Unconventional Bladder Preservation: Factors Predicting Failure to Receive Definitive Surgery following Chemotherapy for Nonmetastatic Muscle Invasive Bladder Cancer in the National Cancer Database.

PURPOSE: Neoadjuvant chemotherapy is an important adjunct to cystectomy for managing muscle invasive bladder cancer. Using the National Cancer Database we investigated factors that predict failure to undergo surgery following multi-agent chemotherapy for nonmetastatic muscle invasive bladder cancer. MATERIALS AND METHODS: We performed a cohort study in patients diagnosed with cT2-4aN0M0 urothelial cell carcinoma of the bladder between 2004 and 2013 who underwent multi-agent chemotherapy. We excluded those with surgery prior to chemotherapy, clinical T4b disease and those who received radiotherapy. Socioeconomic and clinical predictors, including time from diagnosis to treatment, were analyzed using logistic regression for the receipt of surgery after chemotherapy. Cox proportional hazards modeling was applied to perform time dependent analysis. RESULTS: Of the 4,640 patients who met our study inclusion and exclusion criteria 4,244 (91%) proceeded to surgery. Negative predictors of surgery included African American or Hispanic race (OR 0.58, p = 0.007 and 0.48, p = 0.002, respectively), increasing age (OR 0.44, p <0.001) and greater time between diagnosis and chemotherapy initiation (fourth quartile greater than 59 days, OR 0.51, p <0.001). African American race (HR 0.79, p <0.001), Medicare (HR 0.86, p <0.001) and other government insurance (HR 0.73, p <0.001) were associated with delayed chemotherapy. CONCLUSIONS: Increasing age, African American or Hispanic race and longer time to chemotherapy predicted failure to undergo surgery. Furthermore, African American race was associated with delayed chemotherapy. Chemotherapy was also delayed in patients on Medicare or other government insurance. Longer time to neoadjuvant chemotherapy is a modifiable risk factor that should be closely observed in multimodal cancer treatment.

Estrogen effects on vascular inflammation are age dependent: role of estrogen receptors.

OBJECTIVE: 17ß-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones performed in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age dependent. APPROACH AND RESULTS: Young (10 weeks) and aged (52 weeks) female C57BL/6 mice were used as source for primary cultures of bone marrow-derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pretreatment of cells derived from young mice attenuated C-reactive protein (CRP)-induced expression of inflammatory mediators. In contrast, E2 pretreatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER) knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERß. BMMs derived from aged (versus young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice. CONCLUSIONS: E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women.

Cell mediated immune responses through TLR4 prevents DMBA-induced mammary carcinogenesis in mice.

Toll-like receptors (TLRs) activate signals that are critically involved in the initiation of adaptive immune responses and many tumorigenic chemicals have been associated with activation of those pathways. To determine the role of TLR-4 (TLR4) in mammary carcinogenesis, we subjected TLR4 deficient and wild type (WT) mice to oral gavage with carcinogenic polyaromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA). TLR4 deficient mice developed more tumors relative to the WT mice. T cells of TLR4 deficient mice produced elevated levels of IL-17 and lower levels of IFN-γ relative to WT mice. IL-12 secreted by CD11c(+) cells was higher in WT mice, whereas greater amounts of IL-23 were produced by CD11c(+) cells from TLR4 deficient mice. Moreover, there was higher incidence of regulatory T cells in TLR4 deficient mice than WT mice. Similarly, various markers of angiogenesis [matrix metalloproteinases (MMP)-2 and MMP-9, CD31 and vascular endothelial growth factor] were highly expressed in tumors from TLR4 deficient mice than WT mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA induced mouse mammary tumorigenesis and efforts to divert the cell-mediated immune response may, therefore, prove to be beneficial in the prevention of mammary tumors.

Vasectomy reversal outcomes in men after testosterone therapy.

The prevalence of males on testosterone therapy (TT) seeking vasectomy reversal (VR) is rising. As medical therapy (MT) to recover spermatogenesis after TT has been previously described, our study's objective is to present our institution's management and outcomes of VR in men previously on TT. We performed a retrospective case series of vasectomy patients on TT with subsequent VR by a single microsurgeon between March, 2010 and March, 2022. 14 men undergoing VR during the study period met inclusion criteria. The median age at VR was 43 years with a median obstructive interval of 11 years. Median time from MT to VR was 5 months. Post-operative semen analysis was performed in 10 men and all demonstrated patency. 2 patients had very low sperm counts secondary to continuing TT following VR contrary to medical advice and 5 men with patency achieved pregnancy. Our study noted a high rate of vasovasostomy (VV) (96%) and sustained patency despite a 12-year median obstructive interval. Our findings support favorable outcomes with less stringent VV indications after MT in patients previously on TT that desire VR. The use of MT reduces the recommended wait times for VR after TT discontinuation by more than half.

Testicular Mapping: A Roadmap to Sperm Retrieval in Nonobstructive Azoospermia?

