The Role of Aging and Senescence in Immune Checkpoint Inhibitor Response and Toxicity.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system, on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Urologic Complications in 4000 Kidney Transplants Performed at the Saint Barnabas Health Care System.

Renal transplantation is the current standard treatment for end-stage renal disease and is associated with immunologic, vascular, and urologic complications. In this study we report urologic complications following ureteral reimplantation based on 1 urologist's experience at a single high-volume renal transplant institution. METHODS: A retrospective review was performed on all patients who underwent ureteral reimplantation by the transplant urologist at the time of their kidney transplant between July 1, 1993, and December 31, 2016. RESULTS: There was a total of 3951 ureteral reimplantations performed for 3890 renal transplants. The overall complication rate was 7% (276 patients). Vesicoureteral reflux was the most common complication (4.25%), followed by ureteral stricture (1.9%), urine leak (0.6%), and de novo ureteropelvic junction obstruction (0.25%). CONCLUSION: This study is a continuation of our previous case series. Over time, our overall rate of urologic complications has increased. Vesicoureteral reflux has remained the most common complication with increasing incidence compared with our prior reviews. One possible cause for increased incidence is our thorough longitudinal follow-up over more than 2 decades. Some patients who previously had no evidence of reflux eventually did in fact develop reflux. The incidence of ureteral stricture, urine leak, and ureteropelvic junction obstruction has overall remained stable over the past 23 years. In our program, 1 transplant urologist has performed almost all ureteroneocystostomies, leading to consistent management and generalizable results. Review of the literature shows variable rates of complications among different studies with multiple surgeons, disparate techniques, and short follow-up. Our study eliminates many of these confounding factors and provides more reliable, reproducible data.

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

Laparoscopic splenectomy to salvage renal transplants from severe acute antibody-mediated rejection.

Purpose. Acute antibody-mediated rejection, a complication of cross match positive and sensitized renal transplants, occurs despite the use of standard desensitization protocols. Rescue therapy consists of plasmapheresis and intravenous immunoglobulin (IVIg). In patients with preformed donor specific antibodies, rejection can be aggressive. We report here a case in which laparoscopic splenectomy was added to the standard rescue regimen. Case Report and Results. A 40-year-old Hispanic female with end stage renal disease had been receiving hemodialysis. The patient had numerous class 1 unacceptable antigens. She was scheduled to undergo an incompatible 1-1-1 mismatch living related donor kidney transplant. Preoperatively, the patient received plasmapheresis, IVIG, and thymoglobulin. There was good graft function until postoperative day 5. At that point, worsening renal function was noted. Renal biopsy was consistent with AMR. The patient became anuric and dialysis was initiated. To salvage the transplant, the patient underwent laparoscopic splenectomy. Postoperatively, renal function improved. Two years after transplant, the patient continues to have excellent graft function. Conclusion. In a small but significant number of renal transplants, antibody production occurs at a rate that traditional treatments are unable to reduce effectively. Based on our experience, the addition of splenectomy to standard rescue therapy can salvage renal transplants.

Vascular constraints in laparoscopic renal allograft: comparative analysis of multiple and single renal arteries in 976 laparoscopic donor nephrectomies.

BACKGROUND: Since the initial description of laparoscopic donor nephrectomy (LDN) in 1995, the field of renal transplantation has continued to evolve. Although the identification of donor kidneys with multiple renal arteries (MRA) was considered a contraindication to LDN, improvement in the surgical technique to surmount the technical challenges of LDN with MRA have been established as the skill and laparoscopic experience of transplant surgeons evolves with time. Consensus regarding LDN with MRA and recipient outcomes is not uniformly documented amongst the transplant community. METHODS: A retrospective analysis of 976 patients who underwent LDN at our institution from January 1999 to August 2009 was performed. Patients were grouped based on the number of arteries and the data were compared with respect to patient demographics, operative characteristics, postoperative course and complications. RESULTS: The two donor groups had comparable outcomes except for operative time, which was significantly prolonged in patients with MRA kidneys when compared to a single renal artery (SRA) kidney (P < 0.01). 1-, 3-year and estimated overall graft survival for the MRA recipient kidneys was significantly inferior when compared to SRA recipient kidneys. CONCLUSIONS: Our decade long experience with LDN demonstrates that operative times for MRA kidneys are longer than for SRA kidneys, however complication rates are similar. Laparoscopic donor nephrectomy with MRA is a safe and effective procedure for living kidney donation; however, the recipient graft outcomes with MRA kidneys warrant appropriate preoperative counseling of recipients.