Ileal Interposition for Ureteral Reconstruction Following Treatment for Abdominopelvic Malignancy: Complications and Outcomes From a Comprehensive Cancer Center.

OBJECTIVE: To characterize the outcomes of ileal interposition for the management of ureteral obstruction from tumor and ureteral stricture following treatment for abdominopelvic malignancy. MATERIALS AND METHODS: A retrospective database analysis was performed for all cases of ileal interposition performed by 5 surgeons from January 2013 to December 2020. Patients were ≥18 years of age and included if undergoing ileal interposition in either the primary setting of a surgical procedure for tumor extirpation or in the delayed setting. RESULTS: In total, 23 patients who underwent repair of 27 ureteral units were included. The mean age was 60.2 years. Median follow-up was 21.6 months. The most common primary diagnoses were urothelial (35%), colorectal (31%), and cervical (22%) cancer. The etiologies of ureteral obstruction were malignant in 48% and ureteral stricture in 52%. Types of repairs included unilateral interposition in 13 patients, bilateral interposition in 1 patient, interposition to an ileal conduit in 3 patients, and interposition with cystoplasty in 6 patients. There was a statistically significant difference between the mean preoperative (Creatinine 1.05 mg/dL, Estimated Glomerular Filtration Rate 77 ml/min/1.73 m2) renal function and postoperative (Creatinine 1.26 mg/dL, Estimated Glomerular Filtration Rate 67 mL/min/1.73 m2) renal function at the most recent follow-up (P = .024). Eight minor (grade 1-2) and 6 major (grade ≥3) complications developed for a minor and major complication rate of 35% and 26%, respectively. CONCLUSION: Ileal interposition is successfully utilized as a reconstructive technique at the time of enbloc resection involving the ureter and to address ureteral stricture in the delayed setting.

Urethrocutaneous fistula repair following hypospadias surgery using the PATIO technique for small fistulae: A single centre experience.

INTRODUCTION: Urethrocutaneous fistula (UCF) development following primary hypospadias repair is a common complication with high rates of recurrence despite attempts at repair. A novel technique for the management of these fistulae, the PATIO (preserve the tract and turn it inside out) repair, has been described and has shown encouraging outcomes in previous reports. OBJECTIVE: The aim of this study was to evaluate fistula repair outcomes in patients undergoing the PATIO technique compared with standard repair. STUDY DESIGN: A retrospective chart-based review was performed for pediatric patients undergoing UCF repair from January 2005 to July 2018. Data including: age, follow-up, meatal location, meatal stenosis, number of fistulae and repairs, UCF location, complications, and outcomes was obtained. Cases were categorized into PATIO repair, standard repair, and PATIO repair following prior standard repair. Surgical outcome with respect to freedom from fistula recurrence was determined. RESULTS: In total, 586 patients underwent hypospadias surgery with 44 patients developing 52 UCF cases that required repair during the study period for a fistula rate of 8.9%. Mean age at repair was 19 months. Median follow-up time was 28 months. For PATIO repair alone, 21/26 (81%) had success. For standard repair alone, 8/18 (44%) had success and for standard repair followed by PATIO repair, 8/8 (100%) were successful. A statistically significant difference was noted for success when comparing standard repair with PATIO repair (p = 0.023, p < 0.05) and PATIO repair following standard repair (p = 0.010, p < 0.05). There was a statistically non-significant difference between PATIO repair and PATIO repair following standard repair (p = 0.309, p < 0.05). Failure following PATIO repair was found in cases where the procedure was early in implementation and experience was limited. DISCUSSION: UCF repair using the PATIO technique has shown encouraging results in the short-term, with a majority of patients achieving a successful outcome compared with standards techniques. As this procedure continues to be used and experience develops, a larger sample of cases will become available for analysis and longer follow-up will prove necessary in examining the long-term outcomes of this procedure. The outcomes examined have demonstrated consistency with previously reported outcomes in the literature. Limitations include small sample size, short-term follow up, and the retrospective nature of the review. CONCLUSIONS: The findings of this study have provided further support to the use of this technique in conventional UCF repair as a means to decrease the risk of recurrence and provide durable results in the short-term. Ongoing follow up will prove necessary to examine success in the long-term.

