"Blocking-like" effects in attentional set-shifting: Redundant cues facilitate shifting in male rats with medial prefrontal cortex inactivation.

Without a functioning prefrontal cortex, humans and other animals are impaired in measures of cognitive control and behavioral flexibility, including attentional set-shifting. However, the reason for this is unclear with evidence suggesting both impaired and enhanced attentional shifting. We inhibited the medial prefrontal cortex (mPFC) of rats while they performed a modified version of an attentional set-shifting task to explore the nature of this apparent contradiction. Twelve adult male Lister hooded rats received AAV5-CaMKIIa-hM4D(Gi)-mCherry viral vector bilaterally into mPFC to express inhibitory 'Designer Receptors Exclusively Activated by Designer Drugs' (iDREADDs). The receptors were activated by systemic clozapine N-oxide (CNO) to inhibit mPFC function. The rats were tested in the standard attentional set-shifting task four times: twice after i.p. administration and twice after oral administration of vehicle or CNO (10 mg/kg). They were then tested twice in a modified task, with or without oral CNO. The modified task had an extra stage before the extradimensional shift, in which the relevant exemplars remained relevant and new exemplars that were fully predictive but redundant replaced the previous irrelevant exemplars. These exemplars then became relevant at the subsequent ED stage. In the standard task, mPFC inactivation impaired attentional set-shifting, consistent with previous findings. However, in the modified task, mPFC inactivation abolished ED shift-costs. The results support the suggestion that the mPFC is needed for the downregulation of attention that prevents learning about redundant and irrelevant stimuli. With mPFC inactivated, the rat learns more rapidly when previously redundant exemplars become the only relevant information.

PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer.

Uterine serous carcinoma (USC), an aggressive variant of endometrial cancer representing approximately 10% of endometrial cancer diagnoses, accounts for ∼39% of endometrial cancer-related deaths. We examined the role of genomic alterations in advanced-stage USC associated with outcome using paired primary-metastatic tumors (n = 29) treated with adjuvant platinum and taxane chemotherapy. Comparative genomic analysis of paired primary-metastatic patient tumors included whole exome sequencing and targeted gene expression. Both PLK3 amplification and the tumor immune microenvironment (TIME) in metastatic tumors were linked to time-to-recurrence (TTR) risk without any such association observed with primary tumors. TP53 loss was significantly more frequent in metastatic tumors of platinum-resistant versus platinum-sensitive patients and was also associated with increased recurrence and mortality risk. Increased levels of chr1 breakpoints in USC metastatic versus primary tumors co-occur with PLK3 amplification. PLK3 and the TIME are potential targets for improving outcomes in USC adjuvant therapy.

Improved Rates of Same-day Discharge in Patients Undergoing Surgery for Endometrial Cancer Following the COVID-19 Pandemic.

STUDY OBJECTIVE: To determine the effect of the coronavirus disease 2019 (COVID-19) pandemic on the rate of same-day discharge (SDD) after minimally invasive surgery for endometrial cancer. DESIGN: Retrospective cohort. SETTING: Teaching hospital. PATIENTS: A total of 166 patients underwent a minimally invasive surgery procedure for the indication of endometrial cancer at a large academic institution from September 1, 2019, to October 1, 2020-80 patients before the implementation of the COVID-19 restrictions and 86 patients after. INTERVENTIONS: COVID-19 pandemic with visitor restrictions and hospital policy changes placed on March 17, 2020. MEASUREMENTS AND MAIN RESULTS: SDD rate was increased by 18% after the start of the COVID-19 pandemic (40% vs 58%, p = .02). There were no differences between the 2 groups with regard to operative time (p = .07), estimated blood loss (p = .21), uterine weight (p = .12), age (p = .06), body mass index (p = .42), or surgery start time (p = .15). In a multivariable logistic regression model, subjects in the COVID-19 group had 3.08 times (95% confidence interval, 1.40-6.74; p = .01) higher odds of SDD than those in the pre-COVID-19 group. There was no difference in 30-day readmission rates (7.5% vs 5.8%, p = .66). CONCLUSION: There was a significant increase in the SDD of patients with endometrial cancer since the start of the COVID-19 pandemic. The pandemic has strained hospital resources and motivated patients and physicians to avoid hospitalization. This shows that with proper motivation, an increase in SDD rates is possible without an increase in complications or rehospitalization.

