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Uterine sarcomas are a rare, heterogenous, group of cancers with limited data on optimal adjuvant treatment. We examined patterns of care for leiomyosarcomas (LMS), endometrial stromal sarcomas (ESS), adenosarcomas (AS), and mixed uterine sarcomas and assessed the utilization of adjuvant therapy for each histology. The National Cancer Database (NCDB) was queried for patients with non-metastatic uterine sarcoma diagnosed between 2004 and 2018 treated with surgery. Uterine carcinosarcomas were excluded. Adjuvant patterns of care and temporal treatment trends are evaluated, stratified by histology. Multivariable logistic regression model was constructed to identify predictors of receipt of radiation adjuvant therapy. Among 12,806 patients, 88% received a total hysterectomy and bilateral salpingo-oophorectomy (TH+BSO) and 42% received lymph node sampling (LNS). Surgery alone was the most common treatment modality for all histology groups (59.0%). Surgery with chemotherapy was the second most common form of treatment for LMS (33.1%) and mixed type tumors (29.6%). Surgery with radiation was the second most common treatment for high-grade ESS (10.8%) and AS (11.8%). External beam radiation therapy (EBRT) was the most common type of adjuvant radiation therapy utilized. Adjuvant radiation therapy (RT) has declined in LMS, from 27% in 2004 to 3% in 2018. Adjuvant chemotherapy for all histology groups has increased in use from 10% in 2004 to 28% in 2018. For uterine sarcomas, TH+BSO without LNS was the main surgical modality. Adjuvant therapy for uterine sarcomas is not commonly used, however high risk features including stage II/III, high grade, and more extensive lymph node sampling appear to increase the likelihood of adjuvant RT. The utilization of adjuvant chemotherapy in uterine sarcomas has increased over time, while RT has been decreasing. [ABSTRACT FROM AUTHOR]

To better understand the risk of developing a mental health disorder and the association on outcomes in endometrial cancer patients. Endometrial cancer patients ≥18 years old diagnosed between 1997-2012 were identified from the Utah Population Database and matched with up to 5 cancer free women from the general population. Mental health disorders were identified by International Classification of Diseases ICD-9 diagnostic codes. Endometrial cancer survivors with pre-existing mental health issues were excluded. Diagnosis of a mental health disorder in endometrial cancer patients was compared with the endemic rate. The impact of a mental health disorders on overall survival (OS) and cause specific survival (CSS) was evaluated. There were 2941 endometrial cancer patients and 12,192 general population matched subjects that met criteria with a median follow up time of 7.1 years (range 0-19.2) and 7.7 years (0.4-19.2) respectively. Within the first 1.5 years from diagnosis, there was an association of endometrial cancer patients being diagnosed with a mental health disorder (Hazard radio (HR) 3.09, 95% confidence interval (CI) 2.66-3.59). However, no association was found in endometrial cancer patients being diagnosed with a mental health disorder between 1.5-3 years (HR 1.07, 95% CI 0.83-1.38) and≥3 years (HR 1.09, 95% CI 0.95-1.26). Treatment with tri-modality (surgery, radiation and chemotherapy) and advanced disease was associated with mental health disorders. OS was worse in endometrial cancer survivors who developed an anxiety disorder (p = 0.0265). CSS was worse in endometrial cancer patients diagnosed with all mental health disorders and anxiety disorders (p < 0.0001, p = 0.002). Endometrial cancer patients have an increased diagnosis of mental health disorders within the first 1.5 years of cancer diagnosis compared to the general population. Endometrial cancer survivors with anxiety disorder have worse OS. Anxiety disorders and all mental health disorders have a worse CSS. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the kinetics of tumor regression in cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) using computed tomography (CT) and magnetic resonance imaging (MRI), and to correlate rate of regression and residual tumor with progression and survival. Thirty-two patients with stage IB2-IVA cervical cancer were randomly selected from an institutional database with a 2:1 ratio of SCC to AC. All available on-treatment weekly cone beam CT (CBCT) and pre- and postexternal beam MRIs were utilized to generate largest two-dimensional area of tumor and tumor gross tumor volumes (GTV), respectively. Tumor volume regression velocity and percent residual tumor were correlated to 5-year progression-free survival (PFS) and disease-specific survival (DSS) using threshold regression modeling. Kaplan-Meier and Fine-Grey estimators were used for survival and cumulative incidence analysis, respectively. With a median follow-up of 2.9 years, 32 patients were included, 22 (69%) with SCC and 10 (31%) with AC. All received concurrent chemoradiation followed by brachytherapy. The 2-year cumulative incidence (CI) of local progression for both SCC and AC was 10%, and 2-year CI of distant progression was 9% vs. 57% (p = 0.02). Deaths occurred in 3/22 (14%) with SCC and 7/10 (70%) with AC, with a 2-year DSS of 90% versus 60%, respectively. Extent and rate of regression on CBCTs were not correlated with progression or survival; however, consistent rates of tumor regression for both SCC and AC. Thresholds of ≥20% residual disease on post-external beam pre-brachytherapy MRI and regression velocity ≤1.8%/day were associated with worse PFS and DSS. This study showed cervical AC is associated with higher rates of distant progression and worse overall survival than SCC. Cervical AC tends to have a higher initial and residual tumor burden. Our identified thresholds of ≥20% residual tumor and tumor regression of ≤1.8%/day may help identify cases warranting dose escalation. [ABSTRACT FROM AUTHOR]

