Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

Petromyzontidae-Biomimetic Multimodal Microneedles-Integrated Bioelectronic Catheters for Theranostic Endoscopic Surgery

Current catheter devices in minimally invasive surgery still possess limited functional options, lacking multimodal integration of both sensing and therapy. Catheter devices usually operate outside the tissue, incapable to detect intra-tissue biochemical information for accurate localization and assessment of lesions during surgery. Inspired by the feature and functions of Petromyzontidae, here a multimodal core-shell microneedles-integrated bioelectronic catheter (MNIBC) for tissue-penetrating theranostics in endoscopic surgery is developed. The microneedle (MN) device possesses individually addressable functionality at single-MN tip resolution, enabling multiplex functions (a total of 11 functions distributed in three types of catheters) including biochemical sensing, myoelectric modulation, electroporation, and drug delivery in a submucosal environment. The MNIBC is prepared through hybrid fabrication and dimensionality reduction strategies, where the MN electrodes are functionalized with an MXene-carbon nanotube (MXene-CNT)-based electron mediator, addressing the challenge of reduced electrode sensitivity on ultra-small MN tip. The functionalities of MNIBC are demonstrated both ex vivo and in vivo on anesthetized rabbits via laparoscopy, simulated cystoscopy, and laparotomy. The MNIBC can effectively detect intra-tissue biochemical signals in the bladder, and offers localized electroporation and intra-tissue drug delivery for precise treatments of lesions. The versatile features of the MNIBC present a highly advanced platform for precise surgeries.     

Antibiotic lock: In vitro stability of gentamicin and sodium citrate stored in dialysis catheters at 37 °C

Catheter‐related bacteremia (CRB) is a major cause of morbidity and mortality especially among patients receiving hemodialysis. Antibiotic lock therapy represents a promising technique in the treatment of CRB. Several studies have evaluated antibiotics in combination with heparin as an interdialytic locking solution for prophylaxis of CRB. The objective of this study was to evaluate the stability of gentamicin and sodium citrate in hemodialysis catheters as an interdialytic lock. Solutions containing gentamicin 2.5 mg/mL and sodium citrate 40 mg/mL (4%) were prepared individually and in combination. The solutions were instilled into dialysis catheters and stored at 37 °C for 96 h. Samples were withdrawn randomly from catheter lumens at 24‐hour intervals for 4 days and stored at ?20 °C until analysis. The samples were analyzed with validated, stability‐indicating HPLC assays. The luminal concentration of gentamicin 2.5 mg/mL, sodium citrate 40 mg/mL (4%), and the combination was determined on study days 0, 1, 2, 3, and 4. When gentamicin was combined with sodium citrate and stored at 37 °C in dialysis catheters, the solution showed no decrease in either the gentamicin or the sodium citrate concentrations over the 96‐hour study period. The percent of the original concentration at 96 h was 102.4±1.03 for gentamicin and 102.9±1.25 for citrate (P=0.5556). The combination of gentamicin 2.5 mg/mL and sodium citrate 40 mg/mL (4%) can be retained in hemodialysis catheters for at least 96 h at 37 °C with no evidence of degradation.     