Enhanced recovery after surgery (ERAS) protocol is associated with lower post-operative opioid use and a reduced office burden after minimally invasive surgery.

OBJECTIVE: Enhanced recovery after surgery (ERAS) has decreased hospital opioid use, but less attention has been directed towards its impact on clinic burden with respect to post-operative care. Our objective was to determine the impact of an ERAS protocol on post-operative opioid prescribing, and the subsequent number of pain medication refill requests and unscheduled patient-provider interactions in the 30-day post-operative period. METHODS: IRB-approved retrospective study comparing post-operative opioid prescription practices 10 months before and 10 months after ERAS protocol implementation after minimally invasive gynecologic surgery. Opioid doses in morphine milligram equivalents (MMEs), number of unscheduled visits, and phone calls were compared before and after ERAS implementation. RESULTS: A total of 791 patients were included; 445 without and 346 with ERAS implementation. ERAS was associated with higher rates of same day discharge (49% vs 39%, p = 0.003) and lower readmission rates (2.0% vs 5.6%, p = 0.011). Post-operatively, patients who received the ERAS protocol were prescribed less opioids (197.8 vs. 223.5 MMEs, p = 0.0087). There was a trend towards less refill requests with ERAS (1.7% vs 3.6%, p = 0.11). ERAS was associated with a decreased number of post-operative phone calls (38% vs 46%, p = 0.023), including calls for pain (10% vs 16%, p = 0.021), and fewer unscheduled visits related to pain (1.5% vs 5.8%, p = 0.001). CONCLUSIONS: Implementation of the ERAS protocol resulted in a decrease in post-operative opioid prescribing. Despite the lower amount of prescribed post-operative opioids, the ERAS protocol translated into a decrease in the need for post-operative interactions with the clinic staff, specifically encounters associated with pain.

Factors Associated with Same Day Discharge after Laparoscopic Surgery in Gynecologic Oncology.

STUDY OBJECTIVE: To identify factors associated with same day discharge (SDD) after laparoscopic surgery in gynecologic oncology. DESIGN: Retrospective cohort. SETTING: Teaching hospital. PATIENTS: Total of 800 patients having minimally invasive surgery in the division of gynecologic oncology during a 20-month period. INTERVENTION: Minimally invasive surgery cases were reviewed for determinants of SDD to identify factors that could improve the SDD rate. MEASUREMENTS AND MAIN RESULTS: During the study period, 800 minimally invasive procedures were performed with a 43.0% SDD rate. Patients who had SDD were younger (52.3 years vs 58.0 years; p <.001), had a lower body mass index (31.1 kg/m2 vs 33.7 kg/m2; p <.001), were less likely to have a malignancy (28.2% vs 55.5%; p <.001), had a lower estimated blood loss (36 vs 72 mL; p <.001), and were more likely to have received an enhanced recovery after surgery protocol (49.8% vs 39.3%; p <.003). Total surgical time was shorter in women with SDD (156 minutes vs 208 minutes) as was total narcotic use in morphine equivalents (MEq) (milligram intravenous MEq, 23.1 mg MEq vs 28.8 mg MEq). SDD was also associated with earlier start time (p <.001). Laparoscopic cases were most likely to have SDD (51.4%) as compared with robotic assisted surgery (16.1%) or minilaparotomy (10.5%). There was a wide range of SDD among surgeons ranging from 19.8% to 56.2% (p <.001). In a multivariate analysis, the factors predicting SDD in order of predictive factors were surgical time (p <.001), recovery time (p <.001), start time (p <.001), surgeon (p <.001), age (p <.001), estimated blood loss (p <.001), and type of surgery (p = .005). CONCLUSION: Multiple factors affect SDD. Modifiable factors for SDD include the start time, surgeon preference, and patient expectations for SDD. Given these data, centers should prioritize surgical order by which patients are more likely to go home, and surgeons should analyze their own data with respect to achieving higher SDD rates.

