promising stem cell therapies, purified CD34+ cell transplantation (PuCeT) has shown favorable short-term results. However, the long-term efficacy of PuCeT has yet to be reported. This study evaluates the long-term efficacy of PuCeT in AICLI patients. Twenty-seven AICLI patients were enrolled from May 2009 to December 2011. Granulocyte colony-stimulating factor (G-CSF) and enoxaparin sodium were administered for 5 days. On day 5, CD34+ cell isolation was performed, and cells were transplanted by intramuscular injection. The primary endpoint, major-amputation-free survival rate (MAFS), as well as secondary endpoints, such as peak pain-free walking time (PPFWT) and the Wong-Baker FACES pain rating scale score (WFPRSS), were routinely evaluated during the 5-year follow-up period. The endpoints were as follows: the MAFS was 88.89%; PPFWT increased from 3 ± 3 to 17 ± 6 minutes; WFPRSS decreased from 7 ± 2 to 0.3 ± 1.7; the ulcer healing rate was 85.71%; the recurrence rate was 11.11%; and SF-36v2 scores were significantly improved at 5 years after PuCeT. The rate of labor recovery 5 years after PuCeT was 65.38%, and no severe adverse effect was observed during the treatment. PuCeT demonstrated long-term efficacy and durability as a treatment of AICLI not only in achieving limb salvage but also in recovering the labor competence and improving the quality of life of patients. Stem Cells Translational Medicine 2018;7:583-590.

Purified CD34+ cells versus peripheral blood mononuclear cells in the treatment of angiitis-induced no-option critical limb ischaemia: 12-Month results of a prospective randomised single-blinded non-inferiority trial.

BACKGROUND: Peripheral blood mononuclear cells (PBMNCs) and purified CD34+ cells (PCCs) are increasingly being used at treating no-option critical limb ischaemia (NO-CLI). We aimed to compare the efficacies and uncover the advantages associated with each treatment approach. METHODS: A randomised single-blinded non-inferiority trial (Number: NCT 02089828) was performed. NO-CLI patients were 1:1 randomised to the PBMNCs and PCCs groups, and compared in relation to safety and efficacy outcomes. The primary efficacy outcomes included major amputation and total amputation over 12 months. The major amputation-free survival (MAFS) and total amputation-free survival (TAFS) rates were calculated. FINDINGS: Fifty patients (25 per group, 47 with thromboangiitis obliterans and 3 with other angiitis) were enrolled, with a median follow-up period of 24.5 months (interquartile range: 17-34 months). One patient in the PCCs group was lost at 2 months and one major amputation occurred in the PBMNCs group at 3 months post-transplantation. The total amputation rates at 6 months post-transplantation were 28.0% in the PCCs group and 16.0% in the PBMNCs group (p = 0.343), and remained unchanged at 12 months. The groups did not differ regarding the MAFS and TAFS (Breslow-Wilcoxon test: p = 0.3014 and p = 0.3414). The PCCs group had a significantly higher probability of rest pain relief than the PBMNCs group (Breslow-Wilcoxon test: p = 0.0454). INTERPRETATION: PCCs was not inferior to PBMNCs at limb salvage in the treatment of angiitis-induced NO-CLI and appeared to induce earlier ischaemia relief. Each cell type had specific advantages. These outcomes require verification from longer-term trials involving larger numbers of patients. FUND: Training program for outstanding academic leaders of Shanghai health and family planning system (Hundred Talent Program，Grant No. 2018BR40); China National Natural Science Funds (Grant No. 30801122); The excellent core member training programme at Zhongshan Hospital, Fudan University, China (Grant No. 2015ZSYXGG02); and Zhongshan Funds for the Institute of Vascular Surgery, Fudan University, China. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (NCT 02089828).

Vinorelbine and capecitabine in anthracycline- and/or taxane-pretreated metastatic breast cancer: sequential or combinational?

PURPOSE: The difference between combinational and pre-planned sequential therapies using regimens that include non-anthracycline and taxane in the first-line setting remains unclear. The purpose of this study is to explore the interaction between vinorelbine (N) and capecitabine (X) in breast cancer cells and to compare the simultaneous or sequential administration of the two drugs in patients with metastatic breast cancer (MBC) as first-line treatment. METHODS: First, we explored the effects of vinorelbine on thymidine phosphorylase (TP) and thymidylate synthase (TS) expression in breast cancer cells. Next, we designed a prospective randomized phase II trial of MBC patients comparing the combinational and pre-planned sequential administration of vinorelbine and capecitabine in the first-line metastatic setting. The primary end point was progression-free survival (PFS). The correlation between clinical characteristics and class III ß-tubulin expression and patient survival was also explored. RESULTS: Vinorelbine upregulates TP and downregulates TS in breast cancer cells, thereby further sensitizing tumor cells to capecitabine, which indicated the proper order for sequential therapy should be N → X. Sixty patients were eligible for the phase II trial. No significant difference was observed between the combinational arm and the sequential arm in terms of progression-free survival (PFS), overall response rate (ORR), and overall survival (OS). Only in the subgroup of patients with liver metastases were median PFS and OS significantly prolonged in the combinational arm (8.5 vs. 6.4 months, P = 0.041 and 23.8 vs. 13.9 months, P = 0.028, respectively). No association between class III ß-tubulin expression and patient outcome was identified. Grade 3/4 adverse events were more common in the combinational arm. CONCLUSIONS: Both the NX regimen and pre-planned sequential N → X regimen are acceptable as first-line treatments with comparable efficacies for MBC patients previously treated with anthracyclines and/or taxanes. Sequential monotherapies are recommended as the preferred approach to first-line chemotherapy for most MBC patients in the absence of an imminent visceral crisis and the need for rapid symptom and/or disease control.

