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Background It has been speculated that women's productivity decreases after maternity leave. In this study, we measured if surgeon clinical productivity decreases after a maternity leave or other types of leave. Methods Data from a large medical center was used to measure surgeon productivity before (pre) and after (post) a leave of absence. Post-to-pre productivity ratios were calculated for each leave based on operative volumes and Relative Value Units (RVUs). Multivariate linear regression analysis was performed for the post/pre productivity ratios, adjusting for surgeon characteristics. Results Fifty leaves of absence, from 30 surgeons, were analyzed. There was no significant difference between post and pre leave productivity for maternity leave or other types of leave. There was also no significant difference when comparing post/pre productivity ratios between maternity leaves versus other types of leave (volume: 0.06, p = 0.52; RVU: 0.08, p = 0.58). Conclusion Surgeons do not significantly reduce clinical productivity after maternity or other types of leaves.

BACKGROUND: The optimal age for endorectal pull-through (ERPT) surgery in infants with short-segment Hirschsprung disease varies, with a trend toward earlier surgery. However, it is unclear if the timing of surgery impacts functional outcomes. We undertook the present study to determine the optimal timing of ERPT in infants with short-segment Hirschsprung disease. METHODS: The NCBI PubMed database was searched for English-language manuscripts published between 2000–2019 analyzing functional outcomes for patient following the initial Soave ERPT for short-segment Hirschsprung disease. Raw data from these studies was obtained from the corresponding author for each manuscript. We combined data from these papers with our own institutional data and performed a meta-analysis. RESULTS: A total of 780 infants were included in our meta-analysis. Constipation occurred in 1.0–31.7%, soiling 1.3–26.0%, anastomotic stricture 0.0–14.6%, and anastomotic leak 0.0–3.4%. Regarding age at ERPT, younger infants at the time of initial corrective surgery had higher rates of soiling, stricture, and leak. On sub-group analysis, patients

Background The literature shows that female surgeons have lower operative volumes than male surgeons. Since volume is dependent on new patient referrals for most surgeons, inequities in referrals may contribute to this employment disparity. Methods Using 1997-2018 data from a large medical center, we examined the number of new patient referrals for surgeons. Multivariate linear analysis was performed, adjusting for surgeon race, calendar year, seniority, and clinical subspecialty. Results A total of 121 surgeons across 12,410 surgeon-months were included. Overall, surgeons had a median of 14 new patient referrals per month (interquartile range (IQR) = 7, 27). On adjusted analysis, female surgeons saw 5.4 fewer new patient referrals per month (95% CI -6.4 to -4.5). Conclusion Female surgeons, with equal training and seniority, received fewer new patient referrals than their male peers, and this may contribute to female surgeon under-employment. Surgeon gender may be one of the factors contributing to this differential referral pattern.

OBJECTIVE To compare the complexity of operations performed by female versus male surgeons. BACKGROUND Prior literature has suggested that female surgeons are relatively underemployed when compared to male surgeons, with regards to operative case volume and specialization. METHODS Operative case records from a large academic medical center from 1997 to 2018 were evaluated. The primary end point was work relative value unit (wRVU) for each case with a secondary end point of total wRVU per month for each surgeon. Multivariate linear analysis was performed, adjusting for surgeon race, calendar year, seniority, and clinical subspecialty. RESULTS A total of 551,047 records were analyzed, from 131 surgeons and 13,666 surgeon-months. Among them, 104,424 (19.0%) of cases were performed by female surgeons, who make up 20.6% (n = 27) of the surgeon population, and 2879 (21.1%) of the surgeon months. On adjusted analysis, male surgeons earned an additional 1.65 wRVU per case, compared to female surgeons (95% confidence interval 1.57-1.74). Subset analyses found that sex disparity increased with surgeon seniority, and did not improve over the 20-year study period. CONCLUSIONS Female surgeons perform less complex cases than their male peers, even after accounting for subspecialty and seniority. These sex differences are not due to availability from competing professional or familial obligations. Future work should focus on determining the cause and mitigating this underemployment of female surgeons.

