Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study.

Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.

HyMoTrack: A Mobile AR Navigation System for Complex Indoor Environments.

Navigating in unknown big indoor environments with static 2D maps is a challenge, especially when time is a critical factor. In order to provide a mobile assistant, capable of supporting people while navigating in indoor locations, an accurate and reliable localization system is required in almost every corner of the building. We present a solution to this problem through a hybrid tracking system specifically designed for complex indoor spaces, which runs on mobile devices like smartphones or tablets. The developed algorithm only uses the available sensors built into standard mobile devices, especially the inertial sensors and the RGB camera. The combination of multiple optical tracking technologies, such as 2D natural features and features of more complex three-dimensional structures guarantees the robustness of the system. All processing is done locally and no network connection is needed. State-of-the-art indoor tracking approaches use mainly radio-frequency signals like Wi-Fi or Bluetooth for localizing a user. In contrast to these approaches, the main advantage of the developed system is the capability of delivering a continuous 3D position and orientation of the mobile device with centimeter accuracy. This makes it usable for localization and 3D augmentation purposes, e.g. navigation tasks or location-based information visualization.

SARS-CoV-2-related mortality and treatment delays for cancer patients in Austria : Findings of a multicentric nationwide study.

BACKGROUND: Cancer patients infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have an increased risk of mortality. Here, we investigated predictive factors for coronavirus disease 2019 (COVID-19) associated mortality in patients with neoplastic diseases treated throughout Austria. METHODS: In this multicentric nationwide cohort study, data on patients with active or previous malignant diseases and SARS-CoV­2 infections diagnosed between 13 March 2020 and 06 April 2021 were collected. Collected data included the stage of the malignant disease and outcome parameters 30 days after the diagnosis of SARS-CoV­2 infection. RESULTS: The cohort consisted of 230 individuals of which 75 (32.6%) patients were diagnosed with hematologic malignancies and 155 (67.4%) with solid tumors. At a median follow-up of 31 days after COVID-19 diagnosis, 38 (16.5%) patients had died due to COVID-19. Compared to survivors, patients who died were older (62.4 vs. 71.4 years, p < 0.001) and had a higher ECOG performance status (0.7 vs. 2.43, p < 0.001). Furthermore, higher neutrophil counts (64.9% vs. 73.8%, p = 0.03), lower lymphocyte counts (21.4% vs. 14%, p = 0.006) and lower albumin levels (32.5 g/l vs. 21.6 g/l, p < 0.001) were observed to be independent risk factors for adverse outcomes. No association between mortality and systemic antineoplastic therapy was found (p > 0.05). In 60.6% of the patients, therapy was postponed due to quarantine requirements or hospital admission. CONCLUSION: Mortality of Austrian cancer patients infected with SARS-CoV­2 is comparable to that of other countries. Furthermore, risk factors associated with higher mortality were evident and similar to the general population. Treatment delays were frequently observed.

Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma.

BACKGROUND: Bortezomib belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma. Preclinical studies suggest that bortezomib has synergistic activity with rituximab, which provides a rationale for the exploration of treatment combinations. DESIGN AND METHODS: The activity and safety of bortezomib in combination with rituximab and dexamethasone were investigated in patients with relapsed or chemotherapy-refractory mantle cell lymphoma. A treatment cycle consisted of bortezomib (1.3 mg/m² on days 1, 4, 8, and 11; six 21-day cycles), rituximab (375 mg/m², day 1) and dexamethasone (40 mg orally, days 1 to 4). Responding patients received four consolidating doses of rituximab. Sixteen patients with progressive mantle cell lymphoma after a median of three prior lines of therapy were enrolled. RESULTS: The overall response rate was 81.3% (13 patients), with seven patients achieving a complete response (43.8%). Six of these patients were also negative for disease activity by positron emission tomography scanning. The median progression-free survival and overall survival were 12.1 and 38.6 months, respectively. In patients achieving a complete response, the median progression-free survival and overall survival have not yet been reached. Adverse events (greater than grade II) included thrombocytopenia (37.5%), fatigue (18.8%) and peripheral neuropathy (12.5%). Two patients discontinued bortezomib because of grade III neuropathy. CONCLUSIONS: Bortezomib combined with rituximab and dexamethasone has promising activity and manageable toxicity in patients with heavily pretreated mantle cell lymphoma. Achievement of complete response emerged as an important factor for sustained disease control. This trial was registered at www.clinicaltrials.gov as #NCT00261612.

