Perioperative outcomes of open versus robot-assisted radical cystectomy in octogenarians: a population based analysis.

Octogenarians undergoing cystectomy experience higher morbidity and mortality compared to younger patients. Though the non-inferiority of robot-assisted radical cystectomy (RARC) compared to open radical cystectomy (ORC) has been established in a generalized population, the benefits of the robotic approach have not been well studied in an aged population. The National Cancer Database (NCDB) was queried for all patients who underwent cystectomy for bladder cancer from 2010 to 2016. Of these, 2527 were performed in patients age 80 or older; 1988 and 539 underwent ORC and RARC, respectively. On Cox regression analysis, RARC was associated with significantly reduced odds for both 30- and 90-day mortality (HR 0.404, p = 0.004; HR 0.694, p = 0.031, respectively), though the association with overall mortality was not significant (HR 0.877, p = 0.061). The robotic group had a significantly shorter length of stay (LOS) compared to open surgery (10.3 days ORC vs. 9.3 days RARC, p = 0.028). The proportion of cases performed robotically increased over the study period from 12.2% in 2010 to 28.4% in 2016 (p = 0.009, R2 = 0.774). The study is limited by a retrospective design and a section bias, which was not completely control for in the analysis. In conclusion, RARC provides improved perioperative outcomes in aged patients compared to ORC and a trend toward greater utilization of this technique was observed.

Genital Sparing Robot-Assisted Radical Cystectomy with Intracorporeal Neobladder & Paravaginal Repair.

OBJECTIVE: Vaginal prolapse is a known complication after radical cystectomy, requiring additional procedures in 10% of the patients.1 This results from loss of level I and II vaginal support due to the removal of pelvic structures. In addition, a neobladder urinary diversion, with Valsalva voiding, predisposes to vaginal prolapse. A genital-sparing approach with paravaginal repair can help prevent such complications. METHODS: The genital sparing technique preserves the uterus, fallopian tubes, ovaries, and vagina, while paravaginal repair involves suturing of the lateral vaginal wall to the arcuate fascia located on the medial aspect of the obturator internus muscle. The procedure begins by placing the patient in a lithotomy position, with a steep Trendelenburg. Standard 6 port cystectomy configuration is utilized with an additional 15 mm port for bowel anastomosis. Initially, the ureters and lateral bladder space are mobilized. Posteriorly a dissection plane is developed separating the bladder from the anterior vaginal wall. Distal dissection is carefully performed in that plane to avoid disrupting the urethral-external sphincter complex. Then the bladder is dropped from anterior attachments, the Dorsal venous complex (DVC) and bladder neck are exposed. Urethra is transected distal to the bladder neck, after circumferential mobilization, to complete the cystectomy, again avoiding disruption of the continence mechanism, and opening the endo-pelvic fascia. Cystectomy and pelvic lymph node dissection are completed in a standard fashion. The arcuate fascia is identified bilaterally for level I paravaginal repair. The lateral aspect of the paravaginal tissue is secured to this ligament, using 3 interrupted Polydioxanone (PDS) sutures, bilaterally. An ileal "Hautman's W pouch" neobladder is constructed using 50 cm of the small intestine, similar to the previously reported technique.2 Bricker-type uretero-ileal anastomosis is performed over a double J stent. Bowel continuity is restored by a side-to-side anastomosis using endo-GIA (gastrointestinal anastamosis EndoGIATM ) staplers. RESULTS: No intra or postoperative complications were noted. Robot dock time was 8 hours and 23 minutes with an EBL of 100 mL. The patient was discharged on post operative day (POD) 6 and Foley catheter with ureteral stents was removed on POD 27 after a cystogram confirmed no leaks. At 6-month follow-up, the patient reported good continence using a single pad, voiding every 3-4 hours. Fluoro-urodynamics demonstrated 651 mL capacity, low-pressure voiding, minimal residual urine, and no reflux. No prolapse was noted on fluoroscopy and pelvic examination with the Valsalva maneuver. The patient reported a good satisfaction level, regarding her urinary symptoms. CONCLUSION: We report satisfactory short-term outcomes of a feasible technique to prevent postcystectomy prolapse; however, long-term follow-up of a larger cohort can help establish its efficacy.

MicroRNA-1911-3p targets mEAK-7 to suppress mTOR signaling in human lung cancer cells.