Proper perception of sounds in the environment requires auditory signals to be encoded with extraordinary temporal precision up to tens of microseconds, but how it originates from the hearing organs in the periphery is poorly understood. In particular, sound-evoked spikes in auditory afferent fibers in vivo are phase-locked to sound frequencies up to 5 kHz, but it is not clear how hair cells can handle intracellular Ca2+ changes with such high speed and efficiency. In this study, we combined patch-clamp recording and two-photon Ca2+ imaging to examine Ca2+ dynamics in hair cell ribbon synapses in the bullfrog amphibian papilla of both sexes. We found that Ca2+ clearance from single synaptic ribbons followed a double exponential function, and the weight of the fast component, but not the two time constants, was significantly reduced for prolonged stimulation, and during inhibition of the plasma membrane Ca2+ ATPase (PMCA), the mitochondrial Ca2+ uptake (MCU), or the sarcolemma/endoplasmic reticulum Ca2+ ATPase (SERCA), but not the Na+/Ca2+ exchanger (NCX). Furthermore, we found that both the basal Ca2+ level and the Ca2+ rise during sinusoidal stimulation were significantly increased by inhibition of PMCA, MCU, or SERCA. Consistently, phase-locking of synaptic vesicle releases from hair cells was also significantly reduced by blocking PMCA, MCU, or SERCA, but not NCX. We conclude that, in addition to fast diffusion mediated by mobile Ca2+ buffer, multiple Ca2+ extrusion pumps are required for phase-locking at the auditory hair cell ribbon synapse. [ABSTRACT FROM AUTHOR]

Proper perception of sounds in the environment requires auditory signals to be encoded with extraordinary temporal precision up to tens of microseconds, but how it originates from the hearing organs in the periphery is poorly understood. In particular, sound-evoked spikes in auditory afferent fibers in vivo are phase-locked to sound frequencies up to 5 kHz, but it is not clear how hair cells can handle intracellular Ca 2+ changes with such high speed and efficiency. In this study, we combined patch-clamp recording and two-photon Ca 2+ imaging to examine Ca 2+ dynamics in hair cell ribbon synapses in the bullfrog amphibian papilla of both sexes. We found that Ca 2+ clearance from single synaptic ribbons followed a double exponential function, and the weight of the fast component, but not the two time constants, was significantly reduced for prolonged stimulation, and during inhibition of the plasma membrane Ca 2+ ATPase (PMCA), the mitochondrial Ca 2+ uptake (MCU), or the sarcolemma/endoplasmic reticulum Ca 2+ ATPase (SERCA), but not the Na + /Ca 2+ exchanger (NCX). Furthermore, we found that both the basal Ca 2+ level and the Ca 2+ rise during sinusoidal stimulation were significantly increased by inhibition of PMCA, MCU, or SERCA. Consistently, phase-locking of synaptic vesicle releases from hair cells was also significantly reduced by blocking PMCA, MCU, or SERCA, but not NCX. We conclude that, in addition to fast diffusion mediated by mobile Ca 2+ buffer, multiple Ca 2+ extrusion pumps are required for phase-locking at the auditory hair cell ribbon synapse. SIGNIFICANCE STATEMENT Hair cell synapses can transmit sound-driven signals precisely in the kHz range. However, previous studies of Ca 2+ handling in auditory hair cells have often been conducted in immature hair cells, with elevated extracellular Ca 2+ concentration, or through steady-state stimulation that may not be physiologically relevant. Here we examine Ca 2+ clearance from hair cell synaptic ribbons in a fully mature preparation at physiological concentration of external Ca 2+ and at physiological temperature. By stimulating hair cells with sinusoidal voltage commands that mimic pure sound tones, we recapitulated the phase-locking of hair cell exocytosis with an in vitro approach. This allowed us to reveal the Ca 2+ extrusion mechanisms that are required for phase-locking at auditory hair cell ribbon synapses., (Copyright © 2021 the authors.)