Hormone Receptor Expression in Primary and Recurrent High-Grade Serous Ovarian Cancer and Its Implications in Early Maintenance Treatment.

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen therapy. The degree of expression is presumed to play a vital role; however, that role is not well-defined in ovarian cancer. We aimed to determine the role of estrogen and progesterone receptor expression in primary and paired relapsed HGSOC. In this study, primary and matched relapsed tumor samples were collected from 80 patients with International Federation of Gynecology and Obstetrics Stage II-IV HGSOC. Tissue microarray was conducted and immunohistochemistry for estrogen and progesterone receptor expression was performed. Two independent pathologists performed the tissue microarray analysis with the Immunoreactive Score and Allred Total score. In the paired analysis, no significant difference in estrogen receptor expression was observed. However, progesterone receptor expression was significantly lower in patients with recurrent platinum-sensitive HGSOC. We conclude that anti-estrogen therapy targeting estrogen receptor positive HGSOC could be administered in primary and relapsed settings. The use of endocrine maintenance with an aromatase inhibitor in patients with estrogen receptor positive HGSOC needs to be further evaluated and validated in a randomized controlled trial.

Pertuzumab as second­ or later­line therapy for human epidermal growth factor receptor 2­positive metastatic breast cancer: A clinical experience.

Trastuzumab and pertuzumab with taxane-based chemotherapy are considered the first-line standard therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). Pertuzumab is also a later-line therapy for mBC in Switzerland, although limited safety and efficacy data are available. The present study assessed the therapeutic regimens, toxicities and clinical outcomes after second- or later-line pertuzumab therapy in patients with mBC who did not receive pertuzumab as a first-line therapy. Physicians from nine major Swiss oncology centers retrospectively completed a questionnaire for each pertuzumab-naive patient who was treated with pertuzumab as a second- or later-line therapy. Of 35 patients with HER2-positive mBC (median age, 49 years; range, 35-87 years), 14 received pertuzumab as a second-line therapy, 6 as a third-line therapy, and 15 as a fourth- or later-line therapy. A total of 20 patients (57%) died during the study period. The median overall survival was 74.2 months (95% confidence interval, 47.6-139.8 months). Grade (G) 3/4 adverse events (AEs) were reported in 14% of patients, with only 1 patient discontinuing therapy due to pertuzumab-related toxicities. The most common AE was fatigue (overall, 46%; G3, 11%). Overall, congestive heart disease occurred in 14% of patients (G3, 6%), nausea in 14% of patients (all G1), and myelosuppression in 12% of patients (G3, 6%). In conclusion, the median overall survival of patients who underwent second- or later-line pertuzumab treatment was similar to that reported for patients who underwent first-line pertuzumab treatment, and the safety profile was acceptable. These data support the use of pertuzumab for second- or later-line therapy when it was not administered as first-line therapy.

Effects of Methylprednisolone on Myocardial Function and Microcirculation in Post-resuscitation: A Rat Model.

Background: Previous studies have demonstrated that inflammation and impaired microcirculation are key factors in post-resuscitation syndromes. Here, we investigated whether methylprednisolone (MP) could improve myocardial function and microcirculation by suppressing the systemic inflammatory response following cardiopulmonary resuscitation (CPR) in a rat model of cardiac arrest (CA). Methods: Sprague-Dawley rats were randomly assigned to (1) sham, (2) control, and (3) drug groups. Ventricular fibrillation was induced and then followed by CPR. The rats were infused with either MP or vehicle at the start of CPR. Myocardial function and microcirculation were assessed at baseline and after the restoration of spontaneous circulation. Blood samples were drawn at baseline and 60-min post-resuscitation to assess serum cytokine (TNF-α, IL-1ß, and IL-6) levels. Results: Myocardial function [estimated by the ejection fraction (EF), myocardial performance index (MPI), and cardiac output (CO)] improved post-ROSC in the MP group compared with those in the control group (p < 0.05). MP decreased the levels of the aforementioned pro-inflammatory cytokines and alleviated cerebral, sublingual, and intestinal microcirculation compared with the control (p < 0.05). A negative correlation emerged between the cytokine profile and microcirculatory blood flow. Conclusion: MP treatment reduced post-resuscitation myocardial dysfunction, inhibited pro-inflammatory cytokines, and improved microcirculation in the initial recovery phase in a CA and resuscitation animal model. Therefore, MP could be a potential clinical target for CA patients in the early phase after CPR to alleviate myocardial dysfunction and improve prognosis.

Functional abnormalities in the cerebello-thalamic pathways in a mouse model of DYT25 dystonia.

Dystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia. DYT25 (Gnal+/-) mice carry a heterozygous knockout mutation of the Gnal gene, which notably disrupts striatal function, and systemic or striatal administration of oxotremorine to these mice triggers dystonic symptoms. Our results reveal an increased cerebello-thalamic excitability in the presymptomatic state. Following the first dystonic episode, Gnal+/- mice in the asymptomatic state exhibit a further increase of the cerebello-thalamo-cortical excitability, which is maintained after θ-burst stimulations of the cerebellum. When administered in the symptomatic state induced by a cholinergic activation, these stimulations decreased the cerebello-thalamic excitability and reduced dystonic symptoms. In agreement with dystonia being a multiregional circuit disorder, our results suggest that the increased cerebello-thalamic excitability constitutes an early endophenotype, and that the cerebellum is a gateway for corrective therapies via the depression of cerebello-thalamic pathways.