Remodeling of the tumor microenvironment through PAK4 inhibition sensitizes tumors to immune checkpoint blockade.

PAK4 inhibition can sensitize tumors to immune checkpoint blockade (ICB) therapy, however, the underlying mechanisms remain unclear. We report that PAK4 inhibition reverses immune cell exclusion by increasing the infiltration of CD8 T cells and CD103+ dendritic cells (DCs), a specific type of DCs that excel at cross-presenting tumor antigens and constitute a source of CXCL10. Interestingly, in melanoma clinical datasets, PAK4 expression levels negatively correlate with the presence of CCL21, the ligand for CCR7 expressed in CD103+ DCs. Furthermore, we extensively characterized the transcriptome of PAK4 knock out (KO) tumors, in vitro and in vivo, and established the importance of PAK4 expression in the regulation of the extracellular matrix, which can facilitate immune cell infiltration. Comparison between PAK4 wild type (WT) and KO anti-PD-1 treated tumors revealed how PAK4 deletion sensitizes tumors to ICB from a transcriptomic perspective. In addition, we validated genetically and pharmacologically that inhibition of PAK4 kinase activity is sufficient to improve anti-tumor efficacy of anti-PD-1 blockade in multiple melanoma mouse models. Therefore, this study provides novel insights into the mechanism of action of PAK4 inhibition and provides the foundation for a new treatment strategy that aims to overcome resistance to PD-1 blockade by combining anti-PD-1 with a small molecule PAK4 kinase inhibitor.

Primary localized amyloidosis causing urethral stricture disease: a mimicker of urothelial carcinoma.

We describe a case of mild lower urinary tract symptoms and microscopic hematuria in a 53-year-old-male with hypertension found to have urethral stricture disease suspicious for urothelial carcinoma. During the investigation, cystoscopy and biopsy demonstrated eosinophilic amyloid proteins consistent with primary localized urethral amyloidosis. No systemic evidence of amyloidosis was demonstrated. Following a trial of conservative management with serial dilatations, the patient elected to proceed with surgical management by anterior urethroplasty using an excision and primary anastomosis technique. The patient has done well with resolution of his symptoms and no further recurrence of urethral amyloid disease at ongoing follow up.

Trends in revision hip and knee arthroplasty observations after implementation of a regional joint replacement registry.

BACKGROUND: National joint replacement registries outside North America have been effective in reducing revision risk. However, there is little information on the role of smaller regional registries similar to those found in Canada or the United States. We sought to understand trends in total hip (THA) and knee (TKA) arthroplasty revision patterns after implementation of a regional registry. METHODS: We reviewed our regional joint replacement registry containing all 30 252 cases of primary and revision THA and TKA performed between Jan. 1, 2005, and Dec. 31, 2013. Each revision case was stratified into early (< 2 yr), mid (2-10 yr) or late (> 10 yr), and we determined the primary reason for revision. RESULTS: The early revision rate for TKA dropped from 3.0% in 2005 to 1.3% in 2011 (R(2) = 0.84, p = 0.003). Similarly, the early revision rate for THA dropped from 4.2% to 2.1% (R(2) = 0.78, p = 0.008). Despite primary TKA and THA volumes increasing by 35.5% and 39.5%, respectively, there was no concomitant rise in revision volumes. The leading reasons for TKA revision were infection, instability, aseptic loosening and stiffness. The leading reasons for THA revision were infection, instability, aseptic loosening and periprosthetic fracture. There were no discernible trends over time in reasons for early, mid-term or late revision for either TKA or THA. CONCLUSION: After implementation of a regional joint replacement registry we observed a significant reduction in early revision rates. Further work investigating the mechanism by which registry reporting reduces early revision risk is warranted.