Sound and credibility in the virtual court: Low audio quality leads to less favorable evaluations of witnesses and lower weighting of evidence.

OBJECTIVES: Recent virtual court proceedings have seen a range of technological challenges, producing not only trial interruptions but also cognitive interruptions in processing evidence. Very little empirical research has focused on how the subjective experience of processing evidence affects evaluations of trial participants and trial decisions. Metacognitive research shows that the subjective ease or difficulty of processing information can affect evaluations of people, belief in information, and how a given piece of information is weighted in decision making. HYPOTHESES: We hypothesized that when people experienced technological challenges (e.g., poor audio quality) while listening to eyewitness accounts, the difficulty in processing evidence would lead them to evaluate a witness more negatively, influence their memory for key facts, and lead them to weigh that evidence less in final trial judgments. METHOD: Across three experiments (total N = 593), participants listened to audio clips of witnesses describing an event, one presented in high-quality audio and one presented in low-quality audio. RESULTS: When people heard witnesses present evidence in low-quality audio, they rated the witnesses as less credible, reliable, and trustworthy (Experiment 1, d = 0.32; Experiment 3, d = 0.55); had poorer memory for key facts presented by the witness (Experiment 2, d = 0.44); and weighted witness evidence less in final guilt judgments (Experiment 3, ηp² = .05). CONCLUSION: These results show that audio quality influences perceptions of witnesses and their evidence. Because these variables can contribute to trial outcomes, audio quality warrants consideration in trial proceedings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Perioperative Recovery and Narcotic Use in Laparoscopic versus Robotic Surgery for Endometrial Cancer.

STUDY OBJECTIVE: To compare intraoperative and perioperative narcotic use, recovery room time, and total hospital stay for patients treated with robotic vs laparoscopic surgery for endometrial cancer. DESIGN: Retrospective cohort. SETTING: Teaching hospital. PATIENTS: All patients having minimally invasive surgery in the division of gynecologic oncology during a 20-month period. INTERVENTION: Laparoscopic cases were compared with robot-assisted cases with respect to perioperative outcome. MEASUREMENT AND MAIN RESULTS: Hospital billing records were used to identify all patients with endometrial cancer treated from January 1, 2018 through July 31, 2019 undergoing either laparoscopic or robotic surgery. Data were collected including total narcotic use converted to intravenous morphine milligram equivalent (MME), total amount of time in recovery, and length of hospital stay. A total of 139 laparoscopic and 101 robotic surgeries were eligible for analysis. There was no difference between the groups with respect to blood loss, alcohol use, or smoking. Patients undergoing laparoscopy had a significantly lower body mass index compared with patients undergoing robotic surgery (32.9 vs 38.0 kg/m2; p <.001). Univariate analysis showed no difference between the 2 groups with respect to narcotic use in surgery (21.7 vs 21.1 MME; p = .64), recovery (4.3 vs 4.5 MME; p = .70), or total dose (26.0 vs 25.6 MME; p = .78). However, patients who underwent a robotic approach had a longer recovery room time (128 minutes vs 163 minutes; p <.001 and a longer surgical time (288 minutes vs 204 minutes; p = .001). Patients in the robotic group were also more likely to undergo full lymphadenectomy than patients in the laparoscopy group (38.0% vs 20.8% p <.001). In a multivariate analysis, the only significant factors for predicting total narcotic dose were age, use of a preoperative enhanced recovery after surgery program, and surgical time. Patients who had laparoscopy were more likely to achieve same-day discharge (39.3% vs 17.8%; p <.001), but in the multivariate analysis, the type of surgery did not predict same-day discharge. CONCLUSION: There was no difference in narcotic use in the perioperative period with robotic surgery compared with laparoscopy. Recovery time was longer for robotic surgery, but this was not significant in multivariate analysis. Same-day discharges were less frequent with robotics, which may be more related to the physician's choice rather than the procedure.

