Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era.

BACKGROUND: Radiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed. METHODS: We retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed. RESULTS: A total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3-5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2-27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported. CONCLUSION: These data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Hyaluronic Acid-Based Nanocarriers for Anticancer Drug Delivery.

Hyaluronic acid (HA), a main component of the extracellular matrix, is widely utilized to deliver anticancer drugs due to its biocompatibility, biodegradability, non-toxicity, non-immunogenicity and numerous modification sites, such as carboxyl and hydroxyl groups. Moreover, HA serves as a natural ligand for tumor-targeted drug delivery systems, as it contains the endocytic HA receptor, CD44, which is overexpressed in many cancer cells. Therefore, HA-based nanocarriers have been developed to improve drug delivery efficiency and distinguish between healthy and cancerous tissues, resulting in reduced residual toxicity and off-target accumulation. This article comprehensively reviews the fabrication of anticancer drug nanocarriers based on HA in the context of prodrugs, organic carrier materials (micelles, liposomes, nanoparticles, microbubbles and hydrogels) and inorganic composite nanocarriers (gold nanoparticles, quantum dots, carbon nanotubes and silicon dioxide). Additionally, the progress achieved in the design and optimization of these nanocarriers and their effects on cancer therapy are discussed. Finally, the review provides a summary of the perspectives, the lessons learned so far and the outlook towards further developments in this field.

Metastasis risk stratification and response prediction through dynamic viable circulating tumor cell counts for rectal cancer in a neoadjuvant setting.

PURPOSE: Distant metastasis (DM) and neoadjuvant treatment response prediction remain critical challenges in the management of locally advanced rectal cancer (LARC). The aim of this study was to investigate the clinical relevance of viable circulating tumor cells (CTCs) for DM or response in patients with LARC in a neoadjuvant setting. METHODS: The detection of viable CTCs at different stages of treatment was planned for consecutive patients from a prospective trial. The Kaplan-Meier method, Cox proportional hazards model, and logistic regression model were utilized to analyze factors associated with DM or pathological complete response (pCR) and clinical complete response (cCR). RESULTS: Between December 2016 and July 2018, peripheral blood samples from 83 patients were collected before any treatment (median follow-up time, 49.3 months). CTCs were present in 76 of 83 patients (91.6%) at baseline, and more than three CTCs detected in the blood sample was considered high risk. Only the CTC risk group was significantly associated with 3-year metastasis-free survival (MFS) (high risk vs. low risk, 57.1% (95% CI, 41.6-72.6) vs. 78.3% (95% CI, 65.8-90.8), p = 0.018, log-rank test). When all the important variables were entered into the Cox model, the CTC risk group remained the only significant independent factor for DM (hazard ratio (HR), 2.74; 95% CI, 1.17-6.45, p = 0.021). The pCR and continuous cCR rates were higher in patients with a decreased number of CTCs of more than one after radiotherapy (HR, 4.00; 95% CI, 1.09-14.71, P = 0.037). CONCLUSIONS: The dynamic detection of viable CTCs may strengthen pretreatment risk assessment and postradiotherapy decision making for LARC. This observation requires further validation in a prospective study.

Research progress on tumor hypoxia-associative nanomedicine.

Hypoxia at the solid tumor site is generally related to the unrestricted proliferation and metabolism of cancerous cells, which can cause tumor metastasis and aggravate tumor progression. Besides, hypoxia plays a substantial role in tumor treatment, and it is one of the main reasons that malignant tumors are difficult to cure and have a poor prognosis. On account of the tumor specific hypoxic environment, many hypoxia-associative nanomedicine have been proposed for tumor treatment. Considering the enhanced targeting effect, designing hypoxia-associative nanomedicine can not only minimize the adverse effects of drugs on normal tissues, but also achieve targeted therapy at the lesion site. Mostly, there can be three strategies for the treatment of hypoxic tumor, including improvement of hypoxic environment, hypoxia responsive drug release and hypoxia activated prodrug. The review describes the design principle and applications of tumor hypoxia-associative nanomedicine in recent years, and also explores its development trends in solid tumor treatment. Moreover, this review presents the current limitations of tumor hypoxia-associative nanomedicine in chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy and immunotherapy, which may provide a reference for clinic translation of tumor hypoxia-associative nanomedicine.

Orphan gene PpARDT positively involved in drought tolerance potentially by enhancing ABA response in Physcomitrium (Physcomitrella) patens.

