Prognostic role of 11C-choline PET/CT scan in patients with metastatic castrate resistant prostate cancer undergoing primary docetaxel chemotherapy.

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 <20% reduction in blood pool-corrected SUVmax (OR: 3.56, 95% CI: 1.04-16.52, p = .0420). Median PFS in the complete response group was 35.1 months (95% CI: 26.0-52.7 months), compared to 9.4 months (95% CI: 6.9-13.0 months) in the incomplete response group (p = .0005). CONCLUSIONS: Our study showed that mid-course and posttherapy 11C-choline PET/CT evaluation for mCRPC patients undergoing primary docetaxel chemotherapy can predict full course treatment response and PFS, respectively. 11C-choline PET/CT imaging may provide valuable prognostic information to guide treatment choices for patients with mCRPC.

Prevalence and Predictors of Climacturia and Associated Patient/Partner Bother in Patients With History of Definitive Therapy for Prostate Cancer.

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 < .05 between all groups). 33 to 45 percent of patients with climacturia noted significant patient/partner bother. Factors significantly associated with climacturia were prior RP, prior RT, history of other prostate surgery, and erectile dysfunction, although erectile dysfunction was not significant on multivariable analysis. Significant reduction in climacturia prevalence was noted for patients who were ≥1 year out from RP, compared with patients who were <1 year out. 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. Jimbo M, Alom M, Pfeifer ZD, et al. Prevalence and Predictors of Climacturia and Associated Patient/Partner Bother in Patients With History of Definitive Therapy for Prostate Cancer. J Sex Med 2020;17:1126-1132.

Discrepancies in Self-Reported and Actual Conflicts of Interest for Robotic Pediatric Urological Surgery.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Cytoplasmic HuR Status Predicts Disease-free Survival in Resected Pancreatic Cancer: A Post-hoc Analysis From the International Phase III ESPAC-3 Clinical Trial.

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.

Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs.

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤ 0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized.

Fusing transcriptomics to progressive prostate cancer.

This commentary highlights the article by Yu et al, describing a set of novel fusion transcripts strongly associated with prostate cancer prognosis.

Sperm telomere length in male-factor infertility and reproduction.

The underlying reasons for male-factor infertility are often unknown. 30% of all men have unexplained semen analysis abnormalities. Moreover, 15%-40% of infertile men have normal semen analyses. There have been increasing efforts to identify causes and associations that may explain idiopathic male-factor infertility. Telomeres have become an area of considerable interest in the field because of the essential roles they have in cellular division and genome integrity. Research to date most consistently supports that men with infertility have shorter sperm telomere length (STL); however, associations between shorter STL and meaningful reproductive health outcomes are less consistent. There is a major need for additional studies to better identify the role of STL in male reproductive health and use the information to improve the counseling and treatment of couples with idiopathic male-factor infertility.

Transgenerational effects of paternal exposures: the role of germline de novo mutations.

Germline de novo mutations (DNMs) refer to spontaneous mutations arising during gametogenesis, resulting in genetic changes within germ cells that are subsequently transmitted to the next generation. While the impact of maternal exposures on germline DNMs has been extensively studied, more recent studies have begun to highlight the increasing importance of the effects of paternal factors. In this review, we have summarized the existing literature on how various exposures experienced by fathers affect the germline DNM burden in their spermatozoa, as well as their consequences for semen analysis parameters, pregnancy outcomes, and offspring health. A growing body of literature supports the conclusion that advanced paternal age (APA) correlates with a higher germline DNM rate in offspring. Furthermore, lifestyle choices, environmental toxins, assisted reproductive techniques (ART), and chemotherapy are associated with the accumulation of paternal DNMs in spermatozoa, with deleterious consequences for pregnancy outcomes and offspring health. Ultimately, our review highlights the clear importance of the germline DNM mode of inheritance, and the current understanding of how this is affected by various paternal factors. In addition, we explore conflicting reports or gaps of knowledge that should be addressed in future research.

Fertility in the aging male: a systematic review.

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.

Patient Attitudes Towards Surgical Management of Peyronie's Disease Prior to Men's Health Consultation.

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.

Characteristics of men who are bothered by rapid ejaculation: results from clinical intake surveys.

The objective of this study is to identify factors associated with bother with rapid ejaculation in a cohort of men presenting to a sexual dysfunction clinic, independent of a diagnosis of PE. A prospective institutional database has been maintained on patients completing an 89-item intake questionnaire querying various areas of sexual dysfunction. Regarding ejaculatory dysfunction, patients are asked "Do you feel bothered, annoyed, and/or frustrated by ejaculating too quickly?" Statistical modeling was performed to identify associations. A total of 1359 men completed the intake survey, and 694 responded to the question on bother with rapid ejaculation. Overall, 42.9% (298/694) of respondents reported bother with rapid ejaculation. Men reporting bother were more likely to report lower intravaginal ejaculatory latency (IELT) time (4.2 vs 12.2 min, p < 0.0001), problems with depression (32% vs 21%, p = 0.001), negative impact on relationship (73% vs 51%, p < 0.0001), and negative impact on partner's sexual satisfaction (26% vs 15%, p < 0.001). These results highlight the importance of asking all men presenting with sexual health concerns about their bother with rapid ejaculation for complete assessment of sexual and mental wellbeing.