The VRNetzer platform enables interactive network analysis in Virtual Reality.

Networks provide a powerful representation of interacting components within complex systems, making them ideal for visually and analytically exploring big data. However, the size and complexity of many networks render static visualizations on typically-sized paper or screens impractical, resulting in proverbial 'hairballs'. Here, we introduce a Virtual Reality (VR) platform that overcomes these limitations by facilitating the thorough visual, and interactive, exploration of large networks. Our platform allows maximal customization and extendibility, through the import of custom code for data analysis, integration of external databases, and design of arbitrary user interface elements, among other features. As a proof of concept, we show how our platform can be used to interactively explore genome-scale molecular networks to identify genes associated with rare diseases and understand how they might contribute to disease development. Our platform represents a general purpose, VR-based data exploration platform for large and diverse data types by providing an interface that facilitates the interaction between human intuition and state-of-the-art analysis methods.

EarVR: Using Ear Haptics in Virtual Reality for Deaf and Hard-of-Hearing People.

Virtual Reality (VR) has a great potential to improve skills of Deaf and Hard-of-Hearing (DHH) people. Most VR applications and devices are designed for persons without hearing problems. Therefore, DHH persons have many limitations when using VR. Adding special features in a VR environment, such as subtitles, or haptic devices will help them. Previously, it was necessary to design a special VR environment for DHH persons. We introduce and evaluate a new prototype called "EarVR" that can be mounted on any desktop or mobile VR Head-Mounted Display (HMD). EarVR analyzes 3D sounds in a VR environment and locates the direction of the sound source that is closest to a user. It notifies the user about the sound direction using two vibro-motors placed on the user's ears. EarVR helps DHH persons to complete sound-based VR tasks in any VR application with 3D audio and a mute option for background music. Therefore, DHH persons can use all VR applications with 3D audio, not only those applications designed for them. Our user study shows that DHH participants were able to complete a simple VR task significantly faster with EarVR than without. The completion time of DHH participants was very close to participants without hearing problems. Also, it shows that DHH participants were able to finish a complex VR task with EarVR, while without it, they could not finish the task even once. Finally, our qualitative and quantitative evaluation among DHH participants indicates that they preferred to use EarVR and it encouraged them to use VR technology more.

Lymphoepithelial Carcinoma of Larynx and Hypopharynx: A Rare Clinicopathological Entity.

(1) Background: Lymphoepithelial carcinoma of the hypopharynx and larynx is a rare tumor with fewer than 50 cases in the published literature. We present a literature review to discuss the clinical findings, viral or genetic associations, diagnostic challenges, histopathological findings and therapeutic aspects of the disease. (2) Methods: A comprehensive literature review was performed through MEDLINE/PubMed from 1968 to 2018. We identified 21 studies comprising 46 patients. Data on all the clinicopathological features, diagnostic modalities, treatment options and viral or genetic etiology were extracted and analyzed using SPSS. (3) Results: The mean age of presentation was 64 years (range 40-82 years) and mostly involved males. The supraglottis and pyriform sinus were the most commonly involved sub-sites, with surgery as the preferred treatment modality. The presence of the Epstein-Barr virus possibly directs a viral etiology. The incidence of cervical and distant metastasis was 54% and 21%, respectively. The median survival time was 30 months. (4) Conclusions: Lymphoepithelial carcinoma of the hypopharynx is an aggressive tumor with a strong predilection for regional and distant metastasis. Surgery, in combination with adjuvant therapy, provides promising results. Immunohistochemistry helps in differentiating LEC from other pathologies.

Playmancer project: a serious videogame as an additional therapy tool for eating and impulse control disorders.

Reviews and few non-controlled studies showed the effectiveness of several specific designed computer video-games as an additional form of treatment in several areas. However, there is a lack in the literature of specially designed serious-games for treating mental disorders. Playmancer (ICT European initiative) aims to develop and assess a serious videogame that may help to treat underlying processes (e.g. lack of self-control strategies) in Eating and Impulse control disorders. Preliminary data will be shown.

Warning: subtle aspects of strategy assessment may affect correlations among spatial tests.

