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The negative effect of advanced female age on fertility and offspring health is well understood. In comparison, much less is known about the implications of male age on fertility, with many studies showing conflicting results. Nevertheless, increasing evidence suggests that advanced paternal age has negative effects on sperm parameters, reproductive success, and offspring health. Herein, we summarize the current body of knowledge on this controversial topic, with the belief that this review will serve as a resource for the clinicians providing fertility counseling to couples with older male partners.

Supplementary Fig. S6. Biodistribution of Cy3-conjugated 3DNA +/- conjugation to folic acid (FA). Following systemic delivery of FA-targeted Cy3-3DNA to ovarian tumor bearing mice, significant Cy3 fluorescence was observed in ovarian tumors, lesser amount in normal ovaries of tumor-bearing mice, very low amounts in brain, liver, spleen, and lung (white arrows), and no fluorescence was observed in heart. No fluorescence was observed in the ovary of non-tumor bearing mouse.

Table S5: Results of RNA sequencing in PDA cell lines (HS-766T and MiaPaCa2) with each modulated by CRISPR/Cas9 to delete HuR expression.

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer. Cancer Res; 77(16); 4460–71. ©2017 AACR.

Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor–bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo–targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer. Cancer Res; 76(6); 1549–59. ©2016 AACR.

Supplementary Table S1. Biological function of 5 up-regulated and 6 down-regulated genes having the highest fold differences in expression in response to HuR inhibition in A2780 cells. Shaded boxes indicate transcripts to which HuR binds directly.

Supplementary.Figures 1-8

Supplemental Methods and Supplemental Figure Legends

PDF file - 83KB

AVI file - 8881KB, siRNA HuR cells progressing through mitosis after MMC treatment.

PDF file - 658KB, HuR manipulation sensitizes PDA cells to chemotherapeutics agents.

AVI file - 8883KB, siRNA Control cells progressing through mitosis after MMC treatment.

PDF file - 2070KB, WEE1 is post-transcriptionally regulated by HuR upon DNA damage.

PDF file - 471KB, HuR silencing induced DNA damage breaks in PL5 cells.

PDF file - 2204KB, Different DNA damaging agents activate HuR.

AVI file - 8882KB, Untreated siRNA HuR cells progressing through mitosis.

PDF file - 350KB, WEE1 is a novel HuR target in DDR pathway.

PDF file - 64KB, Class of drugs used in the drug sensitivity assays performed in MiaPaCa2 cells against siRNA Control and HuR, respective IC50 of each drug identified.

Objective To determine characteristics of providers marketing vasectomy reversal (VR) online, degree of information available online, the ease with which patients can compare providers, and the differences in VR practice patterns between academic and private practices. Materials and Methods We identified VR practices operating within the top 50 most populous metropolitan areas in the US. Practice websites were reviewed to obtain information such as provider educational background, level of magnification, ability to perform vasoepididymostomy, surgical volume, and cost. Based on information available, providers were assigned a novel REVERSAL score created by the authors. Descriptive statistics were used to compare results. Results Of the 107 providers identified (29 academic, 78 private), the majority were male urologists with a Doctor of Medicine degree. Academic providers were more likely to have fellowship training than private practice providers, 96.6 vs 43.6%, respectively (P = 0.00001). Compared to non-urologists, urologists were less likely to purchase online ads or disclose cost. Non-urologists charged significantly less than urologists, $3,584 ± 1,554 and $6,591 ± 1,518, respectively (P = 0.00001). Only one provider provided complete information as defined by REVERSAL score of 12, with the majority (61.7%) of providers achieving score ≤6. Conclusion There is significant lack of transparency in publicly available information from VR practices. Practices should implement measures to improve dissemination of information to the public, so that patients can more easily compare providers and make informed decisions regarding VR.

Nitrous oxide (N2O) is underutilized in ambulatory urology. Here, we review available data regarding application, efficacy, and side effect profile of N2O in ambulatory urologic procedures. Data were available from 11 studies. N2O has been described in the setting of transrectal ultrasound-guided prostate biopsies, flexible cystoscopy, ureteral stent placement, and extracorporeal shockwave lithotripsy in adult patients and catheterization in children. Studies showed significant improvements in peri-procedural pain and anxiety relative to alternative (or none) forms of analgesia. Adverse effects were rare and self-limited. More widespread use of N2O may result in cost savings and better patient tolerance with outpatient procedures.

