Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma

Background

Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC.

Methods

Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium.

Results

Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS.

Conclusions

Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.     

The impact of neighborhoods and friendships on interracial anxiety among medical students and residents: A report from the medical student CHANGES study

Objective

To examine the experience of interracial anxiety among health professionals and how it may affect the quality of their interactions with patients from racially marginalized populations. We explored the influence of prior interracial exposure—specifically through childhood neighborhoods, college student bodies, and friend groups—on interracial anxiety among medical students and residents. We also examined whether levels of interracial anxiety change from medical school through residency.

Data Source

Web-based longitudinal survey data from the Medical Student Cognitive Habits and Growth Evaluation Study.

Study Design

We used a retrospective longitudinal design with four observations for each trainee. The study population consisted of non-Black US medical trainees surveyed in their 1st and 4th years of medical school and 2nd and 3rd years of residency. Mixed effects longitudinal models were used to assess predictors of interracial anxiety and assess changes in interracial anxiety scores over time.

Principal Findings

In total, 3155 non-Black medical trainees were followed for 7 years. Seventy-eight percent grew up in predominantly White neighborhoods. Living in predominantly White neighborhoods and having less racially diverse friends were associated with higher levels of interracial anxiety among medical trainees. Trainees' interracial anxiety scores did not substantially change over time; interracial anxiety was highest in the 1st year of medical school, lowest in the 4th year, and increased slightly during residency.

Conclusions

Neighborhood and friend group composition had independent effects on interracial anxiety, indicating that premedical racial socialization may affect medical trainees' preparedness to interact effectively with diverse patient populations. Additionally, the lack of substantial change in interracial anxiety throughout medical training suggests the importance of providing curricular tools and structure (e.g., instituting interracial cooperative learning activities) to foster the development of healthy interracial relationships.     

Minimum information to report about a flow cytometry experiment on extracellular vesicles: Communication from the ISTH SSC subcommittee on vascular biology

The Extracellular Vesicle Flow Cytometry Working Group ( http://www.evflowcytometry.org ) is formed by members of the International Society for Extracellular Vesicles (ISEV), the International Society for Advancement of Cytometry (ISAC), and the International Society on Thrombosis and Haemostasis (ISTH). This working group of flow cytometry experts develops guidelines for best practices regarding flow cytometry detection of extracellular vesicles. To improve rigor and standardization, this working group published a framework outlining the minimal information to report about a flow cytometry experiment on extracellular vesicles (MIFlowCyt-EV) in the Journal of Extracellular Vesicles, the ISEV journal, in 2020. In parallel, an article explaining MIFlowCyt-EV was published in Cytometry Part A, one of the ISAC journals, and now will be introduced to the ISTH as an SSC Communication in the Journal of Thrombosis and Haemostasis. The goal of this SSC Communication is to explain why flow cytometry is becoming the instrument of choice to characterize single extracellular vesicles, the obstacles that have been identified and (mostly) overcome by developing procedures to calibrate flow cytometers, and the relevance of reporting minimal information to improve reliability and reproducibility of experiments in which flow cytometers are used for characterization of extracellular vesicles.     

Derivation of occupational exposure limits: Differences in methods and protection levels

Frameworks for deriving occupational exposure limits (OELs) and OEL-analogue values (such as derived-no-effect levels [DNELs]) in various regulatory areas in the EU and at national level in Germany were analysed. Reasons for differences between frameworks and possible means of improving transparency and harmonisation were identified. Differences between assessment factors used for deriving exposure limits proved to be one important reason for diverging numerical values. Distributions for exposure time, interspecies and intraspecies extrapolation were combined by probabilistic methods and compared with default values of assessment factors used in the various OEL frameworks in order to investigate protection levels. In a subchronic inhalation study showing local effects in the respiratory tract, the probability that assessment factors were sufficiently high to protect 99% and 95% of the target population (workers) from adverse effects varied considerably from 9% to 71% and 17% to 87%, respectively, between the frameworks. All steps of the derivation process, including the uncertainty associated with the point of departure (POD), were further analysed with two examples of full probabilistic assessments. It is proposed that benchmark modelling should be the method of choice for deriving PODs and that all OEL frameworks should provide detailed guidance documents and clearly define their protection goals by stating the proportion of the exposed population the OEL aims to cover and the probability with which they intend to provide protection from adverse effects. Harmonisation can be achieved by agreeing on the way to perform the methodological steps for deriving OELs and on common protection goals.     

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Two-year results after combined phacoemulsification and iris-fixated phakic intraocular lens removal

Graefe's Archive for Clinical and Experimental Ophthalmology - To describe and present results after a technique for cataract surgery combined with explantation of an iris-fixated phakic...     

Weekly and seasonal variation in the circadian melatonin rhythm in humans: A response

We read with interest the commentary by Skeldon and Dijk about our article “Weekly, seasonal and chronotype-dependent variation of dim light melatonin onset.” The discussion points raised by Skeldon and Dijk are currently among the most hotly debated in human circadian science. What external factors determine human phase of entrainment? How great is the contribution of natural versus artificial light and sun time versus social time? Our intra-individual data add to the still limited evidence from field studies in this matter. In their commentary, Skeldon and Dijk formulate two either-or hypotheses, postulating that humans entrain either solely to the natural light-dark cycle (sun time referenced by midday) (H₁) or solely to the light selected by local clock time and social constraints (H₂). Neither hypothesis accounts for the effect of season on human light exposure. We interpreted our findings along more complex lines, speculating that the 1-h earlier melatonin rise in summer found in our sample is likely the combined result of daylight saving time (DST)-induced behavioral advances and a stronger natural zeitgeber in summer (light exposure determined by social and seasonal factors, H_original). Here, we show how the criticism by Skeldon and Dijk is based on two sentences quoted out of context (misrepresenting our hypothesis as H₁) and that their hypothesis H₂ leaves out important seasonal components in light exposure.     

Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group

Background

Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined.

Methods

This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered.

Results

The study included 61 patients <21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2–111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6–25.7) and 34.9% (95% CI, 22.7–47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered.

Conclusions

The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge.

Plain Language Summary

• Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors.
• Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases.
• This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.