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Achieving satisfactory post-operative pain control for common elective general surgical procedures, while minimizing opioid utilization, remains challenging. Utilizing pre-operative educational strategies, as well as multimodal analgesia, we sought to reduce the post-operative opioid use in elective general surgery cases.Between November 2019 and July 2021, patients undergoing elective inguinal hernia repair or cholecystectomy were enrolled in the study. Patients were divided into three cohorts: Control, opioid sparing (OS), or zero-opioid (ZO). Control patients did not have any intervention; OS patients had an opioid reduction intervention protocol applied (patient education and perioperative multimodal analgesia) and were provided an opioid prescription at discharge; the ZO had the same protocol, however, patients were not provided opioid prescriptions at discharge. Two weeks after discharge, patients were interviewed to record opioid consumption, pain scores, and level of satisfaction since discharge.A total of 129 patients were recruited for the study. Eighty-eight patients underwent inguinal hernia repair and 41 patients underwent cholecystectomy. Median post-operative morphine equivalents consumed in the Control cohort (n = 58); 46 (37.5-75) were significantly reduced when the OS protocol was enacted (n = 42); 15 (11-22.5) and further reduced to zero for every patient in the ZO cohort (n = 29) (P = 0.0001). There were no differences in patient-reported average pain scores after discharge (P = 0.08) or satisfaction levels with experience (P = 0.8302).Our study demonstrates that patient education and preoperative interventions can result in zero opioids prescribed after common general surgery procedures with equivalent patient satisfaction and pain scores.

Background Early cholecystectomy (E-CCY; 8 weeks or less) after percutaneous cholecystostomy tube (PCT) placement has been associated with increased postoperative complications, but this finding has not been validated at a national level and PCT-related complications and interventions (PCT-RCIs) were not evaluated. Study Design Adults with PCT for acute cholecystitis subsequently undergoing CCY were identified within the Nationwide Readmission Database (2010-2015) and our institution (2017-2019). Adjusted relative risks (aRRs) of postoperative complications were estimated using Poisson regression comparing E-CCY with delayed cholecystectomy (D-CCY; more than 8 weeks) within the nationwide cohort. Institutional PCT-RCIs, operative data, and postoperative outcomes were compared between E-CCY and D-CCY using chi-square and Kruskal-Wallis tests. Results Of 6,145 patients from the Nationwide Readmission Database, 32.9% were D-CCY. Risk-adjusted analysis identified no differences between E-CCY and D-CCY in complications (aRR 0.98; 95% CI, 0.89 to 1.07), mortality (aRR 0.88; 95% CI, 0.43 to 1.81), or 30-day readmissions (aRR 1.04; 95% CI, 0.85 to 1.27). Risk-adjusted analyses assessing the association of time to interval cholecystectomy (IC) with morbidity indicated an increased risk of surgical complications in the first month after PCT placement (aRR 1.17; 95% CI, 1.08 to 1.33). In the institutional cohort (E-CCY, n = 23; D-CCY, n = 45), there were no statistically significant differences found in estimated blood loss, length of stay, and postoperative complications. There were increased PCT-RCIs in the D-CCY group (26.9% E-CCY vs 69% D-CCY; p Conclusions Increased operative complications when IC is performed within 1 month of PCT placement and increased PCT-RCIs when IC is performed 8 weeks after PCT placement suggest that the most favorable timing for IC is between 4 and 8 weeks after PCT placement.

Dr Nina Braunwald is celebrated for her work as the first female cardiothoracic surgeon and her key role in the design and implementation of the first prosthetic mitral valve. She began her residency at Bellevue Hospital in 1952, a time in the United States where the scope of women’s work was limited. Once her training took her to the National Institutes of Health (NIH), her historic flexible leaflet valve was developed and Dr Braunwald paved an innovative step toward the advanced prostheses of today. Afterward, she was recognized by the American Board of Thoracic Surgery in 1963. Her extensive research and educational passion for cardiothoracic surgery led to numerous publications, a leadership role with the NIH, and associate professorship at University of California San Diego and Harvard; leaving behind a significant legacy to be memorialized in awards and fellowships to women in academic cardiac surgery. Her work inspired continued evolution of the prosthetic valve and countless women to pursue surgery as a career before passing away in 1992, leaving behind a new generation of women surgeons. Despite her successful career, she was never promoted to full professor by her academic institutions.