Geriatric patients face disparities in prehospital trauma care. We hypothesized that geriatric trauma patients are more likely to experience prolonged prehospital scene time than younger adults.Retrospective analysis of the 2017 National Emergency Medical Services Information System. Patients who met anatomic or physiologic trauma criteria based on national triage guidelines were included (n = 16,356). Geriatric patients (age≥65, n = 3594) were compared to younger adults (age 18-64). The primary outcome was prolonged scene time (10 min). Multivariable logistic regression was performed, controlling for patient demographics, on-scene treatments, and injury severity.Geriatric patients were more likely to experience prolonged scene time than younger adults after controlling for other factors (OR 1.78, 95% CI 1.57-2.04, p 0.001). The likelihood of prolonged scene time reached OR 2.29 (95% CI 1.85-2.84) for patients age 70-79 and OR 2.66 (95% CI 2.07-3.42) for patients age 80-89, relative to age 18-29.Geriatric trauma patients are more likely than younger adults to have prolonged prehospital scene time. This disparity may be caused by delayed recognition of injury severity or age-related cognitive biases.

Importance In the US, approximately 40 000 people die due to firearm-related injuries annually. However, nonfatal firearm-related injuries are less precisely tracked. Objectives To assess the annual incidence of hospitalization for nonfatal firearm-related injuries in New York and to compare the annual incidence by sex, race/ethnicity, county of residence, and calendar years. Design, Setting, and Participants This retrospective cross-sectional study used data from the New York Statewide Planning and Research Cooperative System for patients aged 15 years or older who presented to an emergency department in New York with nonfatal firearm-related injuries from January 1, 2005, to December 31, 2016. Data were analyzed from January 15, 2019, to April 21, 2021. Exposure A nonfatal firearm-related injury, defined byInternational Classification of Diseases, Ninth Revision, Clinical ModificationandInternational Statistical Classification of Diseases, Tenth Revision, Clinical Modificationcodes. Main Outcomes and Measures The annual incidence of nonfatal firearm-related injuries was calculated by determining the number of patients with a nonfatal firearm-related injury each year divided by the total population of New York. Results The study included 31 060 unique patients with 35 059 hospital encounters for nonfatal firearm-related injuries. The mean (SD) age at admission was 28.5 (11.9) years; most patients were male (90.6%) and non-Hispanic Black individuals (62.0%). The overall annual incidence was 18.4 per 100 000 population. Although decreasing trends of annual incidence were observed across the state during the study period, this trend was not present in all 62 counties, with 32 counties (51.6%) having an increase in the incidence of injuries between 2005 and 2010 and 29 (46.8%) having an increase in the incidence of injuries between 2010 and 2015. In 19 of the 30 counties (63.3%) that had a decrease in incidence in earlier years, the incidence increased in later years. Conclusions and Relevance The annual incidence of hospitalization for nonfatal firearm-related injuries in New York during the study period was 18.4 per 100 000 population. Reliable tracking of nonfatal firearm-related injury data may be useful for policy makers, hospital systems, community organizers, and public health officials as they consider resource allocation for trauma systems and injury prevention programs.

Background Circumcision is widely accepted for newborns in the United States. However, circumcision carries a risk of complications, the rates of which are not well described in the contemporary era. Methods We performed a longitudinal population analysis of the California Office of Statewide Health Planning and Development database between 2005 and 2010. Using International Classification of Procedures, Ninth Revision, Clinical Modification and Current Procedural Terminology codes, we calculated early and late complication rates by Kaplan–Meier survival estimates. Late complications were defined as those that occurred between 30 d and 5 y after circumcision. Descriptive analysis of complications was obtained by analysis of variance, chi-square test, or log-rank test. On adjusted analysis, a Cox proportional hazard model was performed to determine the risk of early and late complications, adjusting for patient demographics. Results A total of 24,432 circumcised children under age 5 y were analyzed. Overall, cumulative complication rates over 5 y were 1.5% in neonates, 0.5% of which were early, and 2.9% in non-neonates, 2.2% of which were early. On adjusted analysis, non-neonates had a higher risk of early complications (OR 18.5). In both neonates and non-neonates, the majority of patients with late complications underwent circumcision revision. Conclusions Circumcision has a complication rate higher than previously recognized. Most patients with late complications after circumcision received an operative circumcision revision. Clinicians should weigh the surgical risks against the reported medical benefits of circumcision when counseling parents about circumcision.

