Mainstreaming in parallel with ovarian cancer tumor testing to improve genetic testing uptake.

OBJECTIVES: Although genetic testing (GT) is universally recommended for patients with epithelial ovarian cancer (EOC), rates are low (34%). In 1/2019, we implemented mainstreaming-GT in parallel with tumor testing via MSK-IMPACT within oncology clinics. We sought to determine GT rates pre/post-mainstreaming and patient characteristics associated with GT. METHODS: Patients with newly diagnosed EOC seen at our institution from 7/1/2015-3/31/2022 were included. Clinical data were abstracted including social determinants of health (SDOH) variables, race/ethnicity, marital status, insurance, language, comorbidities, employment, and Yost index, a measure of socioeconomic status. GT rates were calculated overall and pre-/post-mainstreaming (1/2019). Logistic regression models were fit to identify variables associated with GT. RESULTS: Of 1742 patients with EOC, 1591 (91%) underwent GT. Rates of GT increased from 87% to 95% after mainstreaming (p < 0.001). Among 151 patients not undergoing GT, major reasons were lack of provider recommendation (n = 76, 50%) and logistical issues (n = 38, 25%) with few declining (n = 14, 9%) or having medical complications preventing GT (n = 7, 4.6%). High-grade serous histology, advanced stage (III/IV), and having a spouse/partner were associated with increased GT uptake (p < 0.01). Among SDOH variables, there were no differences by insurance, Yost score, language, comorbidities, employment, or race/ethnicity. In multivariable models, likelihood of GT increased with mainstreaming, even after adjustment for histology, stage, and marital status (OR 3.77; 95% CI: 2.56-5.66). CONCLUSIONS: Mainstreaming increased the likelihood of GT in patients with EOC. We found lower testing rates in patients without partners/spouses, non-high-grade serous histology, and early-stage disease, representing potential areas for future interventions.

Ascites volume at the time of primary debulking and overall survival of patients with advanced epithelial ovarian cancer.

OBJECTIVES: To investigate the impact of malignant ascites volume on the outcomes of patients with advanced epithelial ovarian carcinoma who undergo primary debulking surgery. METHODS: Patients diagnosed with stage III-IV epithelial ovarian carcinoma and bulky intra-abdominal (TIIIC) disease between 2010 and 2015, who underwent primary debulking surgery followed by multi-agent chemotherapy and known status of residual disease, were drawn from the National Cancer Database. Based on available information, the presence and volume of malignant ascites was categorized as absent, low (<980 mL), and high (>980 mL) volume. Median overall survival was determined from Kaplan-Meier curves and compared with the log rank test. A multivariate Cox model was constructed to control for confounders. RESULTS: 2493 patients were identified; 31.9% (n=795) had no ascites, 40.2% (n=1001) had low, and 28% (n=697) had high volume malignant ascites. Rate of complete gross resection was higher for patients with no ascites (65.9%) compared with those with low (35.6%) and high (23%) volume ascites (p<0.001). After controlling for stage, histology, grade, age, and comorbidities, compared with those with no ascites, patients with low (odds ratio (OR) 3.49, 95% confidence intervals (CI) 2.89 to 4.26) and high (OR 6.40, 95% CI 5.07 to 8.06) volume ascites were more likely to have gross residual disease. For patients who achieved complete gross resection after controlling for confounders compared with patients with no ascites, those with low (hazard ratio (HR) 1.37, 95% CI 1.09 to 1.72) and high volume ascites (HR 1.94, 95% CI 1.47 to 2.55) had worse overall survival. Similarly, patients with low volume ascites had better survival compared with those with high volume ascites (HR 0.71 95% CI 0.54 to 0.93). CONCLUSIONS: The presence and volume of malignant ascites at the time of primary debulking surgery was associated with the likelihood of achieving a complete gross resection and worse overall survival.

Cervical cancer screening and treatment capacity: A survey of members of the African Organisation for Research and Training in Cancer (AORTIC).

BACKGROUND: Cervical cancer is the second most common cancer among women in Africa, and in half of the sub-Saharan African countries, it is the most common cancer. Currently, there are scarce resources and limited infrastructure to support cervical cancer screening and treatment in many African countries. OBJECTIVES: The aim of this study is to investigate the capacity of cervical cancer screening and treatment among members of the African Organization for Research and Training in Cancer (AORTIC). METHODS: Data were collected from 183 participants through online surveys over a 3-month study period in 2016. RESULTS: The respondents reported large variations among different African countries. This study highlights the differences between African countries in the availability of screening programs as a result of the resources allocated to healthcare development. Radiation therapy capacity remained the most limited treatment modality available, followed by the lack of gynecologists or gynecologic oncologists who can perform radical hysterectomy. CONCLUSIONS: This information is critical for physicians, public health educators, and policymakers aiming to improve the outcomes among women with cervical cancer in Africa.