Marginal ulcer (MU) formation is a serious complication following Roux-en-Y Gastric Bypass (RYGB). Incidental data suggested a higher incidence of MU following conversion of Sleeve Gastrectomy to RYGB (S-RYGB). Herein, we evaluate the incidence of MU after primary versus secondary RYGB.After IRB approval, each institution's electronic medical record and MBSAQIP database were queried to retrospectively identify adult patients who underwent primary RYGB (P-RYGB), Gastric Banding to RYGB (B-RYGB), or S-RYGB between 2014 and 2019, with minimum 1 year follow-up. Patient demographics, operative data, and post-operative outcomes were compared. Numeric variables were compared via two-sample t test, Wilcoxon test or Kruskal Wallis rank sum test. Two-sample proportion test or Fisher's exact test was employed for categorical and binary variables. p 0.05 marked statistical significance.748 patients underwent RYGB: P-RYGB n = 584 [78.1%]; B-RYGB n = 98 [13.1%]; S-RYGB n = 66 [8.8%]. Most patients were female (83.2%). Mean age was 45.7 years. Forty-six (n = 6.1%) patients developed MU, a median of 14 ± 32.2 months (range 0.5-82) post-operatively. Incidence of MU was significantly higher for patients undergoing S-RYGB (n = 9 [13.6%]), compared to P-RYGB (n = 34 [5.8%]) and B-RYGB (n = 3 [3.1%]) (p = 0.023). Median time (months) to MU was significantly shorter for patients who underwent S-RYGB (5 ± 6) compared to P-RYGB or B-RYGB (19 ± 37.5) (p = 0.035). Among those who developed MU, there was no significant difference in H. pylori status, NSAID, steroid, or tobacco use, irrespective of operation performed.In this multi-institutional cohort, patients who underwent S-RYGB had a significantly higher incidence of MU than those with P-RYGB or B-RYGB. Further research is needed to elucidate its pathophysiology and prevention strategies.

With the rising prevalence of obesity, there has been a steady rise in the number of bariatric surgeries performed worldwide. As expected, there has also been an increase in the number of revisional surgeries performed to manage acute and chronic postoperative complications. This review will discuss the major complications that can arise from the most common bariatric surgeries, their diagnosis, medical management, and potential revisional surgical options.

Dr. Joseph Murray was a plastic surgeon who is best known for performing the first successful human organ transplant. After graduating from Harvard Medical School and completing a surgical internship at Peter Bent Brigham Hospital, Murray enlisted in the US Army Medical Corp and spent 5 years at Valley Forge General Hospital treating World War II soldiers injured in combat. He treated hundreds of burn victims with skin grafts and took an interest in the variable process of graft rejection based on both the patient’s relation to the graft donor and the patient’s level of immunocompetency. His work at Valley Forge set the stage for his research investigating the feasibility of kidney transplantation and immunosuppression. He went on to perform the first successful kidney transplant between identical twins in 1954, between fraternal twins in 1959, and between an unrelated donor and recipient in 1962. For his efforts, he was awarded the 1990 Nobel Prize in Medicine.

