Tumoral programmed cell death 1 (PD1) expression in endometrial carcinoma is a prognostic marker for patient outcome.

OBJECTIVE: Immune checkpoint inhibitors have recently demonstrated benefit in patients with advanced and recurrent endometrial carcinoma. This retrospective study investigated immune checkpoint molecules in endometrial carcinoma as they pertain to the molecular subtypes, clinical outcomes, and predictive value. METHODS: Tumoral RNA expression of genes controlling the immune checkpoint, programmed cell death 1 (PD1, encoded by PDCD1), its ligand (PDL1, encoded by CD274), and interferon gamma (IFNG) was determined in 239 endometrial carcinoma tissues by quantitative polymerase chain reaction (qPCR) and compared with endometrial tissue from 25 controls. A total of 81 endometrial carcinoma tissues were analyzed using the ProMiSe molecular classification, and patient trajectories were analyzed for the entire cohort. Findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA; n=548). RESULTS: PD1, PDL1, and IFNG expression was significantly higher in endometrial carcinoma when compared with non-malignant control tissue with a mean expression of 0.12, 0.05, and 0.05 in control tissue and 0.44, 0.31, and 0.35 in endometrial carcinoma, respectively. POLE-mutated and mismatch repair-deficient (MMRd) (immunologically hot) tumors showed the highest expression of PD1 and IFNG. Increased expression of PD1, PDL1, and IFNG was associated with improved recurrence-free (HR 0.32, p<0.001; HR 0.30, p<0.001; HR 0.47, p=0.012, respectively), disease-specific (HR 0.38, p<0.001; HR 0.29, p<0.001; HR 0.45, p=0.017, respectively), and overall survival (HR 0.56, p=0.003; HR 0.38, p<0.001; HR 0.58, p=0.006, respectively). Cox regression confirmed the prognostic significance of PD1 for recurrence-free survival (HR 0.39, p=0.009) and PDL1 for overall survival (HR 0.55, p=0.037). The prognostic value of tumoral PD1 on recurrence-free survival, disease-specific survival, and overall survival was confirmed in the TCGA cohort. CONCLUSIONS: Tumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in "hot tumors", predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials.

Verification of the prognostic precision of the new 2023 FIGO staging system in endometrial cancer patients - An international pooled analysis of three ESGO accredited centres.

BACKGROUND: Recently, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer (EC) critically integrating new pathological and molecular features was published. The present study evaluated the clinical impact of the new 2023 FIGO staging system by comparing it to the previous 2009 system. METHODS: This is an international, pooled retrospective study of 519 EC patients who underwent primary treatment (and molecular characterisation) at three European Society of Gynaecological Oncology (ESGO) accredited centres in Austria/Italy. Patients were categorised according to the 2009 and the 2023 FIGO staging systems. Stage shifts were analysed and (sub)stage specific 5-year progression-free (PFS) and overall survival (OS) rates were calculated and compared. Different statistical tests were applied to evaluate the prognostic precision of the two FIGO staging systems and to compare them to each other. RESULTS: (Sub)stage shifts occurred in 143/519 (27.6%) patients: 123 upshifts (23.7%) and 20 (3.9%) downshifts. 2023 FIGO staging system identified a stage I cohort with a notably higher 5-year PFS rate compared to 2009 (93.0% versus 87.4%, respectively). For stage II disease, the 5-year PFS rate was similar in the 2023 and the 2009 FIGO staging systems (70.2% versus 71.2%, respectively). The two new molecularly defined 2023 FIGO substages IAmPOLEmut and IICmp53abn displayed distinct, particularly favourable and adverse oncologic outcomes within early stage disease, respectively. A remarkably lower 5-year PFS rate for stage III patients was revealed in the 2023 FIGO staging system compared to 2009 (44.4% versus 54.1%, respectively). All applied statistical tests confirmed a more accurate prediction of PFS and OS by the 2023 FIGO staging system compared to 2009. CONCLUSION: The new 2023 FIGO stating system led to a substantial stage shift in about one quarter of patients leading to a higher prognostic precision. In early stage disease, the new substages added further prognostic granularity and identified treatment relevant subgroups.

Off-Axis Layered Displays: Hybrid Direct-View/Near-Eye Mixed Reality with Focus Cues.

This work introduces off-axis layered displays, the first approach to stereoscopic direct-view displays with support for focus cues. Off-axis layered displays combine a head-mounted display with a traditional direct-view display for encoding a focal stack and thus, for providing focus cues. To explore the novel display architecture, we present a complete processing pipeline for the real-time computation and post-render warping of off-axis display patterns. In addition, we build two prototypes using a head-mounted display in combination with a stereoscopic direct-view display, and a more widely available monoscopic direct-view display. In addition we show how extending off-axis layered displays with an attenuation layer and with eye-tracking can improve image quality. We thoroughly analyze each component in a technical evaluation and present examples captured through our prototypes.