In this study, preliminary to a larger experiment, 42 participants completed four different spatial tests and, after each test, a strategy questionnaire. For half of the participants, visualizational strategies were presented first in this questionnaire, and for the other half, analytical strategies. The order of strategy descriptions had effects on the strategies reported and on the intercorrelations among the spatial tests and between the spatial tests and an inductive-reasoning test. In the group first presented with visualizational strategies, intercorrelations among the spatial tests were higher and correlations with the reasoning test were lower than in the group first presented with analytical strategies. Bootstrap analyses with 100 random splits of the sample confirmed this result. The findings are interpreted as indications of a priming effect by the strategy descriptions which affected the way participants dealt with subsequent tests. Implications for strategy assessment are discussed.

Compressing VR: Fitting Large Virtual Environments within Limited Physical Space.

In practice, real-world physical workspaces and technological limitations restrict the free and unlimited exploration of an arbitrary large-scale virtual environment. This article provides an overview of the existing approaches and techniques for enlarging the walkable virtual space. The authors specifically focus on the methods that use spatial manipulation for spatial compression because it is one of the most promising, but underexplored methods for nonintrusive user redirection in a limited physical space.

Low p27Kip1 expression is an independent adverse prognostic factor in patients with multiple myeloma.

PURPOSE: To determine the clinical relevance of p27(Kip1) in multiple myeloma (MM), we examined the relationship between p27(Kip1) expression at diagnosis and clinical as well as laboratory parameters, including response to chemotherapy and overall survival in 74 previously untreated patients with MM. EXPERIMENTAL DESIGN: Expression of p27(Kip1) was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded bone marrow biopsies. p27(Kip1) expression was classified as low (5% p27(Kip1)-positive myeloma cells). RESULTS: Low p27(Kip1) expression was observed in 23 (31%) patients. The response rate to standard dose chemotherapy (including vincristine, doxorubicin, and dexamethasone induction before high-dose chemotherapy) was 70%, with no significant difference between patients with low or high p27(Kip1) expression (83 versus 65%; P = 0.1). Kaplan-Meier analysis of all 74 patients revealed that patients with low p27(Kip1) expression had a significantly shorter overall survival (median, 3.7 years versus 4.7 years; P = 0.03) than those with high p27(Kip1) expression. Patients with high p27(Kip1) expression receiving high-dose chemotherapy experienced prolonged overall survival as compared with those with low p27(Kip1) expression (median not yet reached versus 2.9 years; P = 0.008). By multivariate Cox regression analyses, low p27(Kip1)(P = 0.03), deletion of chromosome 13q14 (P = 0.02), and beta(2)-microglobulin (P = 0.01) were identified as independent adverse prognostic factors for overall survival. According to the number of independent unfavorable prognostic factors present in each patient, low-risk, intermediate-risk, and high-risk patients with different overall survival times were defined (median overall survival, 6.3 versus 4.2 versus 1.8 years; P < 0.001). CONCLUSIONS: Low p27(Kip1) expression is an independent adverse prognostic factor in patients with MM. The proposed risk score might be useful for risk-adapted treatment in the future.

A Serious Exergame for Patients Suffering from Chronic Musculoskeletal Back and Neck Pain: A Pilot Study.

INTRODUCTION: Over recent years, the popularity of videogames has gone beyond youth and gamers and is slowly entering the field of professional healthcare. Exergames are an attractive alternative to physical therapy. The primary aim of this pilot study was to explore the user experience (usability, satisfaction, level of motivation, and game experience) of the patient with the "PlayMancer" exergame. The secondary aim was to explore the progression of the performed motor skills (walking velocity, overhead reach ability, and cervical range of motion) and the clinical changes (to physical condition, disability, and pain intensity) in a group of patients with chronic musculoskeletal pain using an exergame for 4 weeks. MATERIALS AND METHODS: In the European PlayMancer project, an exergame for physical rehabilitation of chronic pain patients was developed. This exergame is controlled by relevant motions of the patient's body captured by a motion suit and several infrared cameras. In three different integrated minigames, the patient can train the following motor skills: Walking velocity, overhead reaching, and neck mobility. RESULTS: Ten patients participated in this study and completed the 4 weeks of gaming. Patients rated the usability of the exergames as good (score of 78.5 [standard deviation 9.7; range, 60.0-97.5]) on the System Usability Scale, and the game motivated all patients to perform their exercises. Patients enjoyed playing and were pleased with both the game environment and the game play. Overall, the patients made a progression in the examined motor skills during the minigames over the 4 weeks of gaming. CONCLUSIONS: The "PlayMancer" exergame is a potential tool for achieving physical rehabilitation because it motivates patients to perform their exercises and as a result increases their motor skills and physical condition.