Dr. Orvar Swenson is best remembered for developing the Swenson pull-through, a technique he developed to treat Hirschsprung's disease. After graduating from Harvard Medical School and beginning his residency at Peter Bent Brigham Hospital, Dr. Swenson observed that patients with Hirschsprung's disease and toxic megacolon resumed normal bowel function after placement of transverse colostomies. His observation led to studying the patency of his patients’ colons using barium enema contrast studies. At the collapsed portion of the colon, he performed rectal biopsies leading to the discovery that the cause of Hirschsprung's disease is that the collapsed portion of the colon lacks the Auerbach plexus. The Swenson pull-through removes this aganglionic portion of the colon and cures the patient. His career grew from there as he traveled to academic institutions teaching his technique. He is remembered fondly for his contributions to pediatric surgery through the restructuring of pediatric surgery departments, pediatric surgery research, and writing and editing multiple volumes of Pediatric Surgery, the standard textbook for pediatric surgeons. He died peacefully in 2012 at the age of 103 years.

War has the unique ability to intensify obstacles that surgeons face daily in civilian hospitals. After a brief overview of the historical context of the first and second world wars, this article will focus on how those daily challenges, namely limited skill, bleeding, and infection, led to an era of surgical innovation and standardization of surgical education.

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.

Bariatric surgery procedures, including laparoscopic sleeve gastrectomy, laparoscopic Roux-en-Y gastric bypass (LRYGB), and laparoscopic adjustable gastric banding (LAGB), are now commonly performed “general surgery” procedures. This chapter gives an overview of the safety of the procedures themselves, as well as the infrastructure, support, and regulating bodies required to maintain that safety. It also gives an outline of the safety of more recent technologies such as robotic surgery, as well as the risks of operating upon special populations, including the elderly, transplant candidates, and patients with ventral hernias.

Background Attrition from general surgery residency remains constant at approximately 20% despite nearly a decade of work-hour reform and studies aiming to identify common risk factors. High rates of attrition from training have a wide impact, from the overall quality of trainees produced to implications on public health and the broader surgical work force. We set out to evaluate a novel character trait, grit, defined as passion and perseverance for long-term goals, as a marker and potential risk factor for resident attrition. Methods Twelve Accreditation Council for Graduate Medical Education–approved general surgery residency programs participated in a prospective, multi-institutional, survey-based analysis of grit and attrition during the 2012–2013 academic year. Participating individuals were blinded with regards to the primary outcome of the study. Participating institutions were blinded to the responses of their trainees. Participating residency programs were located in a variety of settings, from university-based health systems to community hospitals. Results Sixty-eight percent (68%) of residents (180 of 265) at participating institutions completed the study. The primary end point for this study was attrition from residency as a function of grit. Secondary end points included an evaluation of the utility of the grit score in surgical residents, variability of grit according to postgraduate year, sex, measurements of resident satisfaction with current program, lifestyle, and career goals. Finally, the study included an analysis of key resident support strategies. The attrition rate across 12 institutions surveyed was approximately 2% (5 residents). Of those five, three participated in our study. All three had below-median levels of grit. Those residents with below-median grit were more likely to contemplate leaving surgical residency. Given the low attrition rate, no variable surveyed reached statistical significance in our analysis. Key support strategies for residents responding included family, friends outside of residency, co-residents, and formal mentorship through their particular residency. Conclusion In this preliminary underpowered study, grit appears to be a promising marker and risk factor for attrition from surgical residency. In an effort to retain residents, programs should consider screening for grit in current residents and directing support to those residents with below-median values, with a focus on building family, friend, and formal mentor relationships.