Outcomes of Minimally Invasive versus Open Radical Hysterectomy for Early Stage Cervical Cancer Incorporating 2018 FIGO Staging.

STUDY OBJECTIVE: To compare outcomes after minimally invasive surgery (MIS) vs open radical hysterectomy for early stage cervical cancer incorporating 2018 Federation of Gynecology and Obstetrics (FIGO) staging. DESIGN: A retrospective analysis. SETTING: A single teaching hospital. PATIENTS: Patients after radical hysterectomy for stage IA1 with lymphovascular invasion, IA2, or IB1 squamous, adenosquamous, or adenocarcinoma of the cervix between 2007 and 2018, mirroring the Laparoscopic Approach to Cervical Cancer trial criteria. INTERVENTIONS: The use of MIS surgery for performing radical hysterectomy. MEASUREMENTS AND MAIN RESULTS: The outcomes were compared between patients undergoing MIS vs open approaches. A total of 126 patients met the inclusion criteria. The approach was open in 44 patients (35%) and MIS in 82 patients (65%); 49% were laparoscopic and 51% were robotic. Distribution based on the 2009 FIGO staging showed 1 stage IA1 with lymphovascular invasion, 15 stage IA2, and 110 stage IB1 patients. Although not statistically significant, the 3-year disease-free survival (DFS) was higher in the open compared to the MIS group (95% vs 87%; p = .17), and the overall survival was higher in the open compared to the MIS group (97% vs 92%; p = .25). Fourteen patients whose disease recurred were Stage IB1 by FIGO 2009 staging; 11/14 were reclassified to a higher stage by 2018 FIGO staging (5/5 open, 6/9 MIS). Adjuvant therapy was recommended for all these patients based on the Sedlis criteria (10/14) or other risk factors (4/14). Despite this, only 1/9 of MIS patients whose disease recurred received adjuvant therapy compared with 3/5 patients whose disease recurred in the open group (p = .05). CONCLUSION: In a cohort of patients similar to that of the Laparoscopic Approach to Cervical Cancer trial, 2018 FIGO staging may be useful to refine indications for MIS radical hysterectomy in early stage cervical cancer. However, disparate outcomes between MIS and open approaches may be explained by differences in compliance with National Comprehensive Cancer Network guidelines for adjuvant therapy.

Pre-emptive Non-narcotic Pain Medication before Minimally Invasive Surgery in Gynecologic Oncology.

STUDY OBJECTIVE: To review the impact of enhanced recovery after surgery (ERAS) after minimally invasive surgery (MIS) with respect to perioperative narcotics, time in the recovery room, and total time in hospital. DESIGN: Retrospective cohort. SETTING: Teaching hospital. PATIENTS: All patients having MIS in the division of gynecologic oncology during a 20-month period. INTERVENTION: MIS cases were compared before and after the implementation of an ERAS protocol that incorporated orally administered acetaminophen, gabapentin, and celecoxib. MEASUREMENT AND MAIN RESULTS: A total of 800 MIS cases were performed during the period (77% laparoscopy, 18% robotic, 5% mini-lap). Of these, 449 cases were treated without and 351 with the ERAS protocol. There were no significant differences between the groups with respect to age, BMI, surgery type, smoking, surgical indication, blood loss, or diagnosis. Total narcotic use in milligram intravenous equivalents of morphine (mg IV Eq) was significantly less in the ERAS patients (28.5-mg IV Eq vs 23.6-mg IV Eq; p <.001). There was a trend toward less narcotics in recovery (4.8-mg IV Eq vs 4.1-mg IV Eq; p = .08). Postoperative recovery room time was not different between the groups (129 minutes vs 131 minutes; p = .66). ERAS was associated with a higher rate of same day discharge (38.5% vs 49.0%; p = .003) and a shorter length of hospital stay (22.9 hours vs 18.5 hours; p = .008), with a hazard ratio for discharge of 0.82 (0.71-0.94). However, the same day discharge rate varied widely between treating physicians (20% to 56%). CONCLUSIONS: Implementation of an ERAS protocol for MIS appears to reduce total perioperative narcotic use but does not reduce recovery room time. There was a reduction in total hospital time, but this may be dependent on practice patterns of individual physicians.