Almost all genomes have orphan genes, the majority of which are not functionally annotated. There is growing evidence showed that orphan genes may play important roles in the environmental stress response of Physcomitrium patens. We identified PpARDT (ABA-responsive drought tolerance) as a moss-specific and ABA-responsive orphan gene in P. patens. PpARDT is mainly expressed during the gametophytic stage of the life cycle, and the expression was induced by different abiotic stresses. A PpARDT knockout (Ppardt) mutant showed reduced dehydration-rehydration tolerance, and the phenotype could be rescued by exogenous ABA. Meanwhile, transgenic Arabidopsis lines exhibiting heterologous expression of PpARDT were more sensitive to exogenous ABA than wild-type (Col-0) plants and showed enhanced drought tolerance. These indicate that PpARDT confers drought tolerance among land plants potentially by enhancing ABA response. Further, we identified genes encoding abscisic acid receptor PYR/PYL family proteins, and ADP-ribosylation factors (Arf) as hub genes associated with the Ppardt phenotype. Given the lineage-specific characteristics of PpARDT, our results provide insights into the roles of orphan gene in shaping lineage-specific adaptation possibly by recruiting common pre-existed pathway components.

Limitations and challenges of direct cell reprogramming in vitro and in vivo.

Direct reprogramming, whether in vitro or in vivo, has attracted great attention because of its advantages of convenience, short-term conversion, direct targets, no immune rejection, and potential clinical applications. In addition, due to its independence from the pluripotent state, direct programming minimizes some safety concerns associated with the use of human pluripotent stem cells. However, the significant limitations of reprogrammed cells, such as poor proliferative ability, low efficiency, and immature function, need to be addressed before the clinical application potential can be expanded. Here, we review the recent achievements of direct reprogramming in 2D and 3D systems in vitro and in vivo, covering cells derived from the three germ layers from stem/progenitor cells to terminal cells, such as hepatocytes, pancreatic ß cells, cardiomyocytes, endothelial cells, osteoblasts, chondrocytes, neurons, and melanocytes. Combining our lab experiences with current work, we summarize the practical and potential issues that need to be solved and the prospects of strategies for addressing the current dilemmas. Through comprehensive analyses, it is concluded that the directions for dealing with efficiency and functionality issues could be the optimization of transcription factors, the upgradation for delivery systems, the regulation of epigenetic factors and pathways, and the improvement of cellular maintenance conditions. Besides, converting cells into the progenitor state firstly and then differentiating them into the desired cell types with chemical compounds may provide an approach to obtaining functional and safe converted cells in batches with a better proliferative ability. With the emergence of more and more direct reprogramming techniques and approaches with both safety and effectiveness, it is bound to bring a new dawn for mechanism research and therapeutic applications for relevant diseases in the future.

Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR).

PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node-positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

Current trends in three-dimensional visualization and real-time navigation as well as robot-assisted technologies in hepatobiliary surgery.

With the continuous development of digital medicine, minimally invasive precision and safety have become the primary development trends in hepatobiliary surgery. Due to the specificity and complexity of hepatobiliary surgery, traditional preoperative imaging techniques such as computed tomography and magnetic resonance imaging cannot meet the need for identification of fine anatomical regions. Imaging-based three-dimensional (3D) reconstruction, virtual simulation of surgery and 3D printing optimize the surgical plan through preoperative assessment, improving the controllability and safety of intraoperative operations, and in difficult-to-reach areas of the posterior and superior liver, assistive robots reproduce the surgeon's natural movements with stable cameras, reducing natural vibrations. Electromagnetic navigation in abdominal surgery solves the problem of conventional surgery still relying on direct visual observation or preoperative image assessment. We summarize and compare these recent trends in digital medical solutions for the future development and refinement of digital medicine in hepatobiliary surgery.

Heart rate-adjusted PR as a prognostic marker of long-term ventricular arrhythmias and cardiac death in ICD/CRT-D recipients.

OBJECTIVE: To evaluate the PR to RR interval ratio (PR/RR, heart rate-adjusted PR) as a prognostic marker for long-term ventricular arrhythmias and cardiac death in patients with implantable cardioverter defibrillator (ICDs) and cardiac resynchronization therapy with defibrillators (CRT-D). METHODS: We retrospectively analyzed data from 428 patients who had an ICD/CRT-D equipped with home monitoring. Baseline PR and RR interval data prior to ICD/CRT-D implantation were collected from standard 12-lead electrocardiograph, and the PR/RR was calculated. The primary endpoint was appropriate ICD/CRT-D treatment of ventricular arrhythmias (VAs), and the secondary endpoint was cardiac death. RESULTS: During a mean follow-up period of 38.8 ± 10.6 months, 197 patients (46%) experienced VAs, and 47 patients (11%) experienced cardiac death. The overall PR interval was 160 ± 40 ms, and the RR interval was 866 ± 124 ms. Based on the receiver operating characteristic curve, a cut-off value of 18.5% for the PR/RR was identified to predict VAs. A PR/RR ≥ 18.5% was associated with an increased risk of VAs [hazard ratio (HR) = 2.243, 95% confidence interval (CI) = 1.665-3.022, P < 0.001) and cardiac death (HR = 2.358, 95%CI = 1.240-4.483, P = 0.009) in an unadjusted analysis. After adjustment in a multivariate Cox model, the relationship remained significant among PR/RR ≥ 18.5%, VAs (HR = 2.230, 95%CI = 1.555-2.825, P < 0.001) and cardiac death (HR = 2.105, 95%CI = 1.101-4.025, P = 0.024. CONCLUSIONS: A PR/RR ≥ 18.5% at baseline can serve as a predictor of future VAs and cardiac death in ICD/CRT-D recipients.

