Patterns of care and outcomes of risk reducing surgery in women with pathogenic variants in non-BRCA and Lynch syndrome ovarian cancer susceptibility genes.

OBJECTIVES: Guidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. METHODS: Women with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000-9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. RESULTS: 26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. CONCLUSIONS: No occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.

Dissociation of task engagement and arousal effects in auditory cortex and midbrain.

Both generalized arousal and engagement in a specific task influence sensory neural processing. To isolate effects of these state variables in the auditory system, we recorded single-unit activity from primary auditory cortex (A1) and inferior colliculus (IC) of ferrets during a tone detection task, while monitoring arousal via changes in pupil size. We used a generalized linear model to assess the influence of task engagement and pupil size on sound-evoked activity. In both areas, these two variables affected independent neural populations. Pupil size effects were more prominent in IC, while pupil and task engagement effects were equally likely in A1. Task engagement was correlated with larger pupil; thus, some apparent effects of task engagement should in fact be attributed to fluctuations in pupil size. These results indicate a hierarchy of auditory processing, where generalized arousal enhances activity in midbrain, and effects specific to task engagement become more prominent in cortex.

Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of genetic counseling and testing and impact on patient-reported stress, anxiety and depression.

BACKGROUND: Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. METHODS: Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. RESULTS: From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10-189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). CONCLUSIONS: Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information.

Pupil-associated states modulate excitability but not stimulus selectivity in primary auditory cortex.

Recent research in mice indicates that luminance-independent fluctuations in pupil size predict variability in spontaneous and evoked activity of single neurons in auditory and visual cortex. These findings suggest that pupil is an indicator of large-scale changes in arousal state that affect sensory processing. However, it is not known whether pupil-related state also influences the selectivity of auditory neurons. We recorded pupil size and single-unit spiking activity in the primary auditory cortex (A1) of nonanesthetized male and female ferrets during presentation of natural vocalizations and tone stimuli that allow measurement of frequency and level tuning. Neurons showed a systematic increase in both spontaneous and sound-evoked activity when pupil was large, as well as desynchronization and a decrease in trial-to-trial variability. Relationships between pupil size and firing rate were nonmonotonic in some cells. In most neurons, several measurements of tuning, including acoustic threshold, spectral bandwidth, and best frequency, remained stable across large changes in pupil size. Across the population, however, there was a small but significant decrease in acoustic threshold when pupil was dilated. In some recordings, we observed rapid, saccade-like eye movements during sustained pupil constriction, which may indicate sleep. Including the presence of this state as a separate variable in a regression model of neural variability accounted for some, but not all, of the variability and nonmonotonicity associated with changes in pupil size.NEW & NOTEWORTHY Cortical neurons vary in their response to repeated stimuli, and some portion of the variability is due to fluctuations in network state. By simultaneously recording pupil and single-neuron activity in auditory cortex of ferrets, we provide new evidence that network state affects the excitability of auditory neurons, but not sensory selectivity. In addition, we report the occurrence of possible sleep states, adding to evidence that pupil provides an index of both sleep and physiological arousal.

Spectral tuning of adaptation supports coding of sensory context in auditory cortex.

Perception of vocalizations and other behaviorally relevant sounds requires integrating acoustic information over hundreds of milliseconds. Sound-evoked activity in auditory cortex typically has much shorter latency, but the acoustic context, i.e., sound history, can modulate sound evoked activity over longer periods. Contextual effects are attributed to modulatory phenomena, such as stimulus-specific adaption and contrast gain control. However, an encoding model that links context to natural sound processing has yet to be established. We tested whether a model in which spectrally tuned inputs undergo adaptation mimicking short-term synaptic plasticity (STP) can account for contextual effects during natural sound processing. Single-unit activity was recorded from primary auditory cortex of awake ferrets during presentation of noise with natural temporal dynamics and fully natural sounds. Encoding properties were characterized by a standard linear-nonlinear spectro-temporal receptive field (LN) model and variants that incorporated STP-like adaptation. In the adapting models, STP was applied either globally across all input spectral channels or locally to subsets of channels. For most neurons, models incorporating local STP predicted neural activity as well or better than LN and global STP models. The strength of nonlinear adaptation varied across neurons. Within neurons, adaptation was generally stronger for spectral channels with excitatory than inhibitory gain. Neurons showing improved STP model performance also tended to undergo stimulus-specific adaptation, suggesting a common mechanism for these phenomena. When STP models were compared between passive and active behavior conditions, response gain often changed, but average STP parameters were stable. Thus, spectrally and temporally heterogeneous adaptation, subserved by a mechanism with STP-like dynamics, may support representation of the complex spectro-temporal patterns that comprise natural sounds across wide-ranging sensory contexts.

Focal Suppression of Distractor Sounds by Selective Attention in Auditory Cortex.

Auditory selective attention is required for parsing crowded acoustic environments, but cortical systems mediating the influence of behavioral state on auditory perception are not well characterized. Previous neurophysiological studies suggest that attention produces a general enhancement of neural responses to important target sounds versus irrelevant distractors. However, behavioral studies suggest that in the presence of masking noise, attention provides a focal suppression of distractors that compete with targets. Here, we compared effects of attention on cortical responses to masking versus non-masking distractors, controlling for effects of listening effort and general task engagement. We recorded single-unit activity from primary auditory cortex (A1) of ferrets during behavior and found that selective attention decreased responses to distractors masking targets in the same spectral band, compared with spectrally distinct distractors. This suppression enhanced neural target detection thresholds, suggesting that limited attention resources serve to focally suppress responses to distractors that interfere with target detection. Changing effort by manipulating target salience consistently modulated spontaneous but not evoked activity. Task engagement and changing effort tended to affect the same neurons, while attention affected an independent population, suggesting that distinct feedback circuits mediate effects of attention and effort in A1.

Endometrial cancer surveillance adherence reduces utilization and subsequent costs.

OBJECTIVES: In June 2011, the SGO recommended that physical exam and symptoms be the primary surveillance methods in patients with endometrial cancer. We sought to evaluate adherence to these guidelines by comparing the use of CT scans, paps and serum CA125 ordered for endometrial cancer surveillance before and after publication of these guidelines. METHODS: A retrospective review was performed for all patients undergoing surveillance for endometrial cancer at a single institution between June 2009 and June 2013. We assessed the number of patients without symptoms or abnormal physical exam findings who underwent surveillance CT scans, paps and/or CA125 during the 2years pre- and 2years post-SGO guidelines. RESULTS: 92 patients (n=48 pre-6/2011, n=44 post-6/2011) were identified. Mean patient age was 58years. No significant difference in age, ethnicity, body mass index, or disease grade or stage was noted. There was a significant decline in surveillance CT scans (n=13, 27% vs. n=4, 9%, p=0.03), CA125 (n=14, 29% vs. 5, 11%, p=0.035) and paps (n=34, 71% vs. n=8 vs. 18%, p<0.001). There was no significant difference in disease status at the last follow-up. Institutional cost of surveillance also declined ($14,102.46 2years pre-guidelines, $3,054.99 2years post-guidelines). CONCLUSIONS: In a single urban academic public hospital, after only 2years, clinical adherence to the 2011 SGO endometrial cancer surveillance guidelines resulted in a significant decline in the use of CT scans, CA125 and paps. This reduction does not appear to affect patient outcomes and led to an appreciable decrease in surveillance costs.