The purpose of this study was to evaluate trends in demographics and outcomes of pediatric breast cancer in a United States population-based cohort.The Surveillance, Epidemiology, and End Results (SEER) database was utilized to identify all pediatric patients with malignant breast tumors between 1973 and 2014. Analysis was performed using Stata Statistical Software version 13.1. Associations between categorical variables were made using X134 patients with breast malignancies were identified. Carcinoma was the most prevalent histology (48.5%), followed by fibroepithelial tumors (FETs) (35.1%), and sarcoma (14.2%). FETs were twice as common in black compared to nonblack patients (56.3% vs. 29.0%, p 0.01). Analyzing histology by stage revealed that 100% of FETs were early stage disease (p 0.0001). 46.7% of the tumors tested were ER/PR negative, more than twice as many compared to the published adult estimate of 20.0%. Unadjusted survival analysis revealed worse survival for patients with adenocarcinoma/sarcomas, advanced stage, and high grade disease, without a survival difference between races.Breast cancer remains a rare malignancy among pediatric patients. Although black patients were found to have more noncarcinomatous tumors with less advanced disease, this did not confer a survival advantage.Retrospective cohort study.Level III.

Hirschsprung disease is characterized by the absence of enteric ganglia in the distal bowel and is caused by the failure of enteric neural crest–derived cells to complete their craniocaudal migration along the intestine during embryogenesis. Neonates typically present with failure to pass meconium within the first 48 hours after birth. Diagnosis relies on rectal biopsy to document the presence of aganglionosis, and management requires surgical resection of the aganglionic segment. Despite advances in the diagnosis and management of the disease, patients remain at risk for long-term gastrointestinal morbidity, including obstructive symptoms, fecal incontinence, and enterocolitis, with negative implications on quality of life. Neuronal stem cell–based therapy is being explored as a novel treatment for this disease.

A better understanding of the analgesia needs of patients who undergo common operative procedures is necessary as we address the growing opioid public health crisis in the United States. The aim of this study was to evaluate patient experience with our opioid prescribing practice after elective inguinal hernia repairs.A prospective, observational study was conducted between October 1, 2015, and September 30, 2016, in a single-surgeon, high-volume, practice of inguinal hernia operation. Adult patients undergoing elective inguinal herniorrhaphy under local anesthesia with intravenous sedation were invited to participate. All patients were prescribed 10 opioid analgesic tablets postoperatively and were counseled to reserve opioids for pain not controlled by nonopioid analgesics. Their experience was captured by completing a questionnaire 2 to 3 weeks postoperatively during their postoperative visit.A total of 185 patients were surveyed. The majority of the participants were males (177, 95.7%) and ≥60 years old (96, 51.9%). Of the 185 patients, 159 (85.9%) reported using ≤4 opioid tablets; 110 patients (59.5%) reported that they used no opioid analgesics postoperatively. None of the patients was taking opioids within 7 days of their postoperative appointment. Of the 147 patients who were employed, 111 (75.5%) reported missing ≤3 work days, 57 of whom (51.4%) missed no work at all. Patients who were employed were more likely to take opioid analgesics postoperatively (P = .049). Patients who took no opioid analgesics experienced less maximum (P .001) and persistent groin pain (P = .037). Pain interfered less with daily activities (P = .012) and leisure activities (P = .018) for patients who did not use opioids.The majority of our patients reported that they did not require any opioid analgesics, and nearly all of those who thought that they did need opioids used5 tablets. Our data suggest that for elective inguinal hernia repair under a local anesthetic with intravenous sedation, a policy of low opioid analgesic prescribing is achievable; these findings call for further investigation of how to best prescribe opioid medications to patients after an inguinal herniorrhaphy.

Background Surgeons are prone to feelings of sadness, guilt, and anxiety when involved in major adverse events. We aimed to create and evaluate a second victim peer support program for surgeons and surgical trainees. Study Design The second victim peer support program was an intervention performed in the Department of Surgery at a tertiary care academic medical center. Surgical attendings and trainees participated as peer supporters or affected peers. In this article, we describe the design of the program and its 1-year impact, which was evaluated through the number of interventions attempted and realized and feedback received from all participants using an anonymous qualitative and quantitative survey. Results The program was established using the following 5 steps: creation of a conceptual framework, choice of peer supporters, training of peer supporters, multifaceted identification of major adverse events, and design of a systematic intervention plan. In 1 year, the program had 47 interventions distributed evenly between attendings and trainees; 19% of affected peers opted out of receiving support. Most participants expressed satisfaction with the program's confidentiality, the safe/trusting environment it provided, and the timeliness of the intervention (89%, 73%, and 83%, respectively); 81% suggested that the program had a positive impact on the department's “safety and support” culture and would recommend the program to a colleague. Several areas for improvement were identified, including the need to improve identification of events requiring outreach, and the desire for increased awareness of the program throughout the department. Conclusions We successfully designed, implemented, and assessed the impact of the first surgery-specific peer support program in the US. Our 1-year experience suggests that the program is highly used and well received, albeit with opportunities for improvement.