Vasectomy Reversal Online Marketing Practices: What Are We Putting Out There?

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.

Gemcitabine-loaded microbubble system for ultrasound imaging and therapy.

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.

Incidence of Venous Thromboembolism and Safety of Perioperative Subcutaneous Heparin During Inflatable Penile Prosthesis Surgery.

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.

Use of Nitrous Oxide in Office-based Urologic Procedures: A Review.

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.

Full thickness genital burns independently increase the odds of death among pediatric burn patients.

BACKGROUND: There are limited published data characterizing pediatric burn patients with genital burns (GB). OBJECTIVE: Assess prevalence of GB in pediatric burn patients and analyze clinical characteristics including predictors of mortality. STUDY DESIGN: We queried American Burn Association's National Burn Repository to identify all pediatric burn patients who presented to North American burn centers over a 10-year period. We excluded all patients aged ≥18 years and patients with unknown sex, race, and/or mortality. We also excluded subsequent encounters for patients with multiple visits. Demographic and clinical characteristics were compared between patients with and without GB. Univariable and multivariable logistic regression analyses were performed to identify predictors of mortality. RESULTS: Among 38 211 pediatric burn patients, 1244 (3.3%) suffered from second- or third-degree GB. Patients who suffered from third-degree GB (GB3) were significantly older than patients who suffered from second-degree GB (GB2) or patients without GB. Of the patients, 32.3% were aged 0-2 years. Scalding was the most common mechanism of injury for pediatric GB patients at 73.8%. Compared to non-GB patients, GB patients had significantly higher total body surface area (TBSA) burned (16.5% vs 7.0%), higher rates of associated inhalation injury (4.1% vs 2.6%), longer length of stay (LOS) (14.3 days vs 6.7 days), higher rates of urinary tract infection (UTI) (13.0% vs 2.8%) and sepsis (14.1% vs 2.3%), and higher mortality (3.5% vs 0.7%) (P < 0.0001 for all). The differences were more pronounced for the subset of patients who suffered from GB3 (TBSA 43.5%, associated inhalation injury 19.9%, LOS 42.9 days, 21.3% UTI, 33.3% sepsis, and 19.3% mortality). On multivariable analysis, the presence of GB3, TBSA, non-white ethnicity, and the presence of associated inhalation injury were significant predictors of mortality. Only 4.5% of pediatric GB patients underwent genital surgery, with the majority consisting of excision, reconstruction, or repair of the penis, vulva, or perineum. No patient required orchiectomy or suprapubic catheter placement. DISCUSSION: This is the largest study to date of pediatric GB patients. A minority of pediatric burn patients present with GB. However, when they occur, GB are associated with significantly worse clinical outcomes. Importantly, the presence of GB3 is an independent predictor of mortality in pediatric burn patients. CONCLUSION: The presence of GB appears to be a strong marker of severe burn injury. Pediatric GB patients need to be carefully assessed and aggressively managed for additional injuries, complications, surgical needs, and mortality risk.

Photoinitiated destruction of composite porphyrin-protein polymersomes.

Bilayer vesicles assembled from amphiphilic diblock copolymers (polymersomes) adopt asymmetric structures when loaded with moderate concentrations (>or=1.5 mg/mL) of horse spleen ferritin (HSF) or its iron-free variant (HSAF). Incorporation of both ferritin and a zinc porphyrin dimer (PZn(2)) generates photoresponsive vesicles: irradiation with focused light of near-UV to near-IR wavelengths induces polymersome deformation and destruction on the minute time scale. To investigate this phenomenon, polymersomes were loaded with dye-labeled ferritin and PZn(2). Confocal microscopy identified BODIPY-FL-labeled ferritin at the membrane, whereas Cy3-labeled ferritin was found both at the membrane and throughout the aqueous core. Fluorescence recovery after photobleaching (FRAP) experiments confirmed that Cy3- and BODIPY-FL-labeled ferritin and PZn(2) exhibited slow diffusion at the membrane, consistent with membrane association. Furthermore, micropipette aspiration experiments revealed increased elastic moduli and altered bending rigidity in vesicles incorporating HSAF. Finally, a small molecule (biocytin) was encapsulated within the ferritin-PZn(2) vesicles and released upon exposure to light. These data indicate synergy between ferritin, whose membrane association lowers the barrier to deformation, and PZn(2), which embeds in the membrane, harvests light energy and produces local heating that may lead to membrane budding. This appears to be a general protein-polymer membrane phenomenon, as replacement of ferritin with bovine serum albumin or equine skeletal myoglobin resulted in vesicles with similar asymmetric morphology and photosensitivity.

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.

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.

Neoadjuvant Chemotherapy and Appleby Procedure for Pancreatic Acinar Cell Carcinoma: A Case Report.

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.