Regulation of mTOR signaling depends on an intricate interplay of post-translational protein modification. Recently, mEAK-7 (mTOR associated protein, eak-7 homolog) was identified as a positive activator of mTOR signaling via an alternative mTOR complex. However, the upstream regulation of mEAK-7 in human cells is not known. Because microRNAs are capable of modulating protein translation of RNA in eukaryotes, we conducted a bioinformatic search for relevant mEAK-7 targeting microRNAs using the Exiqon miRSearch V3.0 algorithm. Based on the score obtained through miRSearch V3.0, the top predicted miRNA (miR-1911-3p) was studied. miR-1911-3p mimics decreased protein levels of both mEAK-7 and mTORC1 downstream effectors p-S6 and p-4E-BP1 in non-small cell lung carcinoma (NSCLC) cell lines H1975 and H1299. miR-1911-3p levels and MEAK7 mRNA/mEAK-7/mTOR signaling levels were negatively correlated between normal lung and NSCLC cells. miR-1911-3p directly interacted with MEAK7 mRNA at the 3'-UTR to negatively regulate mEAK-7 and significantly decreased mTOR localization to the lysosome. Furthermore, miR-1911-3p significantly decreased cell proliferation and migration in both H1975 and H1299 cells. Thus, miR-1911-3p functions as a suppressor of mTOR signaling through the regulation of MEAK7 mRNA translation in human cancer cells.

mEAK-7 Forms an Alternative mTOR Complex with DNA-PKcs in Human Cancer.

MTOR associated protein, eak-7 homolog (mEAK-7), activates mechanistic target of rapamycin (mTOR) signaling in human cells through an alternative mTOR complex to regulate S6K2 and 4E-BP1. However, the role of mEAK-7 in human cancer has not yet been identified. We demonstrate that mEAK-7 and mTOR signaling are strongly elevated in tumor and metastatic lymph nodes of patients with non-small-cell lung carcinoma compared with those of patients with normal lung or lymph tissue. Cancer stem cells, CD44+/CD90+ cells, yield elevated mEAK-7 and activated mTOR signaling. mEAK-7 is required for clonogenic potential and spheroid formation. mEAK-7 associates with DNA-dependent protein kinase catalytic subunit isoform 1 (DNA-PKcs), and this interaction is increased in response to X-ray irradiation to regulate S6K2 signaling. DNA-PKcs pharmacologic inhibition or genetic knockout reduced S6K2, mEAK-7, and mTOR binding with DNA-PKcs, resulting in loss of S6K2 activity and mTOR signaling. Therefore, mEAK-7 forms an alternative mTOR complex with DNA-PKcs to regulate S6K2 in human cancer cells.

Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration.

Nematode EAK-7 (enhancer-of-akt-1-7) regulates dauer formation and controls life span; however, the function of the human ortholog mammalian EAK-7 (mEAK-7) is unknown. We report that mEAK-7 activates an alternative mechanistic/mammalian target of rapamycin (mTOR) signaling pathway in human cells, in which mEAK-7 interacts with mTOR at the lysosome to facilitate S6K2 activation and 4E-BP1 repression. Despite interacting with mTOR and mammalian lethal with SEC13 protein 8 (mLST8), mEAK-7 does not interact with other mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2) components; however, it is essential for mTOR signaling at the lysosome. This phenomenon is distinguished by S6 and 4E-BP1 activity in response to nutrient stimulation. Conventional S6K1 phosphorylation is uncoupled from S6 phosphorylation in response to mEAK-7 knockdown. mEAK-7 recruits mTOR to the lysosome, a crucial compartment for mTOR activation. Loss of mEAK-7 results in a marked decrease in lysosomal localization of mTOR, whereas overexpression of mEAK-7 results in enhanced lysosomal localization of mTOR. Deletion of the carboxyl terminus of mEAK-7 significantly decreases mTOR interaction. mEAK-7 knockdown decreases cell proliferation and migration, whereas overexpression of mEAK-7 enhances these cellular effects. Constitutively activated S6K rescues mTOR signaling in mEAK-7-knocked down cells. Thus, mEAK-7 activates an alternative mTOR signaling pathway through S6K2 and 4E-BP1 to regulate cell proliferation and migration.