Elevated plasma YKL-40 level is found in the dogs with cancer and is related to poor prognosis

YKL-40, a secreted glycoprotein, may serve as an autoantigen, which mediates multiple inflammatory diseases and cancers. A high YKL-40 serum level is correlated with metastasis and poor survival in a variety of human cancers. However, the role of YKL-40 in dogs is still under evaluation. Herein, we examined the associations between plasma YKL-40 level and YKL-40 autoantibody (YAA) titers with malignancy and prognosis in canine cancer. Plasma levels of YKL-40 in healthy dogs (n = 20) and in dogs (n = 82) with cancer were evaluated using enzyme-linked immunosorbent assay. Our results indicated that plasma YKL-40 levels were significantly higher (p 180 pg/mL) than in the low YKL-40 group (< 180 pg/mL). The results imply that plasma YKL-40 levels might have the potential to be developed as a marker of malignancy progression and prognosis in canine cancers.

Development of an oligonucleotide microarray for simultaneous detection of two canine MDR1 genotypes and association between genotypes and chemotherapy side effects

Canine MDR1 gene mutations produce translated P-glycoprotein, an active drug efflux transporter, resulting in dysfunction or over-expression. The 4-base deletion at exon 4 of MDR1 at nucleotide position 230 (nt230[del4]) in exon 4 makes P-glycoprotein lose function, leading to drug accumulation and toxicity. The G allele of the c.-6-180T>G variation in intron 1 of MDR1 (single nucleotide polymorphism [SNP] 180) causes P-glycoprotein over-expression, making epileptic dogs resistant to phenobarbital treatment. Both of these mutations are reported to be common in collies. This study develops a more efficient method to detect these two mutations simultaneously, and clarifies the genotype association with the side effects of chemotherapy. Genotype distribution in Taiwan was also investigated. An oligonucleotide microarray was successfully developed for the detection of both genotypes and was applied to clinical samples. No 4-base deletion mutant allele was detected in dogs in Taiwan. However, the G allele variation of SNP 180 was spread across all dog breeds, not only in collies. The chemotherapy adverse effect percentages of the SNP 180 T/T, T/G, and G/G genotypes were 16.7%, 6.3%, and 0%, respectively. This study describes an efficient way for MDR1 gene mutation detection, clarifying genotype distribution, and the association with chemotherapy.

Right ventricular outflow tract septal pacing versus apical pacing: A prospective, randomized, single-blind 5-years follow-up study of ventricular lead performance and safety.

Lead placement for ventricular pacing variably impacts the physiological benefit of the patient. This study evaluated the ventricular lead performance and safety of right ventricular outflow tract septal pacing in patients with bradyarrhythmia in South China over 60-month follow-up. Totally, 192 patients (108 males, and 84 females, 63±21 years old) with bradyarrhythmia were randomly divided into two groups. The right ventricular outflow tract septum (RVOTs) group had lead placement near the septum (n=97), while the right ventricular apex (RVA) group had a traditional apical placement (n=95). RV septal lead positioning was achieved with a specialized stylet and confirmed using fluoroscopic projection. All patients were followed up for 60 months. Follow-up assessment included stimulation threshold, R-wave sensing, lead impedance and lead complications. The time of electrode implantation in both the ROVTs and RVA groups were significantly different (4.29±0.61 vs. 2.16±0.22 min; P=0.009). No differences were identified in threshold, impedance or R-wave sensing between the two groups at 1st, 12th, 36th and 60th month during the follow-up period. No occurrence of electrode displacement, increased pacing threshold or inadequate sensing was found. The long-term active fixation ventricular electrode performance in RVOTs group was similar to that in RVA group. RVOTs pacing near the septum using active fixation electrodes may provide stability during long-term follow-up period.

Reduction of atrial fibrillation in remotely monitored pacemaker patients: results from a Chinese multicentre registry.