BACKGROUND Patients and providers are increasingly interested in the utilization, safety, and efficacy of minimally invasive surgery (MIS). We reviewed 11 years of MIS resections (laparoscopic and robotic) for intra-abdominal malignancies. METHODS Patients who underwent gastrectomy, distal pancreatectomy, hepatic resection, and colorectal resection between 2004 and 2014 were identified. Cases were categorized as open, laparoscopic, and robotic based on the initial operation approach. Diagnostic laparoscopies were excluded. RESULTS Of the 10 039 patients who underwent the above procedures, between 2004 and 2014, 2832 (28%) were MIS. In 2004, 12% (100/826) of all resections were performed with MIS approaches, rising to 23% (192/821) of all resections by 2009 and 44% (484/1092) in 2014. The number of open resections has remained largely stable: 726 (88% of all resections) in 2004 and 608 (56% of all resections) in 2014. Initially, laparoscopy experienced incremental adoption. Robotic surgery was implemented in 2009 and is currently the dominant MIS approach, accounting for 76% (368/484) of all MIS resections in 2014. Overall mortality has remained less than 1%. CONCLUSIONS While maintaining patient safety, utilization of MIS techniques has increased substantially since 2004, particularly for gastric and colorectal resections. Since 2009 robotic surgery is the predominant MIS approach.

Vestibular schwannomas (VS) can be managed by observation. The goals were to examine clinical, radiographic, and audiometric variables at presentation and during observation that may predict which patients fail conservative management.A retrospective chart review was performed of 202 patients who elected observation primarily. Data collection included presenting symptoms, symptom progression, tumor size, audiologic measures, and global clinical outcomes. Univariate and multivariate analyses were performed.Follow-up ranged from 1 month to 16 years (mean, 2.48 yr). Nineteen patients (9.4%) in the study group failed. Disequilibrium as a presenting symptom appeared more often in patients who failed observation (58% versus 32%; p = 0.039), as did new-onset disequilibrium. Presenting tumor size differed for patients who failed conservative management, with a mean of 14.0 versus 8.4 mm (p = 0.0006). Neurotologic complications compared favorably to those treated with primary surgery or radiotherapy.Patients with subjective disequilibrium at presentation and subjective disequilibrium developed during observation may be more likely to fail conservative management. Increased tumor size at presentation also may indicate the same, although no threshold could be achieved.

While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly characterized. One thousand one hundred seven patients underwent pancreatectomy at Thomas Jefferson University between 2006 and 2013. Attempts were made to contact all living patients by telephone and a DM-focused questionnaire was administered. Two hundred fifty-nine of 691 (37 %) surviving patients completed the survey, including 179 pancreaticoduodenectomies (PD), 78 distal pancreatectomies (DP), and 2 total pancreatectomies. In the PD group, 44 (25 %) patients reported having DM prior to resection. Of these, 5 (12 %) had improved glucose control after resection and 21 (48 %) reported escalated DM medication requirements post-resection. Of 135 PD patients without preoperative DM, 24 (18 %) had new-onset DM postoperatively. In the DP group, 23 patients (29 %) had DM preoperatively. None had improved glucose control after resection, while six (26 %) had worse control after resection. Seventeen of 55 DP patients (31 %) without preoperative DM developed new-onset DM postoperatively (p = 0.04 vs. PD). Preoperative HgbA1C >6.0 %, glucose >124 mg/dL, and insulin use >2 units per day were associated with an increased risk of new-onset postoperative DM. The development or worsening of DM after pancreatic resection is extremely common, with different types of resections conveying different risks for disease progression. DP places patients at a greater risk for the development of new-onset postoperative diabetes when compared to PD. In contrast, patients with preoperative diabetes are more likely to experience worsening of their disease after PD as compared to DP. Patients should be screened prospectively, particularly those at highest risk, and informed of and educated about the potential for post-resection DM.

PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)–dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs, raising important questions about long-term off-target effects. Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain–domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage–dependent catalytic activation. Furthermore, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anticancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA-damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Finally, the development of a high-throughput PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors. Cancer Res; 74(1); 31–37. ©2013 AACR.