BACKGROUND We sought to assess the prognostic utility of 11C-choline positron emission tomography/computed tomography (PET/CT) in patients with metastatic castrate resistant prostate cancer (mCRPC) undergoing primary docetaxel chemotherapy. METHODS We performed a single institution retrospective analysis of 77 mCRPC patients who were treated with 6 cycles of docetaxel chemotherapy, and who also underwent 11C-choline PET/CT scans at baseline (before chemotherapy), mid-course (after 3 cycles), and posttherapy (after 6 cycles). We evaluated treatment response based on percent change in blood pool-corrected maximum standardized uptake value (SUVmax) of the target lesion on PET/CT, as well as percent change in serum prostate specific antigen (PSA). Logistic regression analysis was used to identify factors associated with complete treatment response. Progression free survival (PFS) analysis was performed using log-rank test and shown on Kaplan-Meier plot. RESULTS Percent change in blood pool-corrected SUVmax on mid-course scan was a significant predictor of complete response (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-0.99, p = .0003), whereas percent change in PSA was not (OR: 0.99, 95% CI: 0.99-1.01, p = .6025). 57 of 77 patients (74%) achieved ≥20% reduction in blood pool-corrected SUVmax on mid-course; these patients were 3.6 times more likely to achieve complete response after full 6 cycles of docetaxel chemotherapy, compared to patients with

Objective To identify the incidence of venous thromboembolism (VTE) risk factors, postoperative VTE, and to assess the morbidity of perioperative pharmacologic VTE prophylaxis in men undergoing inflatable penile prosthesis (IPP) surgery. Methods We retrospectively reviewed 215 patients undergoing IPP surgery between July 2017 and June 2019. Univariate and multivariate statistical analyzes were performed to assess pre-operative Caprini risk score and compare post-operative day 0 scrotal drain output, scrotal hematoma formation, and VTE in men who received subcutaneous heparin (SqH) vs those who did not receive SqH. Results Of 215 IPP patients, 84% were classified as high or highest risk for VTE utilizing the Caprini risk score. A total of 119 (55%) received perioperative SqH with or without additional anti-thrombotics. Post-operative day 0 scrotal drain output was higher in those who received SqH compared to those who did not receive SqH, 99.9 mL vs 75.6 mL, respectively (P = .001). Minor scrotal hematomas occurred in similar rates in patients who received perioperative SqH vs those who did not, 3.8% vs 6.3%, respectively (P = .38). Similar results were found on subgroup analysis when eliminating patients who received SqH concurrently with other anti-thrombotics. The overall rate of postoperative VTE was 0.9%. No post-operative infections occurred. Conclusion Patients undergoing IPP surgery are at elevated risk for VTE. To our knowledge, this is the first study showing SqH use in the perioperative IPP surgery setting is safe when used in conjunction with a scrotal drain. Preoperative VTE risk stratification may be performed and can be used to guide clinical decision making regarding pharmacologic prophylaxis.

Ultrasound imaging presents many positive attributes, including safety, real-time imaging, universal accessibility, and cost. However, inherent difficulties in discrimination between soft tissues and tumors prompted development of stabilized microbubble contrast agents. This presents the opportunity to develop agents in which drug is entrapped in the microbubble shell. We describe preparation and characterization of theranostic poly(lactide) (PLA) and pegylated PLA (PEG-PLA) shelled microbubbles that entrap gemcitabine, a commonly used drug for pancreatic cancer (PDAC). Entrapping 6 wt% gemcitabine did not significantly affect drug activity, microbubble morphology, or ultrasound contrast activity compared with unmodified microbubbles. In vitro microbubble concentrations yielding ≥ 500nM entrapped gemcitabine were needed for complete cell death in MIA PaCa-2 PDAC drug sensitivity assays, compared with 62.5 nM free gemcitabine. In vivo administration of gemcitabine-loaded microbubbles to xenograft MIA PaCa-2 PDAC tumors in athymic mice was well tolerated and provided substantial tumoral image enhancement before and after destructive ultrasound pulses. However, no significant differences in tumor growth were observed among treatment groups, in keeping with the in vitro observation that much higher doses of gemcitabine are required to mirror free gemcitabine activity. Statement of significance The preliminary results shown here are encouraging and support further investigation into increased gemcitabine loading. Encapsulation of gemcitabine within polylactic acid (PLA) microbubbles does not damage its activity towards pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) cells. Excellent imaging and evidence of penetration into the highly desmoplastic PDAC tumors is demonstrated. Microbubble destruction was confirmed in vivo, showing that elevated mechanical index shatters the microbubbles for enhanced delivery. The potential to slow PDAC growth in vivo is shown, but higher gemcitabine concentrations are required. Current efforts are directed at increasing drug loading by inclusion of drug-carrying nanoparticles for effective in vivo treatment.