CONTEXTE: Ailleurs qu'en Amérique du Nord, les registres nationaux des remplacements articulaires ont été efficaces pour réduire le risque de révision. Cependant, il y a peu d'information sur le rôle des plus petits registres régionaux comme ceux qu'on trouve au Canada et aux États-Unis. Nous avons donc cherché à comprendre les tendances en matière de révision des arthroplasties totales de la hanche (ATH) et du genou (ATG) après la création d'un registre régional. MÉTHODES: Nous avons passé en revue notre registre régional des remplacements articulaires, qui contient les 30 252 ATH et ATG primaires et de révision effectuées entre le 1er janvier 2005 et le 31 décembre 2013. Chaque cas de révision a été classé précoce (< 2 ans), moyen (de 2 à 10 ans) ou tardif (> 10 ans), et nous avons déterminé la raison principale de la révision. RÉSULTATS: Le taux de révision précoce pour l'ATG a diminué de 3,0 % en 2005 à 1,3 % en 2011 (R2 = 0,84, p = 0,003). De même, le taux de révision précoce pour l'ATH a diminué de 4,2 % à 2,1 % (R2 = 0,78, p = 0,008). Malgré une augmentation des nombres d'ATG et d'ATH primaires de 35,5 % et de 39,5 %, respectivement, il n'y a pas eu de hausse concomitante du nombre de révisions. Les principaux motifs de révision de l'ATG étaient l'infection, l'instabilité, le descellement aseptique et la raideur. Les principaux motifs de révision de l'ATH étaient l'infection, l'instabilité, le descellement aseptique et les fractures périprothétiques. Aucune tendance n'a été décelée au fil du temps dans les motifs de révision précoce, moyenne et tardive pour l'une ou l'autre des interventions. CONCLUSION: Nous avons observé une baisse significative des taux de révision précoce après la mise en œuvre d'un registre régional des remplacements articulaires. Il serait pertinent d'étudier plus en profondeur le mécanisme par lequel le signalement dans un registre réduit le risque de révision précoce.

Genome-wide analysis of drought induced gene expression changes in flax (Linum usitatissimum).

A robust phenotypic plasticity to ward off adverse environmental conditions determines performance and productivity in crop plants. Flax (linseed), is an important cash crop produced for natural textile fiber (linen) or oilseed with many health promoting products. This crop is prone to drought stress and yield losses in many parts of the world. Despite recent advances in drought research in a number of important crops, related progress in flax is very limited. Since, response of this plant to drought stress has not been addressed at the molecular level; we conducted microarray analysis to capture transcriptome associated with induced drought in flax. This study identified 183 differentially expressed genes (DEGs) associated with diverse cellular, biophysical and metabolic programs in flax. The analysis also revealed especially the altered regulation of cellular and metabolic pathways governing photosynthesis. Additionally, comparative transcriptome analysis identified a plethora of genes that displayed differential regulation both spatially and temporally. These results revealed co-regulated expression of 26 genes in both shoot and root tissues with implications for drought stress response. Furthermore, the data also showed that more genes are upregulated in roots compared to shoots, suggesting that roots may play important and additional roles in response to drought in flax. With prolonged drought treatment, the number of DEGs increased in both tissue types. Differential expression of selected genes was confirmed by qRT-PCR, thus supporting the suggested functional association of these intrinsic genes in maintaining growth and homeostasis in response to imminent drought stress in flax. Together the present study has developed foundational and new transcriptome data sets for drought stress in flax.

Potential for increased photosynthetic performance and crop productivity in response to climate change: role of CBFs and gibberellic acid.

We propose that targeting the enhanced photosynthetic performance associated with the cold acclimation of winter cultivars of rye (Secale cereale L.), wheat (Triticum aestivum L.), and Brassica napus L. may provide a novel approach to improve crop productivity under abiotic as well as biotic stress conditions. In support of this hypothesis, we provide the physiological, biochemical, and molecular evidence that the dwarf phenotype induced by cold acclimation is coupled to significant enhancement in photosynthetic performance, resistance to photoinhibition, and a decreased dependence on photoprotection through non-photochemical quenching which result in enhanced biomass production and ultimately increased seed yield. These system-wide changes at the levels of phenotype, physiology, and biochemistry appear to be governed by the family of C-repeat/dehydration-responsive family of transcription factors (CBF/DREB1). We relate this phenomenon to the semi-dwarf, gibberellic acid insensitive (GAI), cereal varieties developed during the "green revolution" of the early 1960s and 1970s. We suggest that genetic manipulation of the family of C-repeat/dehydration-responsive element binding transcription factors (CBF/DREB1) may provide a novel approach for the maintenance and perhaps even the enhancement of plant productivity under conditions of sub-optimal growth conditions predicted for our future climate.