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, with a 95% five-year mortality rate. For over a decade, gemcitabine (GEM) has been the established first-line treatment for this disease despite suboptimal response rates. The development of PARP inhibitors that target the DNA damage repair (DDR) system in PDA cells has generated encouraging results. Ubiquitin-specific peptidase 11 (USP11), an enzyme that interacts with the DDR protein BRCA2, was recently discovered to play a key role in DNA double-strand break repair and may be a novel therapeutic target. A systematic high-throughput approach was used to biochemically screen 2,000 U.S. Food and Drug Administration (FDA)-approved compounds for inhibition of USP11 enzymatic activity. Six pharmacologically active small molecules that inhibit USP11 enzymatic activity were identified. An in vitro drug sensitivity assay demonstrated that one of these USP11 inhibitors, mitoxantrone, impacted PDA cell survival with an IC50 of less than 10 nM. Importantly, across six different PDA cell lines, two with defects in the Fanconi anemia/BRCA2 pathway (Hs766T and Capan-1), mitoxantrone is 40- to 20,000-fold more potent than GEM, with increased endogenous USP11 mRNA levels associated with increased sensitivity to mitoxantrone. Interestingly, USP11 silencing in PDA cells also enhanced sensitivity to GEM. These findings establish a preclinical model for the rapid discovery of FDA-approved compounds and identify USP11 as a target of mitoxantrone in PDA. Implications: This high-throughput approach provides a strong rationale to study mitoxantrone in an early-phase clinical setting for the treatment of PDA. Mol Cancer Res; 11(8); 901–11. ©2013 AACR.

Understanding the factors contributing to improved postoperative patient outcomes remains paramount. For complex abdominal operations such as pancreaticoduodenectomy (PD), the influence of provider and hospital volume on surgical outcomes has been described. The impact of resident experience is less well understood. We reviewed perioperative outcomes after PD at a single high-volume center between 2006 and 2012. Resident participation and outcomes were collected in a prospectively maintained database. Resident experience was defined as postgraduate year (PGY) and number of PDs performed. Forty-three residents and four attending surgeons completed 686 PDs. The overall complication rate was 44 %; PD-specific complications (defined as pancreatic fistula, delayed gastric emptying, intraabdominal abscess, wound infection, and bile leak) occurred in 28 % of patients. The overall complication rates were similar when comparing PGY 4 to PGY 5 residents (55.3 vs. 43.0 %; p > 0.05). On univariate analysis, there was a difference in PD-specific complications seen between a PGY 4 as compared to a PGY 5 resident (44 vs. 27 %, respectively; p = 0.016). However, this was not statistically significant when adjusted for attending surgeon. Logistic regression demonstrated that as residents perform more cases, PD-specific complications decrease (OR = 0.97; p

The current treatment options for pancreatic ductal adenocarcinoma fall exceedingly short of a cure, providing a sobering 5-year survival rate of only 5% for all patients, and the disease will be responsible for more than 37,000 deaths in the United States alone this year. These numbers continue to grow, and it was recently predicted that, within decades, pancreatic ductal adenocarcinoma will become the second most lethal cancer in this country. Beyond conventional oncologic-based therapies, researchers are working hard, albeit with increasingly limited federal support, to develop multiple novel therapeutic options focusing primarily on targeting specific, disrupted core signaling pathways within pancreatic cancer cells. In line with the history of medical oncology and medical paradigms, many pharmaceutical companies and large academic institutions have been focused on searching for compounds (biologic and chemicals) in an effort to find that unique "magic bullet" that will extend pancreatic cancer patients' lives (e.g., K-ras inhibitors). This magic bullet has been difficult to find in a haystack full of molecular pathways and mutated genes because the challenge is defined by identifying a therapeutic window that kills the tumor, yet spares the host. This therapeutic window has been hard to discover in the backdrop of the heterogeneous cell populations that make up a pancreatic tumor together with a heterogeneous patient population that has multiple, undefined tumor subtypes. Thus, to date, efforts have had limited success. Perhaps the best recent example of limited success is the discovery of the classic combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), extending life by only 4 months when compared with gemcitabine (note that this drug combination does not directly target one single pathway or pancreatic cancer subtype).