Minimally invasive hysterectomy for stage IA cervical carcinoma: a survival analysis of the National Cancer Database.

OBJECTIVE: To evaluate the outcomes of minimally invasive surgery for patients with stage IA cervical carcinoma undergoing hysterectomy. METHODS: Patients with pathological stage IA (IA1, IA2, IA not otherwise specified) squamous, adenocarcinoma, adenosquamous carcinoma of the cervix, no history of another tumor, who underwent radical or simple hysterectomy with known mode of surgery, diagnosed between 2010 and 2015 with at least 1 month of follow-up, were drawn from the National Cancer Database. Comparisons of demographic and clinicopathologic characteristics were made with the χ2 test. The impact of minimally invasive surgery (robotic-assisted or traditional laparoscopic) on overall survival was assessed with the log-rank test following generation of Kaplan-Meier curves. A Cox model was constructed to control for confounders. RESULTS: A total of 1930 patients were identified; the majority (73.3%, 1414 patients) had stage IA1 disease, while 458 (23.7%) patients had stage IA2, and 58 (3%) patients had stage IA not otherwise specified. In the present cohort, 685 patients (35.5%) had open, 438 patients (22.7%) had laparoscopic, and 807 patients (41.8%) had robotic-assisted laparoscopic hysterectomy. Patients who had an open approach were more likely to undergo lymphadenectomy (58.1% vs 52.7%, p=0.021) and have radical hysterectomy (42% vs 32.4%, p<0.001). Patients who had minimally invasive surgery had a shorter hospital stay (median 1 vs 3 days, p<0.001). There was no difference in overall survival between patients who had open and minimally invasive hysterectomy (p=0.87); 4-year overall survival rates were 97.7% and 98.6%, respectively. There was no difference in overall survival between the open and minimally invasive surgery groups for patients who had simple (p=0.61; 4-year overall survival rates 97.6% and 98.7%, respectively) or radical hysterectomy (p=0.70; 4-year overall survival rates 97.8% and 98.4%, respectively). After controlling for patient age, tumor histology, and presence of lymphovascular invasion, minimally invasive hysterectomy was not associated with worse survival (HR 0.94, 95% CI 0.49 to 1.81). In a sensitivity analysis, based on 3048 patients with clinical stage IA after controlling for confounders, minimally invasive surgery was not associated with worse survival than laparotomy (HR 1.06, 95% CI 0.65 to 1.72). CONCLUSIONS: In a large cohort of patients with stage IA cervical carcinoma, performance of minimally invasive hysterectomy was not associated with a detrimental effect on overall survival.

The impact of sentinel lymph node sampling versus traditional lymphadenectomy on the survival of patients with stage IIIC endometrial cancer.

OBJECTIVE: To investigate the survival of patients with lymph node positive endometrial carcinoma by type of surgical lymph node assessment. METHODS: Patients diagnosed between January 2012 and December 2015 with endometrial carcinoma and uterine confined disease and nodal metastases on final pathology who underwent minimally invasive hysterectomy were identified in the National Cancer Database. Patients who had sentinel lymph node biopsy alone or underwent systematic lymphadenectomy were selected. Overall survival was evaluated following generation of Kaplan-Meier curves and compared with the log rank test. A Cox model was constructed to evaluate survival after controlling for confounders. RESULTS: A total of 1432 patients were identified: 1323 (92.4%) and 109 (7.6%) underwent systematic lymphadenectomy and sentinel lymph node biopsy only, respectively. The rate of adjuvant treatment was comparable between patients who had sentinel lymph node biopsy alone and systematic lymphadenectomy (83.5% vs 86.6%, p=0.39). However, patients who had sentinel lymph node biopsy were less likely to receive chemotherapy alone (13.6% vs 36.6%, p<0.001) and more likely to receive radiation therapy alone (19.8% vs 5.4%, p<0.001) compared with patients who had systematic lymphadenectomy. There was no difference in overall survival between patients who had sentinel lymph node biopsy alone and systematic lymphadenectomy (p=0.27 from log rank test), and 3 year overall survival rates were 82.2% and 79.4%, respectively (p>0.05). After controlling for confounders, there was no difference in survival between the systematic lymphadenectomy and sentinel lymph node biopsy alone groups (hazard ratio 0.82, 95% confidence interval 0.46 to 1.45). CONCLUSIONS: Performance of sentinel lymph node biopsy alone was not associated with an adverse impact on survival in patients with lymph node positive endometrial cancer.