Objective To evaluate clinical characteristics associated with patient attitudes toward surgical treatment of Peyronie's disease (PD) prior to consultation in a high-volume male sexual health clinic. Methods : From 2014-2018 a prospective database was created of patients presenting to the sexual health clinic at our institution. Multivariable regression analysis was conducted to determine factors associated with pre-visit consideration of surgery. Results : Of 1359 men presenting to clinic, 342 had a chief complaint of PD. Prior to consultation, 79% of patients (n = 270) stated they were willing to consider surgery to correct their PD symptoms. Factors associated with consideration of surgery included younger patient age (mean 55.8 vs 60.0 years; P = .008), history of depression/anxiety (21% vs 8%, P = .01), greater penile curvature (43.3 vs 34.6 degrees; P = .002), penile shortening (64% vs 44%; P = .003), pain with erections (46% vs 33%; P = .05) and decreased ability to have penetrative intercourse (51.9% vs 65.3%, P = .04). On multivariable analysis, age, history of depression, penile shortening, and mean curvature remained significantly associated. Symptom duration and relationship factors were not associated with a difference in the stated preference to consider surgery prior to consultation (P >.05 for all). Conclusion : Nearly 4 out of 5 patients reported willingness to consider surgical intervention for their PD-related symptoms prior to urologic consultation. On multivariable analysis, younger age, history of depression/anxiety, penile shortening, and curvature were associated with a greater likelihood of considering surgery. This information provides important insight into patient attitude toward undergoing surgery and will help drive patient counseling for men with PD.

Transparency of conflicts of interest is essential when assessing publications that address the benefits of robotic surgery over traditional laparoscopic and open operations. We assessed discrepancies between self-reported and actual conflicts of interest as well as whether conflicts of interest are associated with favorable endorsement of robotic surgery.We searched the Embase® and MEDLINE® databases for articles on robotic surgery within pediatric urology. We included English language articles published since 2013, when data in the Open Payments program (Centers for Medicare and Medicaid Services, Baltimore, Maryland) became available. For all United States based authors Open Payments was used to identify the total amount of financial payment received from Intuitive Surgical®. Chi-square test was used to assess the association between conflicts of interest and favorable endorsement of robotic surgery.A total of 191 articles were initially identified. After exclusion criteria were applied 107 articles remained (267 distinct authors). Of the articles 86 (80.4%) had at least 1 author with a history of payment from Intuitive Surgical, with 79 (91.9%) having at least 1 author who did not declare a conflict of interest despite history of payment. A total of 44 authors (16.5%) had a history of payment from Intuitive Surgical, with an average payment of $3,594.15. Articles with a first and/or last author with a history of payment were more likely to contain a favorable endorsement of robotic surgery compared to articles without a history of payment (85.1% vs 63.6%, p = 0.0124).Nondisclosure of conflict of interest with Intuitive Surgical is extremely common within pediatric urology. Steps to ensure accurate reporting of conflicts of interest are essential. There appears to be an association between a history of payment and favorable endorsement of robotic surgery.

INTRODUCTION AND OBJECTIVE:Rezūm is a minimally invasive technique to treat benign prostatic hyperplasia (BPH). Major advantages include no de novo erectile dysfunction and low rate of retrograde e...

INTRODUCTION AND OBJECTIVE:Patients with erectile dysfunction frequently have cardiovascular/cerebrovascular risk factors requiring antithrombotics (anticoagulation/antiplatelets). Limited data are...

INTRODUCTION AND OBJECTIVE:Climacturia is an underreported complication of definitive therapy for prostate cancer (PCa); i.e. radical prostatectomy (RP) or radiation therapy (RT). We sought to iden...

INTRODUCTION AND OBJECTIVE:Patients with erectile dysfunction frequently have concurrent risk factors for venous thromboembolism (VTE) including obesity, smoking history, hypertension, and advanced...