Blood Access Outcomes Associated with Short Daily Hemodialysis

With the growing number of reports that daily hemodialysis (DHD) improves clinical outcomes and quality of life, there has been increased interest in the effects of more frequent venipunctures on blood accesses. Since 1996, we have converted 30 patients (27 in‐center, 3 home) from conventional 3/week dialysis to short, daily, 6/week dialysis (sDHD). Twenty‐five patients started for medical indications. End‐stage renal disease (ESRD) causes were diabetes mellitus (in 7), hypertension (6), glomerulonephritis (8), hereditary nephritis (2), and other (7). Mean (±SD) age was 57 ± 16 years. Patients had an average of 3.8 major comorbidities in addition to ESRD. Thirty patients were followed on sDHD for 388 patient‐months: 9 patients died after 4.2 ± 6.7 months, 3 were transplanted at 5.4 ± 2.2 months, and 3 were disenrolled at 9.3 ± 10.5 months. Fifteen patients remain on sDHD at 20.4 ± 14.1 months. Access problems for the 12 months prior to sDHD were compared to those that occurred while the patient was on sDHD. Problems were tracked by access type. There were 40 different accesses in 30 patients with a cumulative 28.07 access‐years pre‐DHD; 24 of these accesses were artificial bridge grafts (ABG) of either polytetrafluoroethylene or bovine material. There were 27 access problems pre‐DHD, or 0.962 problems per access‐year. On sDHD these same 30 patients had 41 accesses for 34.44 access‐years; 23 of these were ABGs. There were 31 access problems or 0.900 problems per access‐year. There were no significant differences in access problems comparing pre‐DHD with on‐sDHD, either in aggregate or when analyzed by access type. After 39 months of observation, there does not appear to be an increase in blood access problems when patients are converted from conventional dialysis to sDHD.     

Surgical Revision and Early Cannulation of the Arteriovenous Fistula in Hemodialysis Patients: An Effective Technique

Arteriovenous fistula (AVF) dysfunction is a common problem in hemodialysis patients. After surgical revision for malfunction, we used AVFs early to avoid complications associated with central venous catheters. In this study, we report experience with surgical revisions of native AVFs with suspected arterial dysfunction as the cause of inadequate arterial inflow for dialysis. Exclusion criteria were presence of a central venous catheter as a hemodialysis access, and clinical or radiologic evidence of stenosis or thrombosis of the distal venous segment of the AVF. We prospectively studied 50 patients (mean age 60.2 ± 10.5 years, 25 men and 25 women) with 59 revisions. The patients were followed until change in the modality of dialysis, transplant, or death. The types of AVFs revised were left wrist radiocephalic in 27 patients (54%), left forearm radiocephalic in 10 (20%), right wrist radiocephalic in 6 (12%), left antecubital brachiocephalic in 3 (6%), right antecubital brachiocephalic in 2 (4%), and right forearm radiocephalic in 2 (4%). The causes of inadequate arterial flow were juxta‐anastomotic thrombosis in 20 patients (40%), inadequate arterial anastomotic flow in 16 (32%), inadequate anastomosis in 7 (14%), and juxta‐anastomotic venous stenosis in 7 (14%). The primary surgical revision techniques were proximal neo‐anastomosis using the semiarterialized vein in 43 patients (86%), thrombectomy and re‐anastomosis in 5 (10%), and resection and repair in 2 (4%). Technical success, defined as successful cannulation of the revised AVF for hemodialysis and avoidance of central venous catheter, was achieved in 44 of 50 patients (88%). Technical failure occurred 6 cases, the causes being inadequate arterial flow in 3 patients, failure to cannulate the veins in 2 patients, and steal syndrome in 1 patient. After primary revisions failed, 9 re‐revisions were done in 6 patients. The 1‐year, 2‐year, and 3‐year primary and overall patency rates were 76.2%, 67.6%, 65.0%, and 85.7%, 75.7%, 65.0%, respectively. In conclusion, surgical salvage of the AVF with inadequate arterial flow is an effective approach that can be performed as an outpatient procedure and allows early cannulation of the semi‐arterialized veins, thus avoiding the use of central venous catheters.     

腹膜透析治疗心脏手术后急性肾功能衰竭

目的探讨腹膜透析（PD）对心脏手术后急性肾功能衰竭（ARF）的治疗效果。方法选择心脏手术后ARF患者26例,采用2．5％葡萄糖透析液行PD。观察透析前和透析后24、48、72、96h时尿量、超滤量、电解质、血尿素氮（BUN）、血肌酐（Cr）的变化。结果PD时间3～16d,26例患者中23例患者肾功能恢复至术前水平,1例死于多脏器功能衰竭,2例自动放弃治疗。23例患者经PD治疗后,尿量逐渐增加,BUN、Cr明显低于PD前（P〈0．05）。未发生严重并发症。结论PD安全、经济、有效,是心脏手术后治疗ARF的首要选择。