Outcomes of sentinel lymph node mapping for patients with FIGO stage I endometrioid endometrial carcinoma.

OBJECTIVE: Investigate the overall survival of patients with FIGO stage I endometrioid endometrial carcinoma who underwent sentinel lymph node biopsy (SLNBx). METHODS: Patients diagnosed between 2012 and 2015 with pathological stage I endometrioid endometrial carcinoma who underwent minimally invasive hysterectomy and had at least one month of follow-up were identified in the National Cancer Database (NCDB). Patients who underwent SLNBx or systematic lymphadenectomy (LND) (defined as at least 20 lymph nodes removed) were selected. Overall survival (OS) was evaluated following generation of Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. RESULTS: A total of 13,010 patients with endometrioid endometrial carcinoma who met the inclusion criteria were identified; 9861 (75.8%) and 3149 (24.2%) patients had systematic LND and SLNBx, respectively. Patients who had LND were more likely to receive radiation therapy (27.4% vs 19.3%, p < 0.001) and chemotherapy (13% vs 8.7%, p < 0.001) compared to those who had SLNBx. After controlling for patient age, race, insurance status, depth of myometrial invasion, tumor grade, tumor size, presence of lymph-vascular invasion and receipt of radiation therapy, the performance of SLNBx was not associated with worse survival (HR: 0.99, 95% CI: 0.80, 1.21). For high-intermediate risk patients (based on GOG-99 criteria) after controlling for confounders, performance of SLNBx was not associated with worse survival (HR: 1.07, 95% CI: 0.80, 1.44). For intermediate risk patients who did not receive external beam radiation therapy or chemotherapy after controlling for confounders, performance of SLNBx was not associated with worse survival (HR: 1.58, 95% CI: 0.94, 2.65). CONCLUSIONS: SLNBx had no negative impact on the survival of patients with FIGO stage I endometrioid endometrial carcinoma who undergo hysterectomy.

Oncologic outcomes of uterine preservation for pre-menopausal patients with stage II epithelial ovarian carcinoma.

OBJECTIVE: Fertility-sparing surgery is rarely offered for patients with stage II epithelial ovarian carcinoma. The aim of the present study was to evaluate the overall survival of pre-menopausal patients with stage II epithelial ovarian carcinoma who did not undergo hysterectomy. METHODS: The National Cancer Database was accessed, and patients aged ≤40 years without a history of another tumor diagnosed between 2004 and 2015 with a pathological stage II epithelial ovarian carcinoma, who underwent lymphadenectomy and received multi-agent chemotherapy, were identified. Overall survival was compared with the log-rank test after generation of Kaplan-Meier curves. A Cox model was constructed to control for tumor histology. RESULTS: A total of 185 patients met the inclusion criteria. The rate of uterine preservation was 24.3% (45 patients). Patients who did not undergo hysterectomy were younger (median 32 vs 37 years, p<0.001) and less likely to have high-grade tumors compared with those who underwent hysterectomy. The two groups were comparable in terms of presence of co-morbidities and performance of adequate lymphadenectomy (p>0.05). Median follow-up of the present cohort was 62.3 months (95% CI 53.6 to 71.0) and a total of 22 deaths occurred. There was no difference in overall survival between patients who did and did not undergo hysterectomy (p=0.50; 5-year overall survival rates 87.5% and 91.4%, respectively). After controlling for tumor histology, grade and substage, omission of hysterectomy was not associated with worse survival (HR 0.69, 95% CI 0.22 to 2.12). CONCLUSIONS: Uterine preservation was not associated with worse survival in this cohort of pre-menopausal patients with stage II epithelial ovarian carcinoma.

Perioperative outcomes and disparities in utilization of sentinel lymph node biopsy in minimally invasive staging of endometrial cancer.

