A challenge to lepton universality in B-meson decays.

One of the key assumptions of the standard model of particle physics is that the interactions of the charged leptons, namely electrons, muons and taus, differ only because of their different masses. Whereas precision tests comparing processes involving electrons and muons have not revealed any definite violation of this assumption, recent studies of B-meson decays involving the higher-mass tau lepton have resulted in observations that challenge lepton universality at the level of four standard deviations. A confirmation of these results would point to new particles or interactions, and could have profound implications for our understanding of particle physics.

Sorafenib in advanced, heavily pretreated patients with soft tissue sarcomas.

Therapeutic options for patients with advanced pretreated soft tissue sarcomas are limited. However, in this setting, sorafenib has shown promising results. We reviewed the data of 33 patients with soft tissue sarcoma treated with sorafenib within a named patient program in Austria. Twelve physicians from eight different hospitals provided records for the analysis of data. Among the 33 patients, the predominant histological subtype of sarcoma was leiomyosarcoma (n=18, 55%). Other subtypes were represented by only one or two cases. Fifteen patients presented with metastases at the time of diagnosis. Another 17 patients developed metastases later in the course of the disease (data on one patient are missing). Most of the 33 patients had undergone resection of the primary (n=29, 88%) and half of the patients had received radiotherapy (n=17, 52%). Chemotherapy for metastatic disease had been administered to 30 patients (91%). The majority had received two or more regimens of chemotherapy (n=25, 76%) before sorafenib treatment. The use of sorafenib resulted in a median time to treatment failure of 92 days in patients with leiomyosarcoma and 45 days in patients with other histological subtypes. One-third of the patients derived benefits from treatment: four patients were documented with partial response and six with stabilized disease. In terms of treatment-related toxicity, skin problems of various degrees and gastrointestinal disturbances were frequently reported. In this retrospective analysis of heavily pretreated patients with advanced soft tissue sarcomas, sorafenib was associated with some antitumor activity and an acceptable toxicity profile.

Ultra-high-granularity detector simulation with intra-event aware generative adversarial network and self-supervised relational reasoning.

Simulating high-resolution detector responses is a computationally intensive process that has long been challenging in Particle Physics. Despite the ability of generative models to streamline it, full ultra-high-granularity detector simulation still proves to be difficult as it contains correlated and fine-grained information. To overcome these limitations, we propose Intra-Event Aware Generative Adversarial Network (IEA-GAN). IEA-GAN presents a Transformer-based Relational Reasoning Module that approximates an event in detector simulation, generating contextualized high-resolution full detector responses with a proper relational inductive bias. IEA-GAN also introduces a Self-Supervised intra-event aware loss and Uniformity loss, significantly enhancing sample fidelity and diversity. We demonstrate IEA-GAN's application in generating sensor-dependent images for the ultra-high-granularity Pixel Vertex Detector (PXD), with more than 7.5 M information channels at the Belle II Experiment. Applications of this work span from Foundation Models for high-granularity detector simulation, such as at the HL-LHC (High Luminosity LHC), to simulation-based inference and fine-grained density estimation.

Gastrointestinal stromal tumors: diagnosis, therapy and follow-up care in Austria.

Optimal treatment for patients suffering from gastrointestinal stromal tumors (GIST) is based on an interdisciplinary treatment approach. Austrian representatives of Medical and Surgical Oncology, Pathology, Radiology, Nuclear Medicine, Gastroenterology, and Laboratory Medicine issued this manuscript on a consensual base within the context of currently available and published literature. This paper contains guidelines and recommendations for diagnosis, therapy, and follow-up of GIST patients in Austria.

Ongoing complete response after treatment cessation with dabrafenib, trametinib, and cetuximab as third-line treatment in a patient with advanced BRAFV600E mutated, microsatellite-stable colon cancer: A case report and literature review.

Metastatic BRAFV600E mutated colorectal cancer is associated with poor overall survival and modest effectiveness to standard therapies. Furthermore, survival is influenced by the microsatellite status. Patients with microsatellite-stable and BRAFV600E mutated colorectal cancer have the worst prognosis under the wide range of genetic subgroups in colorectal cancer. Herein, we present a patient case of an impressive therapeutic efficacy of dabrafenib, trametinib, and cetuximab as later-line therapy in a 52-year-old woman with advanced BRAFV600E mutated, microsatellite-stable colon cancer. This patient achieved a complete response after 1 year of triple therapy. Due to skin toxicity grade 3 and recurrent urinary tract infections due to mucosal toxicity, a therapy de-escalation to dabrafenib and trametinib was performed, and the double therapy was administered for further 41 months with ongoing complete response. For 1 year, the patient was off therapy and is still in complete remission.

[GIST: adjuvant treatment in Austria]. / Gastrointestinale Stromatumore: adjuvante Behandlung in Osterreich.

Adjuvant treatment of gastrointestinal stromal tumor (GIST) patients with Imatinib (400 mg/d) is associated with a statistically significant improvement of relapse-free survival. Risk of relapse has been determined according to Fletcher [8] in the majority of the mentioned trials. However, classification according to Miettinen [9] and Joensuu [10] plus consideration of mutational status might be more accurate. Based upon currently available data, the Austrian GIST-Panel recommends adjuvant treatment with 400 mg Imatinib/day for 1 year for KIT positive GIST patients with a high or moderate risk of relapse (according to Joensuu) [10] following complete resection of the primary tumor.