BACKGROUND: Many recipients of implantable cardiac electronic devices have atrial fibrillation (AF) occurrences after device implantation, even if there is no previous history of AF, and some of the episodes are asymptomatic. The purpose of this study was to evaluate trends in AF burden following early AF detection in patients treated with pacemakers equipped with automatic, daily Home Monitoring function. METHODS: Between February 2009 and December 2010, the registry recruited 701 pacemaker patients (628 dual-chamber, 73 biventricular devices) at 97 clinical centers in China. Daily Home Monitoring data transmissions were analyzed to screen for the AF burden. In-office follow-ups were scheduled for 3 and 6 months after implantation. Upon first AF (i.e., mode-switch) detection in a patient, screening of AF burden by Home Monitoring was extended for the next 180 days. RESULTS: At least one episode of AF was observed in 22.9% of patients with dual-chamber pacemakers and in 28.8% of patients with biventricular pacemakers. The first AF detection in a patient occurred, on average, about 2 months before scheduled follow-up visits. In both pacemaker groups, mean AF burden decreased significantly (P < 0.05) over 180 days following first AF detection: from 12.0% to 2.5% in dual-chamber and from 12.2% to 0.5% in biventricular pacemaker recipients. The number of patients with an AF burden >10% per month was significantly reduced over 6 months of implantation in both dual chamber (38 patients in the first month vs. 21 patients in month 6, P < 0.05) and biventricular (7 patients in the first month vs. 0 patient in months 4-6, P < 0.05) pacemaker recipients. CONCLUSIONS: Automatic, daily Home Monitoring of patients treated with cardiac pacemakers allows early detection of AF, and there is a gradual and significant decrease in AF burden.

Hydrogen sulphide protects H9c2 cells against chemical hypoxia-induced injury.

1. The aim of the present study was to investigate the effect of hydrogen sulphide (H(2)S) on cobalt chloride (CoCl(2))-induced injury in H9c2 embryonic rat cardiac cells. 2. After 36 h incubation in the presence of 600 micromol/L CoCl(2), reduced cell viability of H9c2 cells was observed, as well as the induction of apoptosis. In addition, CoCl(2) (600 micromol/L) enhanced the production of reactive oxygen species (ROS) and the expression of cleaved caspase 3, induced a loss of mitochondrial membrane potential (MMP) and decreased reduced glutathione (GSH) production. These results suggest that CoCl(2) induces similar responses to hypoxia/ischaemia. 3. Pretreatment of cells with 400 micromol/L NaHS (a H(2)S donor) for 30 min prior to exposure to CoCl(2) (600 micromol/L) significantly protected H9c2 cells against CoCl(2)-induced injury. Specifically, increased cell viability and decreased apoptosis were observed. In addition, NaHS pretreatment blocked the CoCl(2)-induced increases in ROS production and cleaved caspase 3 expression, as well as the decreases in GSH production and loss of MMP. 4. Pretreatment of cells with 2000 micromol/L N-acetylcysteine (NAC), a ROS scavenger, for 1 h prior to CoCl(2) exposure significantly protected H9c2 cells against CoCl(2)-induced injury, specifically enhancing cell viability, decreasing ROS production and preventing loss of MMP. 5. The findings of the present study suggest that H(2)S protects H9c2 cells against CoCl(2)-induced injury by suppressing oxidative stress and caspase 3 activation.

[Effect of cardiac resynchronization therapy on cardiac function post A-V and V-V optimization].

OBJECTIVE: To assess the effect of A-V, V-V delay optimization on cardiac function and clinical improvement in patients with refractory heart failure underwent cardiac resynchronization therapy (CRT). METHOD: Thirty-two patients with chronic heart failure received CRT and cardiac function was measured at 7 days, 3 months and 6 months post CRT before and after A-V and V-V delay optimizations. RESULTS: A-V delay optimization was initiated in 28, 10 and 6 cases at 7th day, 3rd month and 6th month after CRT. V-V delay optimization was performed in 29, 6 and 5 cases at 7th day, 3rd month and 6th month after CRT. Ts-SD, LVEF, VTI and E/Em were significantly improved after CRT compared to pre-CRT (P < 0.01, P < 0.05, P < 0.05, P < 0.05; respectively). Compared to pre-optimization, the indexes of ventricular synchronization were significantly improved (P < 0.05) while indexes of cardiac function remained unchanged post optimization at 7th day after CRT. The indexes of ventricular synchronization post optimization were similar at 7th, 3rd and 6th months after CRT (P > 0.05). LVEF and diastolic filling time were significantly increased after 6 months CRT post A-V, V-V delay optimization (P < 0.01). CONCLUSION: A-V, V-V delay optimization at 7th day after CRT can significantly improve ventricular synchronization and is associated with further improved cardiac function 6 months after CRT.