Arabidopsis GOLDEN2-LIKE (GLK) transcription factors activate jasmonic acid (JA)-dependent disease susceptibility to the biotrophic pathogen Hyaloperonospora arabidopsidis, as well as JA-independent plant immunity against the necrotrophic pathogen Botrytis cinerea.

Arabidopsis thaliana GOLDEN2-LIKE (GLK1 and 2) transcription factors regulate chloroplast development in a redundant manner. Overexpression of AtGLK1 (35S:AtGLK1) in Arabidopsis also confers resistance to the cereal pathogen Fusarium graminearum. To further elucidate the role of GLK transcription factors in plant defence, the Arabidopsis glk1 glk2 double-mutant and 35S:AtGLK1 plants were challenged with the virulent oomycete pathogen Hyaloperonospora arabidopsidis (Hpa) Noco2. Compared with Col-0, glk1 glk2 plants were highly resistant to Hpa Noco2, whereas 35S:AtGLK1 plants showed enhanced susceptibility to this pathogen. Genetic studies suggested that AtGLK-mediated plant defence to Hpa Noco2 was partially dependent on salicylic acid (SA) accumulation, but independent of the SA signalling protein NONEXPRESSOR OF PATHOGENESIS-RELATED 1 (NPR1). Pretreatment with jasmonic acid (JA) dramatically reversed Hpa Noco2 resistance in the glk1 glk2 double mutant, but only marginally affected the 35S:AtGLK1 plants. In addition, overexpression of AtGLK1 in the JA signalling mutant coi1-16 did not increase susceptibility to Hpa Noco2. Together, our GLK gain-of-function and loss-of-function experiments suggest that GLK acts upstream of JA signalling in disease susceptibility to Hpa Noco2. In contrast, glk1 glk2 plants were more susceptible to the necrotrophic fungal pathogen Botrytis cinerea, whereas 35S:AtGLK1 plants exhibited heightened resistance which could be maintained in the absence of JA signalling. Together, the data reveal that AtGLK1 is involved in JA-dependent susceptibility to the biotrophic pathogen Hpa Noco2 and in JA-independent resistance to the necrotrophic pathogen B. cinerea.

Role of CBFs as integrators of chloroplast redox, phytochrome and plant hormone signaling during cold acclimation.

Cold acclimation of winter cereals and other winter hardy species is a prerequisite to increase subsequent freezing tolerance. Low temperatures upregulate the expression of C-repeat/dehydration-responsive element binding transcription factors (CBF/DREB1) which in turn induce the expression of COLD-REGULATED (COR) genes. We summarize evidence which indicates that the integration of these interactions is responsible for the dwarf phenotype and enhanced photosynthetic performance associated with cold-acclimated and CBF-overexpressing plants. Plants overexpressing CBFs but grown at warm temperatures mimic the cold-tolerant, dwarf, compact phenotype; increased photosynthetic performance; and biomass accumulation typically associated with cold-acclimated plants. In this review, we propose a model whereby the cold acclimation signal is perceived by plants through an integration of low temperature and changes in light intensity, as well as changes in light quality. Such integration leads to the activation of the CBF-regulon and subsequent upregulation of COR gene and GA 2-oxidase (GA2ox) expression which results in a dwarf phenotype coupled with increased freezing tolerance and enhanced photosynthetic performance. We conclude that, due to their photoautotrophic nature, plants do not rely on a single low temperature sensor, but integrate changes in light intensity, light quality, and membrane viscosity in order to establish the cold-acclimated state. CBFs appear to act as master regulators of these interconnecting sensing/signaling pathways.