Comparison of Perioperative Outcomes between Minimally Invasive Sentinel Node Biopsy and Full Lymphadenectomy for Endometrial Cancer.

STUDY OBJECTIVE: To review the perioperative differences between patients undergoing a minimally invasive sentinel lymph node dissection and those undergoing a full lymphadenectomy. DESIGN: Retrospective review. SETTING: Teaching hospital. PATIENTS: All patients undergoing a minimally invasive procedure for endometrial cancer that included nodal evaluation. INTERVENTIONS: Patients who underwent a sentinel lymph node biopsy were compared with those who underwent a full lymphadenectomy at the time of minimally invasive surgery by either laparoscopic or robot-assisted surgery. MEASUREMENTS AND MAIN RESULTS: A total of 241 minimally invasive surgery procedures for endometrial cancer were performed during the 20-month study period. Nodal dissection was indicated and performed in 156 (65%) of these patients, with 93 undergoing a sentinel lymph node biopsy and 63 a full lymphadenectomy. There was no difference between the sentinel group and the lymphadenectomy group with respect to age, estimated blood loss (p = .23), use of a preoperative enhanced recovery after surgery program (p = .82), or body mass index (34.0 kg/m2 vs 33.7 kg/m2; p = .87). The use of full lymphadenectomy was very dependent on the surgeon (p <.001). There was no difference in narcotic use in milligram intravenous equivalents of morphine in surgery (20.9 vs 22.2; p = .37), recovery (4.6 vs 4.9; p = .73), or total dose (25.4 vs 27.0; p = .33). The surgical procedure was longer with lymphadenectomy (185.2 minutes vs 214.2 minutes; p <.001) and the relative risk of discharge from recovery was lower (0.71; 95% confidence interval, 0.51-0.97; p = .03). The hospital stay was longer with lymphadenectomy (16.3 hours vs 25.5 hours; p <.001) and same-day discharge less frequent (48.5% vs 13.8%; p <.001). A multivariate analysis confirmed that sentinel node biopsy was associated with an increased relative risk of discharge of 1.68 (95% confidence interval 1.11-2.53; p = .01) CONCLUSION: Total narcotic requirements are similar between sentinel node biopsy and lymphadenectomy. However, sentinel node biopsy is associated with a shorter surgical time, recovery time, and hospital stay.

Cetuximab in Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Ovarian Cancer Without KRAS, NRAS, or BRAF Mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

BACKGROUND: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. OBJECTIVE: With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. PATIENTS AND METHODS: Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. CONCLUSIONS: Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. CLINICAL TRIAL REGISTRATION: NCT02693535 (26 February, 2016).

Molecular variations in uterine carcinosarcomas identify therapeutic opportunities.

OBJECTIVE: To perform comprehensive genomic profiling on a large cohort of patients with uterine carcinosarcomas to identify potential therapeutic targets. METHODS: Molecular profiling was conducted on 168 retrospectively de-identified patients with uterine carcinosarcomas using the Caris Life Sciences platform. Specimens were evaluated for aberrations in protein expression by immunohistochemistry, DNA sequence mutation using a 592-gene next generation sequencing panel, copy number amplification using next generation sequencing or in situ hybridization, and fusion events using NextGen RNA sequencing. Tumor mutational load and microsatellite instability were also evaluated. RESULTS: We identified 168 patients with uterine carcinosarcoma; median age of the cohort was 67 years. The most common mutations were observed in the following genes: TP53 (86%), PIK3CA (34%), FBXW7 (23%), PTEN (18%), KRAS (16%), PPP2R1A (10%). Tumor mutational load was low to moderate in most cases (50% and 45%, respectively). HER2/neu (ERBB2) was amplified in 9% of tumors. Immunohistochemistry protein expression was elevated in TOP2A (95%), TS (80%), PTEN (76%), and TUBB3 (66%). Mismatch repair deficiency was rare (4%). CONCLUSIONS: Multiple somatic mutations and copy number alterations in genes that are therapeutic targets were identified in half of cases. Uterine carcinosarcomas represent an aggressive histology with limited treatment options and poor outcomes, and clinical trials are needed to validate new therapeutic targets.

