Congenital male genital malformations and paternal health: An analysis of the US claims data.

OBJECTIVE: To investigate the potential association between paternal health and male genital malformations in the offspring. MATERIALS AND METHODS: We analyzed data from 2007 to 2016 derived from the IBM MarketScan Research database, which reports on reimbursed private healthcare claims in the United States. The association between paternal comorbidities (defined as individual and combined measures) and genital malformations in male offspring was analyzed. RESULTS: Of 376,362 male births, 22% of fathers had at least one component of metabolic syndrome (≥1) prior to conception. Totals of 2880 cases of cryptorchidism (0.77%) and 2651 cases of hypospadias (0.70%) were identified at birth. While 0.76% of sons born to fathers with no metabolic syndrome components were diagnosed with cryptorchidism, 0.82% of sons with fathers with multiple metabolic syndrome components had cryptorchidism. Similarly, 0.69% versus 0.88% of sons had hypospadias when fathers had 0 or 2+ components of metabolic syndrome. After adjusting for maternal and paternal factors, the odds of a son being diagnosed with hypospadias increased with two or more paternal metabolic syndrome components (Odds ratio [95% confidence interval]: 1.27 [1.10-1.47]). Specific components of paternal metabolic syndrome were not generally more associated with a son's genital malformations. When we performed a subgroup analysis where genital malformations were defined based on surgical correction, the association with hypospadias persisted. CONCLUSIONS: Fathers with multiple components of metabolic syndrome in the preconception period were observed to be at increased risk for having sons born with hypospadias. The results support the association between a man's andrological and overall health.

Preconception paternal comorbidities and offspring birth defects: Analysis of a large national data set.

BACKGROUND: Despite the fact that the father contributes half the genome to a child, associations between paternal factors and birth defects are poorly understood. OBJECTIVES: To investigate the association between preconception paternal health and birth defects in the offspring. MATERIALS AND METHODS: We conducted analysis of a national cohort study utilizing the IBM Marketscan Research Database, which includes data on reimbursed private healthcare claims in the United States from 2007 to 2016. The potential association between paternal comorbidities, as measured by the components of metabolic syndrome (MetS), and any birth defect in the offspring was analyzed. RESULTS: Of the 712,774 live births identified, 21.2% of children were born to fathers with at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Compared to infants born to fathers with no components of the metabolic syndrome, a modestly higher percentage of infants with cardiac birth defects were born to fathers with more components of MetS (MetS = 1, OR [95% CI]: 1.07 [1.01-1.13]; MetS ≥2, 1.17 [1.08-1.26], in comparison to MetS = 0) after adjusting for maternal and paternal factors. Similarly, a higher percentage of infants with respiratory defects were born to fathers with two or more components of metabolic syndrome (MetS ≥2, OR [95% CI]: 1.45 [1.22-1.71]). DISCUSSION AND CONCLUSION: In this private insurance claims-based study, we found that fathers with metabolic syndrome-related diseases before conception were at increased risk for having a child affected by birth defects, especially cardiac and respiratory defects, and this association was not influenced by paternal age or assessed maternal factors.

Postoperative complications and pelvic organ prolapse recurrence following combined pelvic organ prolapse and rectal prolapse surgery compared with pelvic organ prolapse only surgery.