Practice pattern and work environment differences may impact career advancement opportunities and contribute to the gender gap within highly competitive surgical specialties.Using a 2000-2015 New York statewide dataset, we compared board-certified pediatric surgeons by specialist case volume and Herfindahl-Hirschman Index (HHI), which quantifies surgeon focus within specialist case mix.51 pediatric surgeons were analyzed for 461 surgeon-years. Female surgeons had lower case volume (159 cases/year versus 214, p 0.01), lower shares of specialist cases (14.1% versus 16.7%, p = 0.04), and less focused practices (HHI 0.16 versus 0.20, p = 0.03). Female surgeons' networks had fewer colleagues (7.2 versus 12.1, p 0.01), and lower annual total (388 versus 726, p 0.01) and specialist case volume (83 versus 159, p 0.01), even after accounting for career length. However, female surgeons performed more cases within their networks (49% versus 36%, p = 0.04) and worked at major teaching hospitals as often as men (76% versus 76%, p = 0.97).The challenges that female surgeons face may be reflective of organizational inequities that necessitate intentional scrutiny and change.

It is unknown whether previously noted racial disparities in the use of metabolic and bariatric surgery (MBS) for the management of pediatric obesity could be mitigated by accounting for primary insurance.To examine utilization of pediatric MBS across race and insurance in the United States.Retrospective cross-sectional study.The National Inpatient Sample was used to identify patients 12 to 19 years old undergoing MBS from 2015 to 2016, and these data were combined with national estimates of pediatric obesity obtained from the 2015 to 2016 National Health and Nutrition Examination Survey. Severe obesity was defined as class III obesity, or class II obesity plus hypertension, dyslipidemia, or type 2 diabetes.A total of 1,659,507 (5.0%) adolescents with severe obesity were identified, consisting of 35.0% female, 38.0% white, and 45.0% privately insured adolescents. Over the same time period, 2535 MBS procedures were performed. Most surgical patients were female (77.5%), white (52.8%), and privately insured (57.5%). Black and Hispanic adolescents were less likely to undergo MBS than whites (odds ratio .50, .46, respectively; P.001 both), despite adjusting for primary insurance. White adolescents covered by Medicaid were significantly more likely to undergo MBS than their privately insured counterparts (odds ratio 1.66; P.001), while the opposite was true for black and Hispanic adolescents (odds ratio .29, .75, respectively; P.001 both).Pediatric obesity disproportionately affects racial minorities, yet MBS is most often performed on white adolescents. Medicaid insurance further decreases the use of MBS among nonwhite adolescents, while paradoxically increasing it for whites, suggesting expansion of government-sponsored insurance alone is unlikely to eliminate this race-based disparity.

While gender-based bias and discrimination (GBD) is known to exist in medical training, there is limited guidance for training programs on how to understand and combat this issue locally. The Massachusetts General Hospital Department of Surgery established the Gender Equity Task Force (GETF) to address GBD in the local training environment. In 2017, members of the GETF surveyed residents in surgery, anesthesia, and internal medicine at 2 academic hospitals to better understand perceived sources, frequency, forms, and effects of GBD. Overall, 371 residents completed the survey (60% response rate, 197 women). Women trainees were more likely to endorse personal experience of GBD and sexual harassment than men (P < .0001), with no effect of specialty on rates of GBD or sexual harassment. Patients and nursing staff were the most frequently identified groups as sources of GBD. While an overwhelming majority of both men (86%) and women (96%) respondents either experienced or observed GBD in the training environment, less than 5% of respondents formally reported such experiences, most frequently citing a belief that nothing would happen. Survey results served as the basis for a variety of interventions addressing nursing staff and patients as sources of GBD, low confidence in formal reporting mechanisms, and the pervasiveness of GBD, including sexual harassment, across specialties. These results reproduce other studies' findings that GBD and sexual harassment disproportionately affect women trainees while demonstrating how individual training programs can incorporate local GBD data when planning interventions to address GBD.