Treatment of mantle cell lymphoma: targeting the microenvironment.

Mantle cell lymphoma is a distinct entity among the non-Hodgkin's lymphomas characterized by a specific chromosomal translocation, the t(11;14)(q13;q32), overexpression of cyclin-D1 and frequent disease manifestations at extranodal sites. Mantle cell lymphoma remains difficult to treat and belongs to the lymphomas with the poorest long-term outcome. Recent advances in our understanding of lymphoma biology suggest that both alterations of the lymphoma cells themselves and interactions with the microenvironment are important for the growth and survival of the malignant B-cell clone. This novel approach to therapy is being exploited by evaluating drugs such as bortezomib and thalidomide that target interactions between tumor cells and cells of the microenvironment. Thus, with the use of novel therapeutic interventions, it is hoped that clinicians will be able to improve the outcome of patients with mantle cell lymphoma.

Effective treatment of indolent non-hodgkin's lymphomas with mitoxantrone, chlorambucil and prednisone.

UNLABELLED: Since indolent non-Hodgkin's lymphomas (NHL) represent about 35% of all malignant lymphomas and mainly affect elderly patients, availability of a conventional chemotherapy regimen with high efficacy and low toxicity is of clinical importance. PATIENTS AND METHODS: We retrospectively analysed 13 patients with advanced indolent NHL who were treated with 6-9 cycles of MCP: mitoxantrone 8 mg/m2 (days 1 and 2), chlorambucil 3 x 3 mg/m2 (days 1-5) and prednisone 25 mg (days 1-5) every 4 weeks. RESULTS: The overall response was 84% (61% complete response, 23% partial response), 1 patient had stable disease and 1 patient experienced progressive disease. Median time to progression was 37 months (95% CI: 20-53) and the median survival has not yet been reached. The main toxicity (66%) was neutropenia (WHO grade III). There was no hair loss and no cardial or neurologic adverse event. CONCLUSION: In summary, MCP is an effective and well tolerated chemotherapy regimen and is probably an alternative to the more toxic CHOP regimen, especially in older patients.

New insights into the pathophysiology of multiple myeloma.

For understanding of the pathophysiology of multiple myeloma, features of the malignant clone and changes induced by the bone-marrow microenvironment are equally important. Multiple myeloma plasma cells, which originate from postfollicular B cells, are characterised by complex chromosomal aberrations. Among the earliest genetic events are translocations of the immunoglobulin heavy-chain gene locus, which leads to dysregulation of oncogenes at translocation partner regions (cyclin D1 at 11q13, FGFR3/MMSET at 4p16.3, c-MAF at 16q23, and cyclin D3 at 6p21), and deletions of 13q14, the site of a putative tumour suppressor gene, which is an adverse prognostic indicator. Additional molecular events include epigenetic changes and activation of oncogenes (mutations of N-RAS and K-RAS, and changes in c-MYC), which are usually associated with disease progression. Bone-marrow stromal cells support growth and survival of multiple myeloma cells via various cytokines. Osteoclast activity factors (in particular MIP1alpha) and imbalances between RANKL and osteoprotegerin are major factors for the development of myeloma bone disease. Further characterisation of crucial events in the development of monoclonal gammopathies by novel techniques such as global gene expression profiling will contribute to a molecular classification of multiple myeloma and foster future therapeutic approaches.

DNA-methylation analysis identifies the E-cadherin gene as a potential marker of disease progression in patients with monoclonal gammopathies.