Adherence to bone health guidelines in patients with hormone receptor-positive early breast cancer: Status and clinical impact in a Swiss cohort experience.

AIM: In patients with postmenopausal hormone receptor-positive breast cancer (ER + eBC), aromatase inhibitors (AIs) are widely used for effective relapse prevention. However, AIs reduce bone density and increase bone-related events (BREs). Alongside calcium and vitamin D3 supplementation, bisphosphonates and denosumab are well-known options for improving outcomes in bone health and breast cancer prognosis. This study aimed to evaluate the practice patterns of bone health guideline-based management in real-world patients with ER + eBC. MATERIAL AND METHODS: In total, 68 patients with ER + eBC treated between 2009 and 2014 at the University Hospital Basel were included in this retrospective cohort study. Chart reviews were analyzed. Baseline, clinicopathological, treatment, and BRE data were extracted. Each patient was specifically reviewed for therapy adherence to the Swiss bone health guidelines (Swiss Association against Osteoporosis 2010 [SVGO]). RESULTS: The mean patient age was 66.5 (range, 56-74) years, all post-menopausal. The most frequent tumor characteristics were tumor size of pT1-pT2 (N = 53, 77.9%) and treatment with letrozole (N = 35, 51.5%), followed by tamoxifen as a switch strategy (N = 27, 40.3%). The median treatment time with AIs was 47 (range, 30-60) months. Five patients (7.8%) experienced a fracture during or after AI treatment. Moreover, 51 (75%) patients were treated according to the SVGO recommendations. CONCLUSION: The fracture rate in our retrospective cohort was comparable to that in the larger phase III randomized trials. The adherence to bone health guidelines was satisfactory but still suboptimal. Clinicians should strictly adhere to the current bone health guidelines to ensure the best possible prevention of BREs and maintain bone health and cancer prognosis in patients with ER + eBC.

Reduced Interhemispheric Coherence after Cerebellar Vermis Output Perturbation.

Motor coordination and motor learning are well-known roles of the cerebellum. Recent evidence also supports the contribution of the cerebellum to the oscillatory activity of brain networks involved in a wide range of disorders. Kainate, a potent analog of the excitatory neurotransmitter glutamate, can be used to induce dystonia, a neurological movement disorder syndrome consisting of sustained or repetitive involuntary muscle contractions, when applied on the surface of the cerebellum. This research aims to study the interhemispheric cortical communication between the primary motor cortices after repeated kainate application on cerebellar vermis for five consecutive days, in mice. We recorded left and right primary motor cortices electrocorticograms and neck muscle electromyograms, and quantified the motor behavior abnormalities. The results indicated a reduced coherence between left and right motor cortices in low-frequency bands. In addition, we observed a phenomenon of long-lasting adaptation with a modification of the baseline interhemispheric coherence. Our research provides evidence that the cerebellum can control the flow of information along the cerebello-thalamo-cortical neural pathways and can influence interhemispheric communication. This phenomenon could function as a compensatory mechanism for impaired regional networks.

Reduced Interhemispheric Coherence in Cerebellar Kainic Acid-Induced Lateralized Dystonia.

The execution of voluntary muscular activity is controlled by the primary motor cortex, together with the cerebellum and basal ganglia. The synchronization of neural activity in the intracortical network is crucial for the regulation of movements. In certain motor diseases, such as dystonia, this synchrony can be altered in any node of the cerebello-cortical network. Questions remain about how the cerebellum influences the motor cortex and interhemispheric communication. This research aims to study the interhemispheric cortical communication between the motor cortices during dystonia, a neurological movement syndrome consisting of sustained or repetitive involuntary muscle contractions. We pharmacologically induced lateralized dystonia to adult male albino mice by administering low doses of kainic acid on the left cerebellar hemisphere. Using electrocorticography and electromyography, we investigated the power spectral densities, cortico-muscular, and interhemispheric coherence between the right and left motor cortices, before and during dystonia, for five consecutive days. Mice displayed lateralized abnormal motor signs, a reduced general locomotor activity, and a high score of dystonia. The results showed a progressive interhemispheric coherence decrease in low-frequency bands (delta, theta, beta) during the first 3 days. The cortico-muscular coherence of the affected side had a significant increase in gamma bands on days 3 and 4. In conclusion, lateralized cerebellar dysfunction during dystonia was associated with a loss of connectivity in the motor cortices, suggesting a possible cortical compensation to the initial disturbances induced by cerebellar left hemisphere kainate activation by blocking the propagation of abnormal oscillations to the healthy hemisphere. However, the cerebellum is part of several overly complex circuits, therefore other mechanisms can still be involved in this phenomenon.