OBJECTIVE: To assess the emergence of sentinel lymph node biopsy (SLNB) for disparities in utilization, and impacts on perioperative outcomes. METHODS: Retrospective cohort study of the National Cancer Database, selecting for patients with T1NxM0 endometrial cancer undergoing minimally invasive surgical staging from 2012 to 2016. Disparities in SLNB utilization were described. Propensity matching was performed. Association of SLNB with perioperative outcomes was assessed with logistic regression. RESULTS: Among 67,365 patients, 6356 (9.4%) underwent SLNB, increasing from 2.8% to 16.3% from 2012 to 2016. Disparities were identified within race (7.0% Black, 9.4% non-Black), ethnicity (8.3% Hispanic, 9.5% non-Hispanic), insurance (6.0% uninsured, 9.5% insured), county density (3.7% rural, 9.8% metro), and income (7.0% bottom-quartile, 11.8% top-quartile). Risk of conversion to open surgery was lower with SLNB alone (1.03%) or SLNB followed by LND (1.40%), versus upfront LND (2.80%). SLNB was associated with reduced risk of conversion to open surgery in Intention-To-Treat (SLNB+/-LND vs. upfront LND; ORITT = 0.53; 95%CI 0.39-0.72) and Per-Protocol (PP; SLNB alone vs. upfront LND or SLNB+LND; ORPP = 0.49; 95%CI 0.32-0.75) comparisons. SLNB was also associated with lower risk of length of stay >1 day (overall rate 6.3%; ORITT = 0.51; 95%CI 0.40-0.64; ORPP = 0.39; 95%CI 0.28-0.55), and unplanned readmission (overall rate 2.3%; ORPP = 0.52; 95%CI 0.33-0.81). There were no deaths within 90 days among 1370 SLNB alone cases, versus 2/1294 (0.15%) for SLNB+LND, and 123/28,828 (0.41%) for upfront LND. CONCLUSION: We identified significant disparities in the utilization of SLNB, as well as evidence that this less-invasive technique is associated with lower rates of certain perioperative complications. Equitable access to this emerging technique could lessen disparate outcomes.

The impact of near-infrared angiography and proctoscopy after rectosigmoid resection and anastomosis performed during surgeries for gynecologic malignancies.

OBJECTIVES: Reducing anastomotic leak rates after rectosigmoid resection and anastomosis is a priority in patients undergoing gynecologic oncology surgery. Therefore, we investigated the implications of performing near-infrared angiography (NIR) via proctoscopy to assess anastomotic perfusion at the time of rectosigmoid resection and anastomosis. METHODS: We identified all patients who underwent rectosigmoid resection and anastomosis for a gynecologic malignancy between January 1, 2013 and December 31, 2018. NIR proctoscopy was assessed via the PINPOINT Endoscopic Imaging System (Stryker). RESULTS: A total of 410 patients were identified, among whom NIR was utilized in 133 (32.4%). There were no statistically significant differences in age, race, BMI, type of malignancy, surgery, histology, FIGO stage, hypertension, diabetes, or preoperative chemotherapy between NIR and non-NIR groups. All cases of rectosigmoid resection underwent stapled anastomosis. The anastomotic leak rate was 2/133 (1.5%) in the NIR cohort compared with 13/277 (4.7%) in the non-NIR cohort (p = 0.16). Diverting ostomy was performed in 9/133 (6.8%) NIR and 53/277 (19.9%) non-NIR patients (p < 0.001). Postoperative abscesses occurred in 8/133 (6.0%) NIR and 44/277 (15.9%) non-NIR patients (p = 0.004). The NIR cohort had significantly fewer post-operative interventional procedures (12/133, 9.0% NIR vs. 55/277, 19.9% non-NIR, p = 0.006) and significantly fewer 30-day readmissions (14/133, 10.5% NIR vs. 61/277, 22% non-NIR, p = 0.004). CONCLUSIONS: NIR proctoscopy is a safe tool for assessing anastomotic rectal perfusion after rectosigmoid resection and anastomosis, with a low anastomotic leak rate of 1.5%. Its potential usefulness should be evaluated in randomized trials in patients undergoing gynecologic cancer surgery.

Factors Associated With Use of a High-Volume Cancer Center by Black Women With Ovarian Cancer.