BACKGROUND: There is a growing interest in combined pelvic organ prolapse and rectal prolapse surgery for concomitant pelvic floor prolapse despite a paucity of data regarding complications and clinical outcomes of combined repair. OBJECTIVE: The primary objective of this study was to compare the <30-day postoperative complication rate in women undergoing combined POP + RP surgery with that of women undergoing pelvic organ prolapse-only surgery. The secondary objectives were to describe the <30-day postoperative complications, compare the pelvic organ prolapse recurrence between the 2 groups, and determine the preoperative predictors of <30-day postoperative complications and predictors of pelvic organ prolapse recurrence. STUDY DESIGN: This was a multicenter, retrospective cohort study at 5 academic hospitals. Patients undergoing combined pelvic organ prolapse and rectal prolapse surgery were matched by age, pelvic organ prolapse stage by leading compartment, and pelvic organ prolapse procedure compared with those undergoing pelvic organ prolapse-only surgery from March 2003 to March 2020. The primary outcome measure was <30-day complications separated into Clavien-Dindo classes. The secondary outcome measures were (1) subsequent pelvic organ prolapse surgeries and (2) pelvic organ prolapse recurrence, defined as patients who complained of vaginal bulge symptoms postoperatively. RESULTS: Overall, 204 women underwent combined surgery for pelvic organ prolapse and rectal prolapse, and 204 women underwent surgery for pelvic organ prolapse only. The average age (59.3±1.0 vs 59.0±1.0) and mean parity (2.3±1.5 vs 2.6±1.8) were similar in each group. Of note, 109 (26.7%) patients had at least one <30-day postoperative complication. The proportion of patients who had a complication in the combined surgery group and pelvic organ prolapse-only surgery group was similar (27.5% vs 26.0%; P=.82). The Clavien-Dindo scores were similar between the groups (grade I, 10.3% vs 9.3%; grade II, 11.8% vs 12.3%; grade III, 3.9% vs 4.4%; grade IV, 1.0% vs 0%; grade V, 0.5% vs 0%). Patients undergoing combined surgery were less likely to develop postoperative urinary tract infections and urinary retention but were more likely to be treated for wound infections and pelvic abscesses than patients undergoing pelvic organ prolapse-only surgery. After adjusting for combined surgery vs pelvic organ prolapse-only surgery and parity, patients who had anti-incontinence procedures (adjusted odds ratio, 1.85; 95% confidence interval, 1.16-2.94; P=.02) and perineorrhaphies (adjusted odds ratio, 1.68; 95% confidence interval, 1.05-2.70; P=.02) were more likely to have <30-day postoperative complications. Of note, 12 patients in the combined surgery group and 15 patients in the pelvic organ prolapse-only surgery group had subsequent pelvic organ prolapse repairs (5.9% vs 7.4%; P=.26). In the combined surgery group, 10 patients (4.9%) underwent 1 repair, and 2 patients (1.0%) underwent 2 repairs. All patients who had recurrent pelvic organ prolapse surgery in the pelvic organ prolapse-only surgery group had 1 subsequent pelvic organ prolapse repair. Of note, 21 patients in the combined surgery group and 28 patients in the pelvic organ prolapse-only surgery group reported recurrent pelvic organ prolapse (10.3% vs 13.7%; P=.26). On multivariable analysis adjusted for number of previous pelvic organ prolapse repairs, combined surgery vs pelvic organ prolapse-only surgery, and perineorrhaphy at the time of surgery, patients were more likely to have a subsequent pelvic organ prolapse surgery if they had had ≥2 previous pelvic organ prolapse repairs (adjusted odds ratio, 6.06; 95% confidence interval, 2.10-17.5; P=.01). The average follow-up times were 307.2±31.5 days for the combined surgery cohort and 487.7±49.9 days for the pelvic organ prolapse-only surgery cohort. Survival curves indicated that the median time to recurrence was not statistically significant (log-rank, P=.265) between the combined surgery group (4.2±0.4 years) and the pelvic organ prolapse-only surgery group (5.6±0.4 years). CONCLUSION: In this retrospective cohort study, patients undergoing combined pelvic organ prolapse and rectal prolapse surgery had a similar risk of <30-day postoperative complications compared with patients undergoing pelvic organ prolapse-only surgery. Furthermore, patients who underwent combined surgery had a similar risk of recurrent pelvic organ prolapse and subsequent pelvic organ prolapse surgery compared with patients who underwent pelvic organ prolapse-only surgery.

Oncogene-mediated metabolic gene signature predicts breast cancer outcome.

Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.

Discovery of CASP8 as a potential biomarker for high-risk prostate cancer through a high-multiplex immunoassay.

Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addition, mRNA levels of CASP8 were higher in patients with recurrent prostate cancer when compared to patients with non-recurrent prostate cancer and high expression of CASP8 was associated with worse disease-free survival and overall survival in renal cancer. Together, our results suggest that CASP8 may potentially serve as a biomarker for high-risk prostate cancer and possibly renal cancer.

Trends in the Diagnosis and Management of Combined Rectal and Vaginal Pelvic Organ Prolapse.

OBJECTIVE: To examine the rates of surgical repair of comorbid rectal prolapse (RP) and pelvic organ prolapse (POP) over time in a large population-based cohort. MATERIALS AND METHODS: We queried Optum, a national administrative claims database, from 2003 to 2017. We evaluated female patients age 18 or older with a diagnosis of POP and/or RP. Sociodemographic characteristics, comorbidities, and rates of procedures were collected. RESULTS: We identified 481,051 women diagnosed with RP and/or POP. Only 2.0% of women in the cohort had comorbid POP and RP. While 29.9% of women with RP had dual prolapse, only 2.1% of women with POP had both diagnoses. Overall, 25.8% of women had one or more surgical repairs. Surgical repairs were done in 26.0% of women with POP, 15.0% of women with RP, and 48.2% of women with comorbid POP/RP, though only 19.8% of patients with dual diagnoses had both RP and POP repairs. Over the study period, the rate of multidisciplinary surgical repairs increased by 2.7-fold. CONCLUSION: The prevalence of comorbid RP and POP among women in our cohort is low (2.0%). Rates of multidisciplinary surgery have increased possibly due to the increased use of imaging, laparoscopic surgery, and awareness of the shared pathophysiology of the disease.

Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer.

Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.

Urinary Stone Disease in Pregnancy: Current Management Practices in a Large National Cohort.

OBJECTIVE: To define current national practice patterns of imaging modalities and urologic procedures in pregnant women with urinary stone disease. METHODS: Using the IBM MarketScan national insurance claims database, we identified pregnant women with urinary stone disease and their corresponding gestational age between 2011 and 2016 using administrative claims data. We then assessed each encounter for urinary stone disease or stone-related urologic procedure during their pregnancy. We abstracted demographic information as well as codes for stone procedures and imaging. RESULTS: We identified 14,298 pregnant women with urinary stone disease during the study period. Of the 12,315 undergoing abdominal imaging (86.1%), magnetic resonance imaging was used in 2.8%, x-ray in 9%, and ultrasound in 74.3%. Computed tomography was not used as a diagnostic modality during pregnancy. Procedural intervention was performed in 749 women (5.2%): 476 (3.3%) ureteral stent placement without definitive stone treatment, 93 (0.6%) percutaneous nephrostomy placement, and 180 (1.3%) ureteroscopy (URS) for definitive stone treatment. URS was most commonly performed before 34 weeks gestation with only 27 cases (15%) performed after. CONCLUSION: This large national cohort reveals the current imaging and procedural practice patterns for urinary stone disease during pregnancy and provides a critical baseline as these practice patterns evolve in the future.

Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

Urinary Stone Disease in Pregnancy: A Claims Based Analysis of 1.4 Million Patients.

PURPOSE: Urinary stone disease during pregnancy is poorly understood but is thought to be associated with increased maternal and fetal morbidity. We determined the prevalence of urinary stone disease in pregnancy and whether it is associated with adverse pregnancy outcomes. MATERIALS AND METHODS: We identified all pregnant women from 2003 through 2017 in the Optum® national insurance claims database. We used diagnosis claims to identify urinary stone disease and assess medical comorbidity. We established the prevalence of urinary stone disease during pregnancy stratified by week of pregnancy. We further evaluated associations among urinary stone disease, maternal complications and pregnancy outcomes in univariable and multivariable analyses. RESULTS: Urinary stone disease affects 8 per 1,000 pregnancies and is more common in white women and women with more comorbid conditions. In fully adjusted models pregnancies complicated by urinary stone disease had higher rates of adverse fetal outcomes including prematurity and spontaneous abortions. This analysis is limited by its retrospective, administrative claims design. CONCLUSIONS: The rate of urinary stone disease during pregnancy is higher than previously reported. Urinary stone disease is associated with adverse pregnancy outcomes.

CD47-Targeted Near-Infrared Photoimmunotherapy for Human Bladder Cancer.

PURPOSE: Near-infrared photoimmunotherapy (NIR-PIT) is a localized molecular cancer therapy combining a photosensitizer-conjugated mAb and light energy. CD47 is an innate immune checkpoint widely expressed on bladder cancer cells, but absent from luminal normal urothelium. Targeting CD47 for NIR-PIT has the potential to selectively induce cancer cell death and minimize damage to normal urothelium. EXPERIMENTAL DESIGN: The cytotoxic effect of NIR-PIT with anti-CD47-IR700 was investigated in human bladder cancer cell lines and primary human bladder cancer cells derived from fresh surgical samples. Phagocytosis assays were performed to evaluate macrophage activity after NIR-PIT. Anti-CD47-IR700 was administered to murine xenograft tumor models of human bladder cancer for in vivo molecular imaging and NIR-PIT. RESULTS: Cytotoxicity in cell lines and primary bladder cancer cells significantly increased in a light-dose-dependent manner with CD47-targeted NIR-PIT. Phagocytosis of cancer cells significantly increased with NIR-PIT compared with antibody alone (P = 0.0002). In vivo fluorescence intensity of anti-CD47-IR700 in tumors reached a peak 24-hour postinjection and was detectable for at least 14 days. After a single round of CD47-targeted NIR-PIT, treated animals showed significantly slower tumor growth compared with controls (P < 0.0001). Repeated CD47-targeted NIR-PIT treatment further slowed tumor growth (P = 0.0104) and improved survival compared with controls. CONCLUSIONS: CD47-targeted NIR-PIT increased direct cancer cell death and phagocytosis resulting in inhibited tumor growth and improved survival in a murine xenograft model of human bladder cancer.