Testicular torsion remains the most frequent cause of testicular ischemia, especially in adolescents and young adults. Timely diagnosis and intervention are keys to saving the affected testicle. This review presents current trends in the diagnosis and treatment of torsion, potential pitfalls and consequent outcomes. Additionally, other salient issues surrounding testicular torsion are also discussed, including: pathogenesis of injury, legal ramifications, fertility outcomes, novel management techniques, and recent advances in diagnostic technology.

Background Climacturia is an under-reported complication of definitive therapy for prostate cancer (PCa) - that is, radical prostatectomy (RP) and/or radiation therapy (RT). Aim We sought to identify the prevalence and predictors of climacturia and associated patient/partner bother in patients with and without prior PCa treatment. Methods We analyzed a database of patients who presented to our Men's Health clinic and filled out a questionnaire related to sexual function and pertinent medical histories. The prevalence of climacturia and associated patient/partner bother in patients with/without prior RP/RT was calculated. Univariable and multivariable logistic regressions were performed to identify predictors associated with climacturia and patient/partner bother. Outcomes The primary outcomes were the prevalence and predictors of climacturia and associated patient/partner bother in patients with/without history of definitive PCa treatment. Results Among 1,117 patients able to achieve orgasm, 192 patients (17%) had prior history of definitive therapy for PCa (RP alone = 139 [72%]; RT alone = 22 [11%]; RP + RT = 31 [16%]). Climacturia was reported by 39%, 14%, 52%, and 2.4% of patients with history of RP alone, RT alone, RP + RT, and neither RP nor RT, respectively (P Among patients with prior RP/RT, stress urinary incontinence was associated with increased risk of climacturia, whereas diabetes was associated with decreased risk. No factors were associated with patient/partner bother. Among patients with prior RP, nerve-sparing technique did not predict presence of climacturia but was associated with reduced patient/partner bother. Clinical translation Given significant prevalence of climacturia and associated patient/partner bother, patients should be counseled on the risk of climacturia before undergoing RP/RT. Strengths and limitations Strengths include the large study population and the focus on both RP and RT. Limitations include the facts that this is a single-institution study that primarily relies on patients’ subjective reporting and that the study population may not represent the general population. Conclusions Climacturia affects a significant proportion of patients with history of RP/RT for PCa, and many patients and their partners find this bothersome.

Background: Acinar cell carcinoma is a rare form of pancreatic cancer, accounting for 1–2% of all cases of exocrine pancreatic neoplasms in adults. Due to its rarity, no randomized controlled trials have been performed to determine the optimal treatment options. As such, high-quality case reports and case series are needed to help guide clinicians in the management of this deadly disease. Case Presentation: A 56-year-old Caucasian male presenting with abdominal pain and weight loss was diagnosed with stage III acinar cell carcinoma of the pancreatic body with celiac axis involvement. Although initially deemed unresectable, the patient responded favorably to nine cycles of 5-fluorouracil-based neoadjuvant chemotherapy. The tumor was successfully resected through distal pancreatectomy with en bloc splenectomy and en bloc celiac artery resection (Appleby procedure). Final pathology analysis showed negative resection margins and complete chemotherapeutic response within the pancreas, with residual tumor cells detected in only a single peripancreatic lymph node. Conclusion: 5-fluorouracil-based chemotherapy may be a promising option for the neoadjuvant treatment of locally unresectable acinar cell carcinoma. With sufficient expertise, negative surgical resection margins are possible even with vascular involvement. Due to the generally poor prognosis associated with acinar cell carcinoma, such aggressive treatment measures are warranted.

Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor–bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo–targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer. Cancer Res; 76(6); 1549–59. ©2016 AACR.