OBJECTIVE: Disparities exist between population subgroups in the use of gynecologic oncologists and high-volume hospitals. The objectives of this study were to explore the experiences of black women obtaining ovarian cancer (OC) care at a high-volume center (HVC) and to identify patient-, provider-, and systems-related factors affecting their access to and use of this level of care. MATERIALS AND METHODS: Twenty-one semistructured interviews were conducted as part of an institutional review board-approved protocol with women who self-identified as black or African American, treated for OC at a single HVC from January 2013 to May 2017. Recurring themes were identified in transcribed interviews through the process of independent and collaborative thematic content analysis. RESULTS: Five themes were identified: (1) internal attributes contributing to black women's ability/desire to be treated at an HVC, (2) pathways to high- and low-volume centers, (3) obstacles to obtaining care, (4) potential barriers for black women interested in treatment at an HVC, and (5) suggestions for improving HVC use by black women. Study participants who successfully accessed care were comfortable navigating the health care system, understood the importance of self-advocacy, and valued the expertise of an HVC. Barriers to obtaining care at an HVC included lack of knowledge about the HVC, lack of referral, transportation difficulties, and lack of insurance coverage. CONCLUSION: In this qualitative study, black women treated at an HVC shared attributes and experiences that helped them access care. There is a need to collaborate with black communities and establish interventions to reduce barriers, facilitate access, and disseminate information about the value of receiving care for OC at an HVC.

Continuous improvement in primary Debulking surgery for advanced ovarian cancer: Do increased complete gross resection rates independently lead to increased progression-free and overall survival?

OBJECTIVES: To assess complete gross resection (CGR) rates and survival outcomes in patients with advanced ovarian cancer who underwent primary debulking surgery (PDS) during a 13-year period in which specific changes to surgical paradigm were implemented. METHODS: We identified all patients with stage IIIB-IV high-grade ovarian carcinoma who underwent PDS at our institution, with the intent of maximal cytoreduction, from 1/2001-12/2013. Patients were categorized by year of PDS based on the implementation of surgical changes to our approach to ovarian cancer debulking (Group 1, 2001-2005; Group 2, 2006-2009; Group 3, 2010-2013). RESULTS: Among 978 patients, 78% had stage IIIC disease and 89% had disease of serous histology. Carcinomatosis was found in 81%, and 60% had bulky upper abdominal disease (UAD). Compared to Group 1, those who underwent PDS during the latter 2 time periods had higher ASA scores (p < 0.001), higher-stage disease (p < 0.001), and more often had carcinomatosis (p = 0.015) and bulky UAD (p = 0.009). CGR rates for Groups 1-3 increased from 29% to 40% to 55%, respectively (p < 0.001). Five-year progression-free survival (PFS) rates increased over time (15%, 16%, and 20%, respectively; p = 0.199), as did 5-year overall survival (OS) rates (40%, 44%, and 56%, respectively; p < 0.001). On multivariable analysis, CGR was independently associated with PFS (p < 0.001) and OS (p < 0.001). CONCLUSIONS: Despite higher-stage disease and greater tumor burden, CGR rates, PFS and OS for patients who underwent PDS increased over a 13-year period. Surgical paradigm shifts implemented specifically to achieve more complete surgical cytoreduction are likely the reason for these improvements.

Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase-mTORC1 Translational Pathway.

A homozygous nonsense mutation in the cereblon (CRBN) gene results in autosomal recessive, nonsyndromic intellectual disability that is devoid of other phenotypic features, suggesting a critical role of CRBN in mediating learning and memory. In this study, we demonstrate that adult male Crbn knock-out (CrbnKO) mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knock-out of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior. Cellular studies identify deficits in long-term potentiation at Schaffer collateral CA1 synapses. We further show that Crbn is robustly expressed in the mouse hippocampus and CrbnKO mice exhibit hyperphosphorylated levels of AMPKα (Thr172). Examination of processes downstream of AMP-activated protein kinase (AMPK) finds that CrbnKO mice have a selective impairment in mediators of the mTORC1 translation initiation pathway in parallel with lower protein levels of postsynaptic density glutamatergic proteins and higher levels of excitatory presynaptic markers in the hippocampus with no change in markers of the unfolded protein response or autophagy pathways. Acute pharmacological inhibition of AMPK activity in adult CrbnKO mice rescues learning and memory deficits and normalizes hippocampal mTORC1 activity and postsynaptic glutamatergic proteins without altering excitatory presynaptic markers. Thus, this study identifies that loss of Crbn results in learning, memory, and synaptic defects as a consequence of exaggerated AMPK activity, inhibition of mTORC1 signaling, and decreased glutamatergic synaptic proteins. Thus, CrbnKO mice serve as an ideal model of intellectual disability to further explore molecular mechanisms of learning and memory.SIGNIFICANCE STATEMENT Intellectual disability (ID) is one of the most common neurodevelopmental disorders. The cereblon (CRBN) gene has been linked to autosomal recessive, nonsyndromic ID, characterized by an intelligence quotient between 50 and 70 but devoid of other phenotypic features, making cereblon an ideal protein for the study of the fundamental aspects of learning and memory. Here, using the cereblon knock-out mouse model, we show that cereblon deficiency disrupts learning, memory, and synaptic function via AMP-activated protein kinase hyperactivity, downregulation of mTORC1, and dysregulation of excitatory synapses, with no changes in social or repetitive behaviors, consistent with findings in the human population. This establishes the cereblon knock-out mouse as a model of pure ID without the confounding behavioral phenotypes associated with other current models of ID.