Guiding a couple with nonobstructive azoospermia requires an integrated approach to care by the urologist and the reproductive endocrinologist. After informing the couple of the implications of the diagnosis, care must be taken to outline the options of parenthood. Most experts agree that sperm retrieval in men can be challenging. This article describes various options of sperm retrieval, historic and contemporary, and highlights the advantages and disadvantages of each. The authors find that using a testicular map can invariably help guide sperm retrieval and overall fertility care. The right approach is one that involves a shared decision with the couple.

An institutional assessment of sperm cryospreservation and fertility counselling in pubertal male cancer survivors.

INTRODUCTION: Improved survivorship after treatment of pediatric malignancies has dramatically increased, while pre-treatment fertility preservation in this population has not kept pace. New guidelines emphasize fertility preservation in young adolescents, but the impact of these guidelines is unknown. OBJECTIVES: We sought to evaluate the rate of fertility preservation among at-risk adolescents diagnosed with cancer at our institution, as well as evaluate barriers to fertility preservation. DESIGN: We performed an IRB-approved historical cohort study of adolescent males 13 years and older evaluated in the Pediatric Hematology-Oncology clinic at Doernbecher Children's Hospital from 2010 to 2018. Electronic chart review was used assess discussion of fertility preservation and barrier to successful preservation in boys with a new diagnosis of cancer who received systemic chemotherapy and/or gonadal or pelvic irradiation. RESULTS: 82 boys were included in the study. Forty-two (51%) received counselling about fertility preservation, and of those 29 (70%) successfully banked sperm. Neither counseling for fertility preservation nor success at sperm banking differed by patient age, but both differed by malignancy. Patients with Hodgkin's lymphoma had the highest rate of counselling, while those with leukemia had the lowest. Acute illness as a barrier to preservation was found in 40% of those who did not receive counselling. DISCUSSION: Our study demonstrates a stagnant rate of fertility counseling and preservation despite increased advocacy. The retrospective nature of our study limited our ability to assess the counselling that occurred, and the lack of granular race data limited study of the implicit selection bias that may be involved in such counseling. As more institutions move toward a multi-disciplinary care model, we believe that pediatric urologists or fertility specialists must play a vocal role in the care of these at-risk adolescents. CONCLUSION: Despite increasing advocacy for fertility preservation, our data shows no significant change in previously reported trends. Patients with Hodgkin's lymphoma have a higher rate of counseling and cryopreservation in comparison to those with other malignancies.

A Simple Neobladder Using a Porcine Model: The Double Limb U-Pouch.

OBJECTIVE: To create a simple neobladder and determine whether the double-limb U-Pouch (D-LUP) has the same capacity and compliance as a Studer or Camey I neobladder. To develop an orthotopic diversion that can be applied to robotic surgery with laboratory data supporting the concept. MATERIALS AND METHODS: Kidneys, ureters, bladders, and small intestine were obtained from pigs at the time of scheduled autopsy after completion of institutionally approved investigational trauma protocols. A Camey I neobladder, spherical neobladder, and D-LUP, were constructed from 40-cm segments of small intestine. They were compared for capacity, compliance, and pouch-to-urethra anastomotic distance. RESULTS: The cystometric capacity at 30 cm H2O for the Camey I, Studer, and D-LUP neobladders were 250 mL, 350 mL, and 430 mL, respectively. The pouch-to-urethra anastomotic distance was 0 cm for the Camey I, 10 cm for the spherical reservoir, and 0 cm for the D-LUP. Compliance was 10 mL/cm H20 for the Camey 1, 15 mL/cm H2O for the sphere, and 16 mL/cm H20 for the D-LUP. CONCLUSION: The D-LUP neobladder was simple to construct, had a more dependent ileo-urethrostomy site, larger capacity, and similar compliance when compared with a spherical neobladder.

Reconsidering vasectomy reversal over assisted reproduction in older couples.

OBJECTIVE: To provide pregnancy and live birth rates from a contemporary series of vasectomy reversals in men with female partners aged ≥35 years and to correlate the results with IVF. SETTING: Tertiary academic referral center. DESIGN: Retrospective comparative study of prospectively collected database. PATIENT(S): Two hundred forty-six men who underwent vasectomy reversal for fertility with female partner aged ≥35 years. INTERVENTION(S): Vasovasostomy or vasoepididymostomy. MAIN OUTCOME MEASURE(S): Correlation of pregnancy and live birth rate of this cohort by age groups with most recently published pregnancy and live birth rate per IVF cycle. RESULT(S): One hundred thirty-six men who underwent vasectomy reversal between 2006 and 2014 met our inclusion criteria. Overall pregnancy and live birth rates were 35% and 30%, respectively. Subgroup analysis by female age groups (35-37, 38-40, >40 years) demonstrated pregnancy and live birth rates comparable to those per IVF cycle by age groups according to a recently published (2015) national report. CONCLUSION(S): Vasectomy reversal should be strongly considered in men with a partner aged ≤40 years. Additionally, vasectomy reversal can be considered in carefully selected patients even with a partner aged >40 years.