BACKGROUND: Silencing of tumor suppressor genes (TSG) by aberrant methylation (referred to as methylation) contributes to the pathogenesis of various human malignancies. However, little is known about the methylation of known and putative TSGs in monoclonal gammopathies. Thus, the authors investigated the methylation frequencies of 10 genes in patients with monoclonal gammopathies. METHODS: The methylation patterns of the genes p16(INK4a) (p16), tissue inhibitor of metalloproteinase 3 (TIMP3), p15(INK4b) (p15), E-cadherin (ECAD), death-associated protein kinase (DAPK), p73, RAS-association domain family 1A (RASSF1A), p14, O(6)-methylguanine DNA methyltransferase (MGMT), and retinoid acid receptor beta2 (RARbeta) were determined in patients with monoclonal gammopathy of undetermined significance (MGUS; n = 29), smoldering multiple myeloma (SMM; n = 5), multiple myeloma (MM; n = 113), or plasma cell leukemia (PCL; n = 7) by methylation-specific polymerase chain reaction analysis. RESULTS: Methylation frequencies for p16, TIMP3, p15, ECAD, DAPK, p73, RASSF1A, p14, MGMT, and RARbeta were as follows: 28%, 35%, 10%, 0%, 17%, 21%, 14%, 14%, 7%, and 0%, respectively, in patients with MGUS and 36%, 29%, 27%, 27%, 22%, 15%, 15%, 9%, 4%, and 0%, respectively, in patients with MM. Methylation of at least 1 of these genes was detected in 79% of patients with MGUS and in 80% of patients with MM. Although methylation of ECAD was not detected in patients with MGUS, it was observed frequently in patients with MM and with even greater frequency in patients with PCL. It is noteworthy that an association was found between ECAD methylation and poor prognostic markers in patients with MM. CONCLUSIONS: Methylation of certain genes can be detected frequently in patients with monoclonal gammopathies. The current data suggest that methylation of ECAD is a marker of disease progression in patients with MM and PCL.

Both chromosome 13 abnormalities by metaphase cytogenetics and deletion of 13q by interphase FISH only are prognostically relevant in multiple myeloma.

OBJECTIVES: Deletion of chromosome 13q [del(13q)] has emerged as a major adverse prognostic factor in multiple myeloma (MM). Del(13q) is detected two to three times more frequently by interphase fluorescence in situ hybridization (FISH) than by metaphase cytogenetics (CG). However, it has remained unclear whether or not del(13q) detected by FISH only provides the same prognostic information as its detection by CG. METHODS: We investigated the outcome of 118 consecutive patients with newly diagnosed MM who were studied by both CG and FISH (RB-1 and/or D13S319 probes). RESULTS: CG revealed informative MM karyotypes in 35 patients (29.7%), with monosomy 13/del(13q) in 16 of them. FISH was indicative for a del(13q) in 43 patients (36.4%). A del(13q) by FISH was present in all 16 patients with monosomy 13/del(13q) by CG and also in four of 19 patients with informative karyotypes and diploid chromosome 13. Furthermore, del(13q) was present by FISH in 23 of 84 patients with diploid/non-informative metaphases by CG. Overall survival of patients with monosomy 13/del(13q) by CG and of patients with del(13q) by FISH only was not significantly different (median, 35.2 months vs. 33.2 months, P = 0.58). In contrast, patients with diploid chromosome 13 by either technique experienced prolonged survival (median, 65.6 months). Presence of abnormal karyotypes was significantly associated with an increased Ki67 growth fraction. CONCLUSION: FISH of chromosome 13q adds prognostic information to that provided by CG. It is suggested to use FISH analysis in clinical trials if risk stratifications take into consideration the chromosome 13q status.

Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma.

We evaluated a treatment strategy targeting both lymphoma cells (by rituximab) and the microenvironment (by thalidomide) in 16 patients with relapsed/refractory mantle cell lymphoma (MCL). Rituximab was administered at 375 mg/m(2) for 4 weekly doses concomitantly with thalidomide (200 mg daily, with a dose increment to 400 mg on day 15), which was continued as maintenance therapy until progression/relapse. Thirteen patients (81%) experienced an objective response, with 5 complete responders (31%). Median progression-free survival (PFS) was 20.4 months (95% confidence interval [CI], 17.3-23.6 months), and estimated 3-year survival was 75%. In patients achieving a complete response, PFS after rituximab plus thalidomide was longer than PFS after the preceding chemotherapy. Severe adverse events included 2 thromboembolic events and 1 grade IV neutropenia associated with thalidomide. Our results suggest that rituximab plus thalidomide has marked antitumor activity in relapsed/refractory MCL and a low toxicity profile, which warrants further evaluation in MCL.

Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation.

OBJECTIVES: Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem cell transplantation in the context of beta(2) microglobulin and chromosome 13q. METHODS: All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. RESULTS: There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5-128) nine patients (70%) are still alive, and six of them have remained progression free. Among five patients with low beta(2) microglobulin and normal chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated ss(2) microglobulin and/or deletion of chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. CONCLUSIONS: Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.