Brain-derived neurotrophic factor genotype impacts the prenatal cocaine-induced mouse phenotype.

Prenatal cocaine exposure leads to persistent alterations in the growth factor brain-derived neurotrophic factor (BDNF), particularly in the medial prefrontal cortex (mPFC) and hippocampus, brain regions important in cognitive functioning. BDNF plays an important role in the strengthening of existing synaptic connections as well as in the formation of new contacts during learning. A single nucleotide polymorphism in the BDNF gene (Val66Met), leading to a Met substitution for Val at codon 66 in the prodomain, is common in human populations, with an allele frequency of 20-30% in Caucasians. To study the interaction between prenatal cocaine exposure and BDNF, we have utilized a line of BDNF Val66Met transgenic mice on a Swiss Webster background in which BDNF(Met) is endogenously expressed. Examination of baseline levels of mature BDNF protein in the mPFC of prenatally cocaine-treated wild-type (Val66Val) and Val66Met mice revealed significantly lower levels compared to prenatally saline-treated mice. In contrast, in the hippocampus of prenatally saline- and cocaine-treated adult Val66Met mice, there were significantly lower levels of mature BDNF protein compared to Val66Val mice. In extinction of a conditioned fear, we found that prenatally cocaine-treated Val66Met mice had a deficit in recall of extinction. Examination of mature BDNF protein levels immediately after the test for extinction recall revealed lower levels in the mPFC of prenatally cocaine-treated Val66Met mice compared to saline-treated mice. However, 2 h after the extinction test, there was increased BDNF exons I, IV, and IX mRNA expression in the prelimbic cortex of the mPFC in the prenatally cocaine-treated BDNF Val66Met mice compared to prenatally saline-treated mice. Taken together, our results suggest the possibility that prenatal cocaine-induced constitutive alterations in BDNF mRNA and protein expression in the mPFC differentially poises animals for alterations in behaviorally induced gene activation, which are interactive with BDNF genotype and differentially impact those behaviors. Such findings in our prenatal cocaine mouse model suggest a gene X environment interaction of potential clinical relevance.

Behavioral characterization of cereblon forebrain-specific conditional null mice: a model for human non-syndromic intellectual disability.

A nonsense mutation in the human cereblon gene (CRBN) causes a mild type of autosomal recessive non-syndromic intellectual disability (ID). Animal studies show that crbn is a cytosolic protein with abundant expression in the hippocampus (HPC) and neocortex (CTX). Its diverse functions include the developmental regulation of ion channels at the neuronal synapse, the mediation of developmental programs by ubiquitination, and a target for herpes simplex type I virus in HPC neurons. To test the hypothesis that anomalous CRBN expression leads to HPC-mediated memory and learning deficits, we generated germ-line crbn knock-out mice (crbn(-/-)). We also inactivated crbn in forebrain neurons in conditional knock-out mice in which crbn exons 3 and 4 are deleted by cre recombinase under the direction of the Ca(2+)/calmodulin-dependent protein kinase II alpha promoter (CamKII(cre/+), crbn(-/-)). crbn mRNA levels were negligible in the HPC, CTX, and cerebellum (CRBM) of the crbn(-/-) mice. In contrast, crbn mRNA levels were reduced 3- to 4-fold in the HPC, CTX but not in the CRBM in CamKII(cre/+), crbn(-/-) mice as compared to wild type (CamKII(cre/+), crbn(+/+)). Contextual fear conditioning showed a significant decrease in the percentage of freezing time in CamKII(cre/+), crbn(-/-) and crbn(-/-) mice while motor function, exploratory motivation, and anxiety-related behaviors were normal. These findings suggest that CamKII(cre/+), crbn(-/-) mice exhibit selective HPC-dependent deficits in associative learning and supports the use of these mice as in vivo models to study the functional consequences of CRBN aberrations on memory and learning in humans.