PURPOSE: Breast masses in pediatric patients are often managed in a similarly to adult breast masses despite significant differences in pathology and natural history. Emerging evidence suggests that clinical observation is safe. The purpose of this study was to quantify the clinical appropriateness of the management of benign breast disease in pediatric patients. METHODS: A multi-institutional retrospective cohort study was completed between 1995–2017. Patients were included if they had benign breast disease and were 19 years old or younger. A timeline of all interventions (ultrasound, biopsy, or excision) was generated to quantify the number of patients who were observed for at least 90 days, deemed appropriate care. To quantify inappropriate care, the number of interventions performed within 90 days, and the pathologic concordance to clinical decisions was determined by reviewing the radiology reports of all ultrasounds and pathology reports of all biopsies and excisions. RESULTS: A total of 1,909 patients were analyzed. Mean age was 16.4 years old (± 2.1). The majority of masses were fibroadenomas (60.4%). Only half of patients (54.3%) were observed for 90 or more days. 81.1% of interventions were unnecessary, with pathology revealing masses that would be safe to observe. The positive predictive value (PPV) of clinical decisions made based on suspicious ultrasound findings was 16.2%, not different than a PPV of 21.9% (p

Study Objective Current literature lacks data-driven guidelines for surgical treatment of adolescent and young adult (AYA) patients with chronic pelvic pain. We hypothesized that there is a significant variation in treatment of these patients, which might be an indicator of over- or undertreatment by some providers. Design and Setting We completed a retrospective population-based analysis of the Nationwide Inpatient Sample from 1998 to 2016. Participants We included AYA patients aged 9-25 years whose primary diagnosis was adenomyosis, endometriosis, or chronic pelvic pain. Patients who might have undergone pelvic or abdominal procedures for other primary diagnoses were excluded. Interventions and Main Outcome Measures Trends of inpatient surgical intervention were calculated. Logistic regression was performed to determine the likelihood of undergoing an intervention, adjusted for patient demographic characteristics. Results A total of 13,111 AYA patients were analyzed. Median age at diagnosis was 22 (interquartile range, 20-24) years. The overall inpatient intervention rate was 5879/13111 (45.0%) (2445/5897 (18.6%) for excision/ablation, 2057/5897 (15.7%) for hysterectomy, 1239/5897 (9.5%) for diagnostic laparoscopy, and 156/5897 (1.2%) for biopsy). Rate of hysterectomy increased in the late 2000s while rates of all other interventions decreased. Patients in the northeast were less likely to undergo an intervention than patients in the rest of the country. Rates of intervention also differed according to race, insurance status, and type of hospital. Conclusion There is wide variation in the use of surgical treatment for chronic pelvic pain in AYA patients across the country and between types of institutions. Of concern, the rate of hysterectomy has increased over time. There is a need for data-directed treatment guidelines for the management of AYA patients with chronic pelvic pain to ensure appropriate application of surgical treatments and expand high-value surgical care.

There is limited and conflicting data on the optimal intervention for the treatment of achalasia in adolescents and young adults (AYA), Heller myotomy (HM), esophageal dilation (ED) or botulinum toxin injection (botox). The goal of this study is to determine the most appropriate index intervention for achalasia in the AYA population.We completed a longitudinal, population-based analysis of the California (2005-2010) and New York (1999-2014) statewide databases. We included patients 9-25 years old with achalasia who underwent HM, ED or botox. Comparisons were made based on the patients' index procedure. Rates of 30-day complications, long-term complications, and re-intervention up to 14 years were calculated. Cox regression was performed to determine the risk of re-intervention, adjusting for patient demographics.A total of 442 AYAs were analyzed, representing the largest cohort of young patients with this disease studied to date. Median follow-up was 5.2 years (IQR 1.8-8.0). The overall rate of re-intervention was 29.3%. Rates of re-intervention for ED and botox were equivalent and higher than HM (65.0% for ED, 47.4% for botox and 16.4% for HM, p 0.001). Ultimately, 46.9% of ED and botox patients underwent HM. The overall short-term complication rate was 4.3% and long-term, 1.9%. There was no difference in the short-term and long-term complication rates between intervention groups (p 0.05). On adjusted analysis, ED and botox were associated with increased risks of re-intervention when compared to HM (HR 5.9, HR 4.8, respectively, p 0.01). Black patients were found to have a risk of re-intervention twice that of white patients (HR 2.0, p = 0.05).HM has a similar risk of complications but a significantly lower risk of re-intervention when compared to ED and botox. Based on our findings, we recommend HM as the optimal index procedure for AYAs with achalasia.