Video See-Through Mixed Reality with Focus Cues.

This work introduces the first approach to video see-through mixed reality with full support for focus cues. By combining the flexibility to adjust the focus distance found in varifocal designs with the robustness to eye-tracking error found in multifocal designs, our novel display architecture reliably delivers focus cues over a large workspace. In particular, we introduce gaze-contingent layered displays and mixed reality focal stacks, an efficient representation of mixed reality content that lends itself to fast processing for driving layered displays in real time. We thoroughly evaluate this approach by building a complete end-to-end pipeline for capture, render, and display of focus cues in video see-through displays that uses only off-the-shelf hardware and compute components.

The impact of COVID-19 pandemic on the rate of newly diagnosed gynecological and breast cancers: a tertiary center perspective.

PURPOSE: The aim of the present study was to assess the impact of postponed screening examinations and lockdown measures on gynecological and breast cancer diagnoses throughout the year 2020 in a gynecological oncological center in Austria. METHODS: Data of 889 patients with either newly diagnosed gynecological or breast cancer between January 2019 and December 2020 were collected. Clinical parameters including symptoms, performance status, comorbidities and referral status were compared in patients, who were newly diagnosed with cancer in the period of the first lockdown from March 2020 to April 2020 and the second lockdown from November 2020 to December 2020 and compared to the same period in 2019. RESULTS: Our results showed a strong decline in newly diagnosed cancers during the lockdown periods: -45% in gynecological cancer and -52% in breast cancer compared to the same period in 2019. Compared to the analogue period of 2019, breast cancer patients reported significantly more tumor-associated symptoms (55% vs. 31%, p = 0.013) during and in between (48% vs. 32%, p = 0.022) the lockdowns. During the lockdown, periods in the group of breast cancer patients' tumor stage varied significantly compared to 2019 (T2-T4; p = 0.047). CONCLUSION: Both lockdowns led to a strong decrease in newly diagnosed gynecological and breast cancers. Treatment delays in potentially curable disease could lead to inferior clinical outcomes, with the risk of missing the optimal treatment window. As the COVID-19 pandemic will be a challenge for some time to come, new strategies in patient care are needed to optimize cancer screening and management during the pandemic.

Do increases in deep grey matter volumes after electroconvulsive therapy persist in patients with major depression? A longitudinal MRI-study.

BACKGROUND: Previous MRI studies reported deep grey matter volume increases after electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). However, the clinical correlates of these changes are still unclear. It remains debated whether such volume changes are transient, and if they correlate with affective changes over time. We here investigated if ECT induces deep grey matter volume increases in MDD-patients; and, if so, whether volume changes persist over more than 9 months and whether they are related to the clinical outcome. METHODS: We examined 16 MDD-patients with 3Tesla MRI before (baseline) and after an ECT-series and followed 12 of them up for 10-36 months. Patients' data were compared to 16 healthy controls. Affective scales were used to investigate the relationship between therapy-outcome and MRI changes. RESULTS: At baseline, MDD-patients had lower values in global brain volume, white matter and peripheral grey matter compared to healthy controls, but we observed no significant differences in deep grey matter volumes. After ECT, the differences in peripheral grey matter disappeared, and patients demonstrated significant volume increases in the right hippocampus and both thalami, followed by subsequent decreases after 10-36 months, especially in ECT-responders. Controls did not show significant changes over time. LIMITATIONS: Beside the relatively small, yet carefully characterized cohort, we address the variability in time between the third scanning session and the baseline. CONCLUSIONS: ECT-induced deep grey matter volume increases are transient. Our results suggest that the thalamus might be a key region for the understanding of the mechanisms of ECT action.

Decrease in gynecological cancer diagnoses during the COVID-19 pandemic: an Austrian perspective.