[Gastrointestinal stromal tumors: recommendations for diagnosis, treatment and aftercare in Austria]. / Klinische Empfehlungen. Gastrointestinale Stromatumore: Empfehlungen zu Diagnose, Behandlung und Nachsorge in Osterreich.

Diagnosis and treatment of gastrointestinal stromal tumors (GIST) requires an interdisciplinary treatment approach. This strategy should be reflected by the content of this article. Austrian representatives of 'GIST relevant' specialties authored this publication on a consensual base. This manuscript should be regarded as a guideline for 'GIST involved' colleagues in Austria.

Treatment Algorithm for Patients With Gastric Adenocarcinoma: An Austrian Consensus on Systemic Therapy.

Despite recent advances in the treatment of gastric cancer, mortality related to this disease is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Targeted treatments that include anti-angiogenic agents and the advent of immunotherapies can contribute to improved patient prognosis. Herein, we present an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and lower gastroesophageal junction, including those with human epidermal growth factor receptor 2 (HER2)-positive disease. The consensus considers the curative setting, as well as first-line to late-line systemic treatment options in the palliative setting. For HER2-positive disease, first-line and second-line therapies are discussed, as well as HER2 testing. Potential future therapies are also listed, with a focus on anti-angiogenic treatments and checkpoint inhibition, that might provide a further step forward in the management of patients with gastric cancer.

p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder.

We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRbeta fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRbeta. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRbeta, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.

CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia.

OBJECTIVE: Expression of the catalytic subunit of the telomerase enzyme hTERT is essential for prolonging the replicative lifespan and is the rate-limiting step in cellular immortalization and carcinogenesis. Because hTERT expression is positively correlated with telomerase activity, its regulation is suggested as the major determinant of enzymatic activity. The hTERT promoter region contains two CpG islands, which are known to be target sites for de novo DNA methylation. To elucidate the impact of this epigenetic mechanism on telomerase activity, we analyzed the degree of hTERT promoter methylation in 30 patients with B-cell chronic lymphocytic leukemia. MATERIALS AND METHODS: hTERT promoter methylation was assessed using a methylation-specific competitive polymerase chain reaction assay. The assay is based on digestion of genomic DNA with a methylation-sensitive restriction enzyme before amplification with an internal standard. RESULTS: Patients exhibiting high telomerase activity showed significantly less methylation of the hTERT promoter core domain than patients with low enzyme activity. In addition, telomerase activity was significantly associated with telomere length and overall survival. CONCLUSIONS: Our data show that the degree of CpG island methylation of the hTERT promoter exhibits an impact on telomerase activity in a subgroup of patients with B-cell chronic lymphocytic leukemia and therefore is assumed to play a role in regulating hTERT gene expression in these patients.

Automated real-time PCR to determine K-ras codon 12 mutations in non-small cell lung cancer: comparison with immunohistochemistry and clinico-pathological features.

A real-time PCR technique with automated computerized analysis (TaqMan ) was tested to detect K-ras mutations in 66 patients suffering from NSCLC. This technology is characterized by high reproducibility of data and a time-saving analysis procedure. In 11% (7/66) of the tumour specimens and 2% (1/58) of adjacent tumour-free lung specimens a K-ras codon 12 mutation was detected. In adenocarcinomas containing > or =40% tumour cells, however, K-ras mutations were seen in 25% of the cases. The point mutations detected in tumours were GGT right curved arrow TGT in five cases and GGT right curved arrow GTT in two cases. As compared with immunohistochemical parameters, the K-ras mutated group was characterized by a c-erbB-2 negativity (p=0.04) and a smaller number of c-erbB-3 (p=0.02) positive cases. EGFR, bcl-2, p53, Ki-67 and p120 expression did not differ significantly. Determination of the K-ras point mutations by automated TaqMan PCR in NSCLC tumour specimens is feasable and highly specific. Due to its high throughput capacity this method represents a valuable tool for routine screening.

Experience with lenalidomide in an Austrian non-study population with advanced myelofibrosis.

Current literature provides conflicting evidence regarding the efficacy of lenalidomide in patients with myelofibrosis (MF). The aim of this work was to evaluate the efficacy of lenalidomide in patients with MF treated within a named patient program in Austria. A total of 22 patients with MF were treated with lenalidomide in 7 different centres throughout Austria. Median age of patients was 68 years. Primary MF was present in 13 patients. Eight patients had post-polycythemia vera (post-PV) and 1 post-essential thrombocythemia (post-ET) MF. According to the Dynamic International Prognostic Scoring System (DIPSS), all patients were scored within the intermediate-2 or high-risk group. Approximately one-third of patients were treated with 2 or more prior therapies. The overall response rate according to International Working Group (IWG) criteria was 12.5 %. Efficacy of lenalidomide was moderate in this non-study patient population. Limiting factors seemed to be stage of disease and risk profile of patients included in this analysis.

Gastrointestinal stromal tumors: Recommendations on diagnosis, therapy and follow-up care in Austria.

Adequate treatment of gastrointestinal stromal tumors (GISTs) is linked to an interdisciplinary treatment approach. Austrian representatives of medical oncology, surgery, pathology, radiology and gastroenterology have issued this consensus manuscript within the context of currently available and published literature. The paper contains guidelines and recommendations for diagnosis, therapy and follow-up of GIST patients in Austria.