Exacerbation of the credit assignment problem in rats with lesions of the medial prefrontal cortex is revealed by Bayesian analysis of behavior in the pre-solution period of learning.

Our internal models of the world help us to process information rapidly: in general model-based learning is more rapid than model-free learning. However, the cognitive flexibility required to overcome cognitive predispositions can let us down: it is not fully developed until adulthood; predispositions can be unconscious biases; and cognitive flexibility is impaired in many psychiatric and neurological conditions. To understand these limits to flexibility, we need to know how the brain generates predispositions and deploys flexibility. We performed a detailed analysis of the exploratory behavior of rats in the pre-solution period of a two-alternative forced choice discrimination learning task. Rats readily learn in which of two bowls, filled with differentially scented and textured digging materials, there is hidden bait. In a single session, they are presented with a series of discrimination learning and reversal stages. We performed a simple Bayesian analysis on the data from 68 rats, 33 of which had lesions of the medial prefrontal cortex, to examine patterns of responding in the pre-solution period. Control rats rapidly focussed on the relevant stimulus attributes and showed flexibility when required to learn about a different stimulus attribute. Rats with prefrontal cortex damage had reduced sensitivity to negative feedback. They were able to overcome this deficit and solve the credit assignment problem when there were limited alternatives or when attention was appropriately focused and predispositions matched the required response. However, the learning impairment presents as a problem with shifting attention due to the additional difficulty of solving the credit assignment problem when the attentional set is inconsistent with the required response.

Increased expression of neurotensin in high grade serous ovarian carcinoma with evidence of serous tubal intraepithelial carcinoma.

High grade serous ovarian carcinoma (HGSC) without identifiable serous tubal intraepithelial carcinoma (STIC) within the fallopian tube (FT) occurs in approximately 50% of patients. The objective of this study was to use a multisite tumor sampling approach to study HGSC with and without STIC. RNAseq analysis of HGSC samples collected from multiple sites e.g. ovary, FT and peritoneum, revealed moderate levels of intrapatient heterogeneity in gene expression that could influence molecular profiles. Mixed-model ANOVA analysis of gene expression in tumor samples from patients with multiple tumor sites (n = 13) and patients with a single site tumor sample (n = 11) to compare HGSC-STIC to HGSC-NOSTIC identified neurotensin (NTS) as significantly higher (> two-fold change, False Discovery Rate (FDR) < 0.10) in HGSC-STIC. This data was validated using publicly available RNA-Seq datasets. Concordance between higher NTS gene expression and NTS peptide levels in HGSC-STIC samples was demonstrated by immunohistochemistry. To determine the role of NTS in HGSC, five ovarian cancer (OvCa) cell lines were screened for expression of NTS and its receptors, NTSR1 and NTSR3. Increased expression of NTS and NSTR1 was observed in several of the OvCa cells, whereas the NTSR3 receptor was lower in all OvCa cells, compared to immortalized FT epithelial cells. Treatment with NTSR1 inhibitor (SR48692) decreased cell proliferation, but increased cell migration in OvCa cells. The effects of SR48692 were receptor mediated, since transient RNAi knockdown of NTSR1 mimicked the migratory effects and knockdown of NTSR3 mimicked the anti-proliferative effects. Further, knockdown of NTSR1 or NTSR3 was associated with acquisition of distinct morphological phenotypes, epithelial or mesenchymal, respectively. Taken together, our results reveal a difference in a biologically active pathway between HGSC with and without STIC. Furthermore, we identify neurotensin signaling as an important pathway involved in cell proliferation and epithelial-mesenchymal transition in HGSC-STIC which warrants further study as a potential therapeutic target. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

More rapid reversal learning following overtraining in the rat is evidence that behavioural and cognitive flexibility are dissociable.