[A clinical comparative study on treatment of severe newly diagnosed immune thrombocytopenia by recombinant human thrombopoietin combined with glucocorticoid].

OBJECTIVE: To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with glucocorticoid in treatment of severe newly diagnosed primary immune thrombocytopenia (ITP). METHODS: From June 2009 to December 2012, 24 male patients and 38 female patients with the diagnosis of severe primary ITP in our hospital were randomized into trial group (31 cases) or control group (31 cases), the median age was 50 years (range: 21-84 years). Trial group was treated with rhTPO combined with glucocorticoid, and control group was treated with glucocorticoid only. RESULTS: At the day 3, 7 and 14 from the beginning of treatment, the average platelet count (APC) in trial group[(35.5±24.9)×109/L, (135.2±94.9)×109/L and (192.0±109.1)×109/L]were significantly higher than that in control group[(24.5±15.6)×109/L, (78.2±121.9)×109/L and (95.8±60.5)×109/L, P=0.022, 0.009 and 0.001, respectively]. There was no significant difference in APC between the two groups at day 28 and 90 after treatment[(147.8±59.1)×109/L vs (105.1±56.9)×109/L, P=0.243; (137.4±52.3)×109/L vs (104.3±59.8)×109/L, P=0.568, respectively]. At the day 7, 14 and 28, the complete response rates in trial group were 61.3%, 87.1% and 80.6%, which were also significantly higher than that in control group (16.1%, 29.0% and 48.3%, P=0.000, 0.000 and 0.004, respectively). The median time to response in trial group was 3 days while in the control group was 5 days; the median duration of complete response in trial group was 76 days while in the control group was 54 days. In trial group, there were 4 cases treated with platelet transfusion, while in control group there were 11 cases, respectively. CONCLUSION: For patients with severe primary ITP, rhTPO combined with glucocorticoid could rapidly increase the platelet count, significantly improve the complete response rate and prolonged the effect with a low incidence of tolerable adverse events compared to single use of glucocorticoid. rhTPO combined with glucocorticoid could be a new therapeutic choice to those patients.

ERCC2 Lys751Gln polymorphism is associated with lung cancer among Caucasians.

To derive a more precise estimation of the relationship between the excision repair cross-complementing rodent repair deficiency, group 2 (ERCC2) Lys751Gln polymorphism and lung cancer risk, a meta-analysis was performed. A total of 23 studies including 8137 cases and 9824 controls were involved in this meta-analysis. Overall, significantly elevated lung cancer risk was associated with ERCC2 Gln allele when all studies were pooled into the meta-analysis (Lys/Gln versus Lys/Lys: odds ratio (OR)=1.10, 95% confidence interval (CI)=1.03-1.19; Gln/Gln versus Lys/Lys: OR=1.20, 95% CI=1.06-1.35; dominant model: OR=1.13, 95% CI=1.05-1.20; and recessive model: OR=1.15, 95% CI=1.03-1.29). In the subgroup analysis by ethnicity, significantly increased risk was only found for Caucasians (Gln/Gln versus Lys/Lys: OR=1.25, 95% CI=1.08-1.45; dominant model: OR=1.10, 95% CI=1.00-1.22; and recessive model: OR=1.22, 95% CI=1.06-1.40). When stratified by study design, statistically significantly elevated risks were found in hospital-based studies (Lys/Gln versus Lys/Lys: OR=1.12, 95% CI=1.03-1.22; Gln/Gln versus Lys/Lys: OR=1.24, 95% CI=1.06-1.44; dominant model: OR=1.15, 95% CI=1.06-1.24; and recessive model: OR=1.19, 95% CI=1.03-1.37) and population-based studies (Gln/Gln versus Lys/Lys: OR=1.57, 95% CI=1.12-2.20 and recessive model: OR=1.50, 95% CI=1.08-2.07). In the subgroup analysis whether or not the studies were matched on smoking, significantly increased risk was found not in those matched studies but in the unmatched studies (Lys/Gln versus Lys/Lys: OR=1.11, 95% CI=1.03-1.19; Gln/Gln versus Lys/Lys: OR=1.22, 95% CI=1.07-1.40; dominant model: OR=1.13, 95% CI=1.05-1.22; and recessive model: OR=1.18, 95% CI=1.04-1.33). In conclusion, this meta-analysis suggests that the ERCC2 Lys751Gln polymorphism may contribute to lung cancer susceptibility among Caucasians.