This retrospective study aimed to investigate the role that an RNA-binding protein, HuR, plays in the response of high-grade serous ovarian tumors to chemotherapeutics. We immunohistochemically stained sections of 31 surgically-debulked chemo-naive ovarian tumors for HuR and scored the degree of HuR cytoplasmic staining. We found no correlation between HuR intracellular localization in tumor sections and progression free survival (PFS) of these patients, 29 of whom underwent second-line gemcitabine/platin combination therapy for recurrent disease. Ribonucleoprotein immunoprecipitation (RNP-IP) analysis of ovarian cancer cells in culture showed that cytoplasmic HuR increases deoxycytidine kinase (dCK), a metabolic enzyme that activates gemcitabine. The effects of carboplatin treatment on HuR and WEE1 (a mitotic inhibitor) expression, and on cell cycle kinetics, were also examined. Treatment of ovarian cancer cells with carboplatin results in increased HuR cytoplasmic expression and elevated WEE1 expression, arresting cell cycle G2/M transition. This may explain why HuR cytoplasmic localization in chemo-naive tumors is not predictive of therapeutic response and PFS following second-line gemcitabine/platin combination therapy. These results suggest treatment of recurrent ovarian tumors with a combination of gemcitabine, carboplatin, and a WEE1 inhibitor may be potentially advantageous as compared to current clinical practices.

Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO(2)) and decreased O(2) intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3’-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR’s regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.

Mucin1 (MUC1) is overexpressed in pancreatic ductal adenocarcinoma (PDA) and is associated with tumor aggressiveness, suggesting that MUC1 is a promising therapeutic target for promoter-driven diphtheria toxin A (DTA). Endogenous MUC1 transcript levels were analyzed by quantitative PCR (qPCR) in multiple PDA cells (Capan1, HPAFII, Su.86.86, Capan2, Hs766T, MiaPaCa2, and Panc1). Expression levels were correlated with luciferase activity and cell death after transfection with MUC1 promoter–driven luciferase and DTA constructs. MUC1-positive (+) cells had significantly elevated MUC1 mRNA expression compared with MUC1-negative (−) cells. Luciferase activity was significantly higher in MUC1+ cells when transfected with MUC1 promoter–driven luciferase and MUC1+ cells underwent enhanced cell death after transfection with a single dose of MUC1 promoter–driven DTA. IFNγ pretreatment enhanced MUC1 expression in MUC1− cells and induced sensitivity to MUC1–DTA therapy. Matched primary and metastatic tumor lesions from clinical specimens revealed similar MUC1 IHC labeling patterns, and a tissue microarray of human PDA biopsies revealed increased immunolabeling with a combination of MUC1 and mesothelin (MSLN) antibodies, compared with either antibody alone. Combining MUC1 with MSLN-targeted DTA enhanced drug efficacy in an in vitro model of heterogeneous PDA. These data demonstrate that MUC1 promoter–driven DTA preferentially kills MUC1-expressing PDA cells and drugs that enhance MUC1 expression sensitize PDA cells with low MUC1 expression. Implications: MUC1 expression in primary and metastatic lesions provides a rationale for the development of a systemic MUC1 promoter–driven DTA therapy that may be further enhanced by combination with other promoter-driven DTA constructs. Mol Cancer Res; 13(3); 439–48. ©2014 AACR.

OBJECTIVES: We tested cytoplasmic HuR (cHuR) as a predictive marker for response to chemotherapy by examining tumor samples from the international European Study Group of Pancreatic Cancer-3 trial, in which patients with resected pancreatic ductal adenocarcinoma (PDA) received either gemcitabine (GEM) or 5-fluorouracil (5-FU) adjuvant monotherapy. BACKGROUND: Previous studies have implicated the mRNA-binding protein, HuR (ELAVL1), as a predictive marker for PDA treatment response in the adjuvant setting. These studies were, however, based on small cohorts of patients outside of a clinical trial, or a clinical trial in which patients received multimodality therapy with concomitant radiation. METHODS: Tissue samples from 379 patients with PDA enrolled in the European Study Group of Pancreatic Cancer-3 trial were immunolabeled with an anti-HuR antibody and scored for cHuR expression. Patients were dichotomized into groups of high versus low cHuR expression. RESULTS: There was no association between cHuR expression and prognosis in the overall cohort [disease-free survival (DFS), P = 0.44; overall survival, P = 0.41). Median DFS for patients with high cHuR was significantly greater for patients treated with 5-FU compared to GEM [20.1 months, confidence interval (CI): 8.3–36.4 vs 10.9 months, CI: 7.5–14.2; P = 0.04]. Median DFS was similar between the treatment arms in patients with low cHuR (5-FU, 12.8 months, CI: 10.6–14.6 vs GEM, 12.9 months, CI: 11.2–15.4). CONCLUSIONS: Patients with high cHuR-expressing tumors may benefit from 5-FU-based adjuvant therapy as compared to GEM, whereas those patients with low cHuR appear to have no survival advantage with GEM compared with 5-FU. Further studies are needed to validate HuR as a biomarker in both future monotherapy and multiagent regimens.