Background: The number of pancreatic resections performed each year in the United States according to the Nationwide Inpatient Sample is growing (currently around 5000). Nearly half of the patients undergoing resection (many with benign disease) will experience prolonged survival (>2 years), yet the long-term risk of pancreatogenic (type III) diabetes remains unknown. Previous estimates from small studies outside of the U.S. suggest a risk between 10-20%. Methods: After IRB approval, 1107 patients were identified who underwent pancreatectomy at a single institution from 2005 to 2012. Living patients were contacted by telephone, and preand postoperative diagnoses of diabetes mellitus (DM) were confirmed using a verbal questionnaire. Only individuals who completed the survey were included in the study. Results: Calls were made to all 691 living patients who underwent partial pancreatectomy. DM-specific information was successfully obtained for 257 patients (23% of the total cohort), including 179 pancreaticoduodenectomies (PD) and 78 distal pancreatectomies (DP). In the PD group: 44 (25%) patients reported having DM prior to resection (median onset 7 years prior, range 0.1 to 30), with 10 (6%) reporting onset within 1 year of resection. Of the group carrying a pre-operative diagnosis of DM, 3 (7%) had improved glucose control after resection (dose reduction in DM medicines), while 21 (48%) required escalated doses/medicines. Of 135 patients without preoperative DM, 24 (18%) were newly diagnosed with DM postoperatively (median onset 7.5 months postoperatively, range 1-64). In the DP group: 23 patients (29%) had DM preoperatively, with just 4 having onset within 1 year of resection (5%). No patients had improved glucose control after resection, while 6 (26%) patients carrying a preoperative diagnosis of DM had worse control after resection. Out of 55 patients without preoperative DM, 17 (31%) developed new onset DM after resection (median 6 months, range 0-60). In the total cohort of patients who developed DM after resection (n=41), the most common pathologic diagnoses at the time of resection were ductal adenocarcinoma (36%), IPMN adenoma (28%), and chronic pancreatitis (8%). Out of 190 patients without a diagnosis of preoperative DM, a high preoperative HgbA1C level (> 6%) was associated with an increased risk of developing new-onset DM postresection (38% of patients in the >6% group vs. 11% in the ≤6% group, p 6% identifies patients at highest risk. Incidence of perioperative DM with partial pancreatectomy

179 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of androgen receptor (AR) function in models of prostatic adenocarcinoma (PCa), and is recruited to regulatory sites of select AR target genes. Pharmacological inhibition of PARP-1 enzymatic activity results in diminished AR and PARP-1 residency at AR target gene regulatory loci, reduced AR target gene expression (more than 50%), and reduced AR-driven, PCa-associated phenotypes, including castrate-resistant PCa (CRPC) AR function, tumor cell growth, and transition to CRPC. These data, in part, served as critical rationale for current clinical trials combining PARP inhibition and abiraterone for patients with metastatic CRPC NCT01576172 . Given the clinical importance of targeting AR function in PCa, preclinical studies were performed to assess the impact of leveraging the dual roles of PARP-1 as a means to improve therapy for advanced disease. Methods: In vitro and in vivo model systems were utilized to assess impact on AR and tumor growth. Multiple PARP inhibitors were used for additional studies. The impact of PARP-1 on gene expression was also assessed using unbiased analyses. PARP-1 mutants were also utilized to segregate the DNA damage and transcriptional regulatory roles of PARP-1. Results: Critically, PARP-1 inhibitors cooperated with castration to elicit an enhanced therapeutic response, and PARP-1 inhibitors were effective at suppressing CRPC growth in vivo. Multiple PARP inhibitors diminished AR chromatin occupancy, altered AR transcriptional output and reduction in PCa and CRPC cell growth. Conclusions: These data identify PARP-1 as a feasible therapeutic target for advanced prostate cancer. Multiple PARP inhibitors show pre-clinical efficacy in models of PCa and CRPC and merit consideration for clinical trial, and a concept will be presented.