Cognitive flexibility is a term used to describe the brain processes underlying the phenomenon of adaptive change in behaviour in response to changed contingencies in the internal or external environment. Cognitive flexibility is often assessed in complex tasks measuring perceptual attentional shifting or response or task switching, but, arguably, reversal learning is a simple assay of cognitive flexibility. Reversal learning requires the detection of a changed outcome, the cessation of a previously-rewarded response and the selection of an alternative, previously-unrewarded, response. This study addressed the issue of the relationship between reversal learning and cognitive flexibility. In a single testing session, rats completed a series of 2-alternative forced-choice discriminations between digging bowls. The bowls differed according to both the medium within the bowl and the odor of the bowl. Having learned which cue (one of the odors or one of the digging media) indicated the food-baited bowl, half the rats were given additional trials of "over-training". To test reversal learning, the meaning of the cues predictive of reward/non-reward was then switched. There was a robust effect of over-training, with over-trained rats performing reversal learning in fewer trials than rats trained to criterion only. The pattern of errors supported the hypothesis that more rapid reversing results from the formation of an attentional set. This is the same attentional mechanism that results in less rapid shifting or switching. We conclude that the behavioural flexibility demonstrated in reversal learning does not provide a scale on which cognitive flexibility can be measured.

When Less Is More: Minimally Invasive Surgery Compared with Laparotomy for Interval Debulking After Neoadjuvant Chemotherapy in Women with Advanced Ovarian Cancer.

STUDY OBJECTIVE: To compare outcomes of advanced ovarian cancer patients who had minimally invasive surgery (MIS) with outcomes of advanced ovarian cancer patients who had laparotomy for interval cytoreduction after neoadjuvant chemotherapy (NACT). DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: One large teaching hospital with a tertiary referral function for gynecologic oncology and MIS. PATIENTS: All consecutive patients with stages III to IV epithelial ovarian, tubal, or peritoneal cancer who underwent MIS or laparotomy for interval cytoreduction after at least 1 NACT cycle from 2006 to 2017 at 1 institution. INTERVENTIONS: Patients underwent either MIS or laparotomy for interval cytoreduction after at least 1 cycle of NACT. MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed and data abstracted and analyzed. Survival was estimated by the Kaplan-Meier method, and outcomes were compared with Fisher's exact test, Student's t test, Wilcoxon rank sum test, and the log-rank test. In total, 157 assessable patients underwent interval cytoreductive surgery through MIS (n = 53) or laparotomy (n = 104). MIS was completed without conversion in 44 of 53 patients (83%), of whom 20 required a hand port and/or mini-laparotomy. R-zero and optimal resections were achieved in 60.4% and 96.3% of MIS patients respectively, compared with 42.3% and 82.7% of laparotomy patients (p = .02). MIS patients had lower estimated blood loss (EBL; 156 vs 278 mL, p <.001), fewer intraoperative transfusions (2% vs 17%, p = .006), and shorter hospital stay (3.0 vs 5.7 days, p < .001). Operative time was longer (171 vs 150 minutes, p = .007), but complications, intensive care unit stay, readmission, median progression-free survival (27 vs 29 months, p = .45), and median overall survival (37 vs 35 months, p = .74) were similar. CONCLUSION: MIS is feasible and effective for interval cytoreduction after NACT in advanced ovarian cancer patients. MIS is associated with less EBL, lower transfusion rate, and shorter length of hospital stay with no difference in patient outcomes.

Patients with BRCA mutations have superior outcomes after intraperitoneal chemotherapy in optimally resected high grade ovarian cancer.