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer. Cancer Res; 77(16); 4460–71. ©2017 AACR.

144 Background: Despite having well-recognized limitations, urologists often rely on serial PSA testing as a marker for treatment response or disease progression. To determine if PSA was indeed a reliable marker for treatment response or disease progression, we compared PSA levels against C-11 choline PET/CT in the evaluation of patients with advanced prostate cancer treated with second generation hormonal therapy (2nd-HT). Methods: We retrospectively identified 239 patients who were undergoing treatment with 2nd-HT (enzalutamide or abiraterone) for advanced prostate cancer. While on treatment, patients underwent serial PSA testing and C-11 choline PET/ CTs every 3 – 6 months. Paradoxical response was defined as increasing blood pool-corrected SUVmax of known choline-avid lesions and/or identification of new choline-avid lesions, despite stable or down-trending PSA. Results: Median (IQR) age was 70.4(64.3 – 75.7) years and median (IQR) primary Gleason Score was 8 (7 – 9). In our study, 19% of patients (n = 46/239) who were receiving 2nd-HT exhibited paradoxical response. Median (IQR) PSA and corrected SUVmax at baseline evaluation were 1.3 ng/mL (0.3 – 12.8 ng/mL) and 3.5 (1.8 – 5.8), respectively. Median (IQR) PSA and corrected SUVmax at the time of paradoxical response were 0.4 ng/mL (0.1 – 5.4 ng/mL) and 4.5 (2.8 – 6.8), respectively. The median duration of 2nd-HT treatment prior to detection of paradoxical response was 4.8 months (2.9 – 10.1 months). No significant difference was noted between patients receiving enzalutamide versus abiraterone (p = 0.35). Independent predictors of paradoxical response were prior primary systemic treatment (i.e. hormonal/chemo-hormonal therapy versus local therapy) and patient’s age at time of 2nd-HT initiation on univariate and multivariate analysis. Conclusions: Our retrospective review demonstrated prostate cancer disease progression discordant with PSA down-trending in 19% of patients receiving 2nd-HT. We conclude that in this subset of patients with advanced prostate cancer, PSA may not be a reliable marker of treatment response of disease progression, and routine radiographic evaluation in these patients is warranted.

143 Background: Systemic treatment in the management of metastatic prostate cancer is inevitable. However, there is a growing interest in metastases-directed therapy (MDT). We sought to investigate the efficacy of MDT in treating patients with solitary metastatic prostate cancer and hence, delaying initiation of systemic treatment (i.e., Androgen deprivation therapy or chemotherapy). Methods: We retrospectively identified 61 patients treated with targeted therapy in the form of surgery (n = 30), stereotactic body radiation therapy (SBRT) (n = 25), or cryotherapy (n = 7) for their solitary metastases prostate cancer. Complete response was defined by achieving a PSA value of ≤0.2 ng/ml plus resolution of the solitary metastatic lesion on C-11 choline PET choline scan, while incomplete response was defined by a residual PSA of > 0.2 ng/ml and/or radiographic evidence of disease following metastases-targeted therapy. Results: Mean (±SD) age was 68.4 (±7.8) yrs., median (IQR) primary Gleason Score was 7 (7-9) and median (IQR) pre-MDT PSA was 2 (1.3-3.8) ng/ml. Median (IQR) time from primary treatment of the prostate to MDT was 5.1 (2.7-10.1) years. None of the patients were on hormone therapy at the time of presentation with solitary metastases prostate cancer. 30 patients had bone metastases, 29 patients had lymph node metastases, 1 patient had soft tissue metastasis (pelvic metastatic mass), and another patient had visceral metastasis (to the lung). 42% of the patients (n = 26) achieved complete response to targeted therapy. Median time to initiation of 2nd line systemic treatment following MDT was 17.8 months for the complete responders versus 9.3 months for incomplete responders. 11% of the patients (n = 7) did not require 2nd line therapy after their MDT for a mean (±SD) time of 56.9 (±22.5) months. Conclusions: The use of targeted therapy in the management of patients with solitary metastatic disease or low-volume metastatic disease can provide comparable outcomes to those of systemic treatment. Further studies are warranted.