BACKGROUND: On March 16, 2020, the federal government of Austria declared a nationwide lockdown due to the COVID-19 pandemic. Since the lockdown, screening examinations and routine checkups have been restricted to prevent the spread of the virus and to increase the hospitals' bed capacity across the country. This resulted in a severe decline of patient referrals to the hospitals. OBJECTIVE: To assess the impact of the COVID-19 pandemic on the rate of newly diagnosed gynecological and breast cancers in Austria. METHODS: Data of 2077 patients from 18 centers in Austria with newly diagnosed gynecological or breast cancer between January and May 2019 and January and May 2020 were collected. Clinical parameters, including symptoms, performance status, co-morbidities, and referral status, were compared between the time before and after the COVID-19 outbreak. RESULTS: Our results showed a slight increase of newly diagnosed cancers in January and February 2020 as compared with 2019 (+2 and +35%, respectively) and a strong decline in newly diagnosed tumors since the lockdown: -24% in March 2020 versus March 2019, -49% in April 2020 versus April 2019, -49% in May 2020 versus May 2019. Two-thirds of patients diagnosed during the pandemic presented with tumor-specific symptoms compared with less than 50% before the pandemic (p<0.001). Moreover, almost 50% of patients in 2020 had no co-morbidities compared with 35% in 2019 (p<0.001). Patients, who already had a malignant disease, were rarely diagnosed with a new cancer in 2020 as compared with 2019 (11% vs 6%; p<0.001). CONCLUSIONS: The lockdown led to a decreased number of newly diagnosed gynecological and breast cancers. The decreased accessibility of the medical services and postponed diagnosis of potentially curable cancers during the COVID-19 pandemic may be a step backwards in our healthcare system and might impair cancer treatment outcomes. Therefore, new strategies to manage early cancer detection are needed to optimize cancer care in a time of pandemic in the future.

[Remission of a complex periodic catatonic syndrome under electroconvulsive therapy]. / Remission eines komplexen periodischen katatonen Syndroms unter Elektrokonvulsionstherapie.

This article is reporting about a spontaneous occurred catatonic syndrome in a 52 years old female patients with no prior psychiatric illness record. The catatonia followed a severe depressive episode with psychotic symptoms. At the beginning additionally to the catatonic-symptoms severe disorientation and memory disturbances were prominent in a way it can be seen in neurodegenerative diseases like Lewy-Body-Dementia and Creutzfeldt-Jacob-Disease. The patient didn't respond on any medication or showed severe side-effects which led to discontinue the medication. After applying widespread somatic diagnostics, which has excluded a neurodegenerative disease a electroconvulsive therapy was applied. During this treatment the patient showed a recurrence of her catatonic symptoms but they remitted if there was a too long period between the convulsive treatments. After establishing a sufficient period between the convulsive treatments the symptoms remitted totally.

Depression-Burnout Overlap in Physicians.

BACKGROUND: Whether burnout is a distinct phenomenon rather than a type of depression and whether it is a syndrome, limited to three "core" components (emotional exhaustion, depersonalization and low personal accomplishment) are subjects of current debate. We investigated the depression-burnout overlap, and the pertinence of these three components in a large, representative sample of physicians. METHODS: In a cross-sectional study, all Austrian physicians were invited to answer a questionnaire that included the Major Depression Inventory (MDI), the Hamburg Burnout Inventory (HBI), as well as demographic and job-related parameters. Of the 40093 physicians who received an invitation, a total of 6351 (15.8%) participated. The data of 5897 participants were suitable for analysis. RESULTS: Of the participants, 10.3% were affected by major depression. Our study results suggest that potentially 50.7% of the participants were affected by symptoms of burnout. Compared to physicians unaffected by burnout, the odds ratio of suffering from major depression was 2.99 (95% CI 2.21-4.06) for physicians with mild, 10.14 (95% CI 7.58-13.59) for physicians with moderate, 46.84 (95% CI 35.25-62.24) for physicians with severe burnout and 92.78 (95% CI 62.96-136.74) for the 3% of participants with the highest HBI_sum (sum score of all ten HBI components). The HBI components Emotional Exhaustion, Personal Accomplishment and Detachment (representing depersonalization) tend to correlate more highly with the main symptoms of major depression (sadness, lack of interest and lack of energy) than with each other. A combination of the HBI components Emotional Exhaustion, Helplessness, Inner Void and Tedium (adj.R2 = 0.92) explained more HBI_sum variance than the three "core" components (adj.R2 = 0.85) of burnout combined. Cronbach's alpha for Emotional Exhaustion, Helplessness, Inner Void and Tedium combined was 0.90 compared to α = 0.54 for the combination of the three "core" components. CONCLUSIONS: This study demonstrates the overlap of burnout and major depression in terms of symptoms and the deficiency of the three-dimensional concept of burnout. In our opinion, it might be preferable to use multidimensional burnout inventories in combination with valid depression scales than to rely exclusively on MBI when clinically assessing burnout.