OBJECTIVES: To compare the outcomes after intraperitoneal (IP) chemotherapy in patients with and without pathogenic BRCA mutations. METHODS: Patients with high grade ovarian cancer who were treated with adjuvant IP chemotherapy in the initial setting between 2005 and 2016 were identified. Outcomes were compared between patients with pathogenic mutations in BRCA (BRCA+) and those who tested negative or were unknown (BRCA-). RESULTS: A total of 100 eligible patients were identified. The median follow-up was 47.0 months (range, 6.6-144.1 months). Of these 100 patients, 77 patients underwent BRCA testing; 25 patients (32%) were BRCA+ (23 germline, 2 somatic). No differences were noted between groups with respect to number of IP cycles, stage, or residual disease after surgery. The median progression-free survival (PFS) was longer in the BRCA+ group; median PFS was not reached in the BRCA+ group compared to 17.3 months in the BRCA- group (HR = 0.38; 95% CI 0.20-0.73, P = 0.003). Median overall survival (OS) was longer in the BRCA+ group at 110.4 months versus 67.1 months (HR = 0.28, 95% CI 0.11-0.73, P = 0.009). CONCLUSIONS: Pathogenic BRCA mutations are more common than expected in optimally resected ovarian cancer patients selected for IP therapy. IP therapy was associated with a dramatic improvement in PFS and OS in BRCA+ patients compared with BRCA- patients. This improvement is greater than has been reported for BRCA+ patients with IV chemotherapy. The magnitude of this benefit suggests that patients with pathogenic mutations in BRCA may benefit from IP therapy.

Clonal lineage of high grade serous ovarian cancer in a patient with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene encoding neurofibromin, which negatively regulates Ras signaling. NF1 patients have an increased risk of developing early onset breast cancer, however, the association between NF1 and high grade serous ovarian cancer (HGSOC) is unclear. Since most NF1-related tumors exhibit early biallelic inactivation of NF1, we evaluated the evolution of genetic alterations in HGSOC in an NF1 patient. Somatic variation analysis of whole exome sequencing of tumor samples from both ovaries and a peritoneal metastasis showed a clonal lineage originating from an ancestral clone within the left adnexa, which exhibited copy number (CN) loss of heterozygosity (LOH) in the region of chromosome 17 containing TP53, NF1, and BRCA1 and mutation of the other TP53 allele. This event led to biallelic inactivation of NF1 and TP53 and LOH for the BRCA1 germline mutation. Subsequent CN alterations were found in the dominant tumor clone in the left ovary and nearly 100% of tumor at other sites. Neurofibromin modeling studies suggested that the germline NF1 mutation could potentially alter protein function. These results demonstrate early, biallelic inactivation of neurofibromin in HGSOC and highlight the potential of targeting RAS signaling in NF1 patients.

A Comprehensive Program Enabling Effective Delivery of Regional Genetic Counseling.

OBJECTIVES: The aim of this study was to demonstrate the utility of a comprehensive program involving management-based evidence, telemedicine, and patient navigation to provide genetic counseling services for patients with ovarian and breast cancer across a geographically large health care system. METHODS: We identified all patients with newly diagnosed ovarian and breast cancer in our health care system from January 2013 to December 2015 through the cancer registry. Referral characteristics and testing outcomes were recorded for each year and compared using the χ or Fisher exact test. RESULTS: Because the implementation of this program, the number of new ovarian cancer cases remained constant (109-112 cases/year) but patients referred for genetic counseling increased annually from 37% to 43% to 96% (P < 0.05). The percentage of ovarian cancer patients who underwent genetic testing increased annually from 24% to 27% to 53% (P < 0.05). The number of new breast cancer patients was constant (1543-1638 cases/year). The percentage of patients with triple negative breast cancer referred for genetic counseling rose from 69% in 2013 to 91% in 2015; the percentage of patients who underwent testing increased annually from 59% to 86% (P < 0.05). Of women with breast cancer diagnosed at less than 45 years of age, 78% to 85% were referred for genetic counseling across this period; the percentage of patients who underwent testing increased annually from 66% to 82% (P < 0.05). Patient navigation was initiated and was available to all patients in the system during this period. Telemedicine consults were performed in 118 breast/ovarian patients (6%) during this period. CONCLUSIONS: A comprehensive program may improve access to effective genetic counseling services in patients with ovarian and breast cancer despite geographic barriers.