Increase in Blood Pressure Associated With Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor.

OBJECTIVES: This study quantified the change in blood pressure (BP) during antivascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy, compared BPs between TKIs, and analyzed change in BP during antihypertensive therapy. BACKGROUND: TKIs targeting VEGF are associated with hypertension. The absolute change in BP during anti-VEGF TKI treatment is not well characterized outside clinical trials. METHODS: A retrospective single-center study included patients with metastatic renal cell carcinoma who received anti-VEGF TKIs between 2007 and 2018. Mixed models analyzed 3,088 BPs measured at oncology clinics. RESULTS: In 228 patients (baseline systolic blood pressure [SBP] 130.2 ± 16.3 mm Hg, diastolic blood pressure [DBP] 76.8 ± 9.3 mm Hg), anti-VEGF TKIs were associated with mean increases in SBP of 8.5 mm Hg (p < 0.0001) and DBP of 6.7 mm Hg (p <0.0001). Of the anti-VEGF TKIs evaluated, axitinib was associated with the greatest BP increase, with an increase in SBP of 12.6 mm Hg (p < 0.0001) and in DBP of 10.3 mm Hg (p < 0.0001) relative to baseline. In pairwise comparisons between agents, axitinib was associated with greater SBPs than cabozantinib by 8.4 mm Hg (p = 0.004) and pazopanib by 5.1 mm Hg (p = 0.01). Subsequent anti-VEGF TKI courses were associated with small increases in DBP, but not SBP, relative to the first course. During anti-VEGF TKI therapy, calcium-channel blockers and potassium-sparing diuretic agents were associated with the largest BP reductions, with decreases in SBP of 5.6 mm Hg (p < 0.0001) and 9.9 mm Hg (p = 0.007), respectively. CONCLUSIONS: Anti-VEGF TKIs are associated with increased BP; greatest increases are observed with axitinib. Calcium-channel blockers and potassium-sparing diuretic agents were associated with the largest reductions in BP.

Racial and Sociodemographic Differences of Semen Parameters Among US Men Undergoing a Semen Analysis.

OBJECTIVE: To characterize sociodemographic differences in semen parameters among US men undergoing a semen analysis. MATERIALS AND METHODS: Men who provided a semen sample were identified from insurance claims between 2007 and 2016. Differences in semen parameters were characterized according to age, race, education, and region. Mean semen parameters and proportions of men with suboptimal parameters were compared and risks of oligospermia and azoospermia were assessed by logistic regression. RESULTS: Of the 7263 men included, most men were white (55.1%), Hispanic (20.2%), or Asian (10.2%). Asians had the highest mean semen concentrations (69.2 × 106/mL), whereas blacks had the lowest (51.3 × 106/mL). Men from the Midwest were more likely to have oligospermia (odds ratio [OR] 1.62; 95% confidence interval [CI] 1.34-1.94), whereas men from the West were less likely (OR 0.82; 95% CI 0.82-0.94) when compared with men from South. An association between education and sperm concentration was observed. For example, men with a high school diploma or less were more likely to have oligospermia (OR 1.09; 95% CI 0.95-1.26), whereas men with at least a bachelor degree were less likely (OR 0.87; 95% CI 0.76-1.0) when compared with men with less than a bachelor degree. CONCLUSION: As we observed differences in semen quality based on sociodemographic factors, these findings may have clinical implications as relying on a single reference value when guiding infertile couples may be problematic given these variations. Further work is warranted to understand the etiology of such differences and determine if different normative reference values may apply for different populations.

Consolidative Radiotherapy in Metastatic Urothelial Cancer.

BACKGROUND: We report outcomes of a retrospective, single-institution experience with consolidative radiation after chemotherapy in metastatic urothelial cancer (MUC). PATIENTS AND METHODS: From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with MUC who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. Overall survival (OS) was defined as time from start of chemotherapy to death or last follow-up. RESULTS: In the selected group of patients with MUC, the median age was 67 years; 59% had received previous cisplatin-based chemotherapy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases. Median survival from diagnosis to cystectomy was 48 months. Median PFS was 13 months and median OS was 29 months. Eight patients (36%) were alive and disease-free 6 years after radiation therapy. Patients who were rendered disease-free were those with nodal metastases and delivery of radiation to a single site of metastasis. CONCLUSION: In this highly selective cohort of patients with MUC treated with consolidative radiation after chemotherapy, 36% were rendered disease-free. This suggests that radiation is feasible and might contribute to long-term disease control. Further prospective studies are needed to better characterize the benefit of combined modality treatment.