Clinical effects of electroconvulsive therapy in severe depression and concomitant changes in cerebral glucose metabolism--an exploratory study.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective mode of treatment--especially for severe depression and for depression refractory to pharmacotherapy, nevertheless the mode of action of ECT is far from being fully understood. This study assessed the effects of a series of ECT in depressive subjects on cerebral glucose metabolism measured by FDG-PET scans pre- and post-therapy in thus far the largest group of 12 patients. METHODS: Our analysis included careful repeated evaluation of clinical changes in mood and behaviour by standardised questionnaires, which allowed testing for a potential correlation between clinical and cerebral metabolic changes. PET scanning was done within a predefined time window and we used predefined ROIs with counts normalized to the pons activity. RESULTS: We observed few changes in cerebral glucose metabolism over time. There was a marginal increase in the left temporal and a trend for a decrease in left frontobasal areas subsequent to treatment in our sample. FDG uptake patterns remained remarkably stable in all the other predefined ROIs pre- and post-treatment. There were no significant correlations between changes in relative metabolic rates and changes in depression scores and parameters derived from neurocognitive testing. CONCLUSIONS: Our study thus cannot support the view that FDG-PET can assess the functional brain changes that are likely to occur subsequent to ECT in such a scenario, but this may be related to limited sensitivity given the sample size. Future studies thus might wish to challenge this notion in larger patient samples to clarify this issue.

Cloning, expression, and mapping of allergenic determinants of alphaS1-casein, a major cow's milk allergen.

Milk is one of the first components introduced into human diet. It also represents one of the first allergen sources, which induces IgE-mediated allergies in childhood ranging from gastrointestinal, skin, and respiratory manifestations to severe life-threatening manifestations, such as anaphylaxis. Here we isolated a cDNA coding for a major cow's milk allergen, alphaS1-casein, from a bovine mammary gland cDNA library with allergic patients' IgE Abs. Recombinant alphaS1-casein was expressed in Escherichia coli, purified, and characterized by circular dichroism as a folded protein. IgE epitopes of alphaS1-casein were determined with recombinant fragments and synthetic peptides spanning the alphaS1-casein sequence using microarrayed components and sera from 66 cow's milk-sensitized patients. The allergenic activity of ralphaS1-casein and the alphaS1-casein-derived peptides was determined using rat basophil leukemia cells transfected with human FcepsilonRI, which had been loaded with the patients' serum IgE. Our results demonstrate that ralphaS1-casein as well as alphaS1-casein-derived peptides exhibit IgE reactivity, but mainly the intact ralphaS1-casein induced strong basophil degranulation. These results suggest that primarily intact alphaS1-casein or larger IgE-reactive portions thereof are responsible for IgE-mediated symptoms of food allergy. Recombinant alphaS1-casein as well as alphaS1-casein-derived peptides may be used in clinical studies to further explore pathomechanisms of food allergy as well as for the development of new diagnostic and therapeutic strategies for milk allergy.

Mobile teledermatology: a feasibility study of 58 subjects using mobile phones.

We investigated the diagnostic agreement between teledermatology based on images from a mobile phone camera and face-to-face (FTF) dermatology. Diagnostic agreement was assessed for two teledermatologists (TD) in comparison with FTF consultations in 58 subjects. In almost three-quarters of the cases (TD1: 71%; TD2: 76%), the telediagnosis was fully concordant with the FTF diagnosis. Furthermore, the diagnosed diseases were almost all in the same diagnostic category (TD1: 97%; TD2: 90%). If mobile teledermatology had been used for remote triage, TD1 could have treated 53% subjects remotely and 47% subjects would have had to consult a dermatologist FTF. TD2 could have treated 59% subjects remotely, whereas 41% subjects would have had to consult a dermatologist FTF. Forty-eight subjects responded to a questionnaire, of whom only 10 had any concerns regarding teledermatology. Thirty-one subjects stated that they would be willing to pay to use a similar service in future and suggested an amount ranging from euro5 to euro50 per consultation (mean euro22) (euro = pound0.7, US $1.4). These results are encouraging as patient acceptance and reimbursement represent potential obstacles to the implementation of telemedicine services.

Melanoma screening with cellular phones.

BACKGROUND: Mobile teledermatology has recently been shown to be suitable for teledermatology despite limitations in image definition in preliminary studies. The unique aspect of mobile teledermatology is that this system represents a filtering or triage system, allowing a sensitive approach for the management of patients with emergent skin diseases. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigated the feasibility of teleconsultation using a new generation of cellular phones in pigmented skin lesions. 18 patients were selected consecutively in the Pigmented Skin Lesions Clinic of the Department of Dermatology, Medical University of Graz, Graz (Austria). Clinical and dermoscopic images were acquired using a Sony Ericsson with a built-in two-megapixel camera. Two teleconsultants reviewed the images on a specific web application (http://www.dermahandy.net/default.asp) where images had been uploaded in JPEG format. Compared to the face-to-face diagnoses, the two teleconsultants obtained a score of correct telediagnoses of 89% and of 91.5% reporting the clinical and dermoscopic images, respectively. CONCLUSIONS/SIGNIFICANCE: The present work is the first study performing mobile teledermoscopy using cellular phones. Mobile teledermatology has the potential to become an easy applicable tool for everyone and a new approach for enhanced self-monitoring for skin cancer screening in the spirit of the eHealth program of the European Commission Information for Society and Media.