Purpose of review Neurointestinal diseases are increasingly recognized as causes of significant gastrointestinal morbidity in children. This review highlights the most common pediatric enteric neuropathies and their diagnosis and management, emphasizing insights and discoveries from the most recent literature available. Recent findings The embryologic and histopathologic causes of enteric neuropathies are varied. They range from congenital aganglionosis in Hirschsprung disease, to autoimmune-mediated loss of neuronal subtypes in esophageal achalasia and Chagas disease, to degenerative neuropathies in some cases of chronic intestinal pseudo-obstruction and gastroparesis. Increased awareness of the clinical presentation and diagnostic evaluation of these conditions is essential as it allows for earlier initiation of treatment and improved outcomes. Most current therapies, which include medical management, neurostimulation, and operative intervention, aim to minimize the symptoms caused by these conditions. The evidence base for many of these treatments in children is poor, and multiinstitutional prospective studies are needed. An innovative therapy on the horizon involves using neuronal stem cell transplantation to treat the underlying disorder by replacing the missing or damaged neurons in these diseases. Summary Although recent advances in basic and clinical neurogastroenterology have significantly improved our awareness and understanding of enteric neuropathies, the efficacy of current treatment approaches is limited. The development of novel therapies, including pharmacologic modulators of neurointestinal function, neurostimulation to enhance gut motility, and neuronal cell-based therapies, is essential to improve the long-term outcomes in children with these disorders.

Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of phosphatidylinositol 3-kinase (PI3K)/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors is sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient's tumor. Significance: A subset of ovarian cancers exhibits AKT pathway activation and is sensitive to selective AKT inhibition. Ovarian tumors exhibit significant genetic heterogeneity and thus an individualized approach based on real-time, detailed genomic and proteomic characterization of individual tumors will be required for the successful application of PI3K/AKT pathway inhibitors in this disease. Cancer Discovery; 2(1); 56–67. ©2011 AACR. Read the Commentary on this article by Bast and Mills, p. 16 This article is highlighted in the In This Issue feature, p. 1

Ovarian cancer is a genetically complex disease. Recent data compiled by The Cancer Genome Atlas Project highlights the heterogeneity within this disease, though distinct genetic signatures, such as PI3K pathway aberration, KRas alteration and Rb loss, are emerging that may condition treatment response. The high frequency of AKT activation in ovarian cancer, via PTEN mutation/deletion, PIK3CA/AKT mutation/amplification, RAS mutation, or mutation/amplification of upstream receptor tyrosine kinases (RTK), suggests that inhibitors of this pathway may be particularly effective treatments for this disease. We utilized a selective, allosteric inhibitor of AKT to determine the AKT-dependence of a panel of ovarian cancer cell lines. This AKT1/2 inhibitor (Merck AKTi-1/2) has been extensively tested against panels of kinases and PH-domain containing proteins and based upon these studies appears to be highly selective for AKT1 and AKT2. The drug effectively inhibited AKT activity as measured by a decrease in AKT phosphorylation at serine 473 in all cell lines. Of the 17 cell lines tested to date, 3 were hypersensitive (IC50 = 0.1um) to AKT inhibition, while 1 demonstrated intermediate sensitivity (IC50 = 2uM) and 13 were resistant (IC50 >=5uM). Levels of AKT phosphorylation at serine 473 were inversely correlated with Merck AKTi-1/2 IC50 (p = 0.036) but AKT activation alone was insufficient to confer sensitivity. Activation of the MAPK pathway, via KRas/BRaf/MEK1 mutation or KRas amplification, and Rb loss were predictive of resistance to AKT inhibition. In sensitive cell lines, AKT inhibition resulted in hypophosphorylation of RB and accumulation of cells in G1. Significant induction of apoptosis was not observed even in PTEN null, AKT2 amplified and PIK3CA mutant models. Treatment of a PTEN-mutant xenograft model of ovarian cancer with the AKTi-1/2 was also effective in inhibiting AKT phosphorylation and downstream signaling and resulted in a cytostatic tumor response. Ongoing studies are focused on the identification of rational combination strategies that result in induction of apoptosis in the cell lines in which the AKTi-1/2 alone induces growth arrest. The long-term goal will be to identify genetic predictors of AKT-dependence and AKT-inhibitor resistance to guide patient selection for future clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4504.