Uterine Artery Embolization Versus Hysterectomy in Postpartum Hemorrhage: A Systematic Review With Meta-Analysis.

PURPOSE: The objective of this study is to perform a meta-analysis comparing the effectiveness of uterine artery embolization (UAE) versus peripartum hysterectomy for acute refractory postpartum hemorrhage (PPH) control. MATERIALS AND METHODS: We systematically searched 6 medical databases for studies comparing UAE and hysterectomy in PPH. Outcomes examined were mortality, hospitalization duration (HD) in days, and red blood cells (RBC) units utilization. Statistical analysis used RevMan 5.1.7 and random-effects models. Odds ratios (OR) and mean differences (MDs) with 95% confidence intervals (CIs) were used for dichotomous and continuous outcomes, respectively. RESULTS: We included 833 patients from 4 cohort studies, with 583 (70%) undergoing UAE. The UAE population required fewer RBC units (MD: -7.39; 95% CI: -14.73 to -0.04; p=0.05) and had shorter HD (MD: -3.22; 95% CI: -5.42 to -1.02; p=0.004). Lower mortality rates were noted for UAE in the pooled analysis, but no statistical significance. Uterine artery embolization demonstrated lower procedural complications (16.45% vs. 28.8%), in which UAE had less ureter and bladder lesions (OR: 0.05; 95% CI: 0.01-0.38; p=0.004 and OR: 0.02; 95% CI: 0.00-0.15; p<0.001, respectively). Only 35 (6%) required conversion to hysterectomy, while 27 (4.6%) underwent re-embolization with 100% bleeding control. Uterine artery embolization did not hinder fertility, with normal menstruation restored in 19 patients with postoligomenorrhea. CONCLUSION: Uterine artery embolization for the control of PPH is associated with lower use of RBC units and HD, but similar rates of mortality are noted when compared to hysterectomy. These results associated with uterine preservation could support its importance for refractory PPH management. CLINICAL IMPACT: Uterine Artery Embolization is associated with a shorter hospitalization duration and reduced use of red blood cell units when compared with hysterectomy in refractory postpartum hemorrhage. Although demonstrating similar mortality rates, these findings, together with fertility preservation, support the method incorporation as a valuable option in obstetric services.

[The collaborative project "Personalized medicine for oncology" (PM4Onco) as part of the Medical Informatics Initiative (MII)]. / Das Verbundprojekt "Personalisierte Medizin für die Onkologie" (PM4Onco) als Teil der Medizininformatik-Initiative (MII).

The collaborative project Personalized Medicine for Oncology (PM4Onco) was launched in 2023 as part of the National Decade against Cancer (NKD) and is executed within the Medical Informatics Initiative (MII). Its aim is to establish a sustainable infrastructure for the integration and use of data from clinical and biomedical research and therefore combines the experience and preliminary work of all four consortia of the MII and the leading oncology centers in Germany. The data provided by PM4Onco will be prepared in a suitable form to support decision making in molecular tumor boards. This concept and infrastructure will be extended to 23 participating partner sites and thus improve access to targeted therapies based on clinical information and analysis of molecular genetic alterations in tumors at different stages of the disease. This will help to improve the treatment and prognosis of tumor diseases.Clinical cancer registries are involved in the project to improve data quality through standardized documentation routines. Clinical experts advise on the expansion of the core datasets for personalized medicine (PM). Information on quality of life and treatment outcomes reported by patients in questionnaires, which is rarely collected outside of clinical trials, will make a significant contribution. Patient representatives are involved from the onset to ensure that the important perspective of patients is taken into account in the decision-making process. PM4Onco thus creates an alliance between the MII, oncological centers of excellence, clinical cancer registries, young scientists, patients, and citizens to strengthen and advance PM in cancer therapy.

Primary results of patients with genitourinary malignancies presented at a Molecular Tumor Board.

PURPOSE: Personalized medicine poses great opportunities and challenges. While therapeutic landscape markedly expands, descriptions about status, clinical implementation and real-world benefits of precision oncology and molecular tumor boards (MTB) remain sparse, particularly in the field of genitourinary (GU) cancer. Hence, this study characterized urological MTB cases to better understand the potential role of MTB in uro-oncology. METHODS: We analyzed patients with complete data sets being reviewed at an MTB from January 2019 to October 2022, focusing on results of molecular analysis and treatment recommendations. RESULTS: We evaluated 102 patients with GU cancer with a mean patient age of 61.7 years. Prostate cancer (PCa) was the most frequent entity with 52.9% (54/102), followed by bladder cancer (18.6%, 19/102) and renal cell carcinoma (14.7%, 15/102). On average, case presentation at MTB took place 54.9 months after initial diagnosis and after 2.7 previous lines of therapy. During the study period 49.0% (50/102) of patients deceased. Additional MTB-based treatment recommendations were achieved in a majority of 68.6% (70/102) of patients, with a recommendation for targeted therapy in 64.3% (45/70) of these patients. Only 6.7% (3/45) of patients - due to different reasons - received the recommended MTB-based therapy tough, with 33% (1/3) of patients reaching disease control. Throughout the MTB study period, GU cancer case presentations and treatment recommendations increased, while the time interval between initial presentation and final therapy recommendation were decreasing over time. CONCLUSION: Presentation of uro-oncological patients at the MTB is a highly valuable measure for clinical decision-making. Prospectively, earlier presentation of patients at the MTB and changing legislative issues regarding comprehensive molecular testing and targeted treatment approval might further improve patients' benefits from comprehensive molecular diagnostics.

Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia: Genetic evidence of driver function and implications for diagnostic workup.

Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1.

Extending cBioPortal for Therapy Recommendation Documentation in Molecular Tumor Boards: Development and Usability Study.

BACKGROUND: In molecular tumor boards (MTBs), patients with rare or advanced cancers are discussed by a multidisciplinary team of health care professionals. Software support for MTBs is lacking; in particular, tools for preparing and documenting MTB therapy recommendations need to be developed. OBJECTIVE: We aimed to implement an extension to cBioPortal to provide a tool for the documentation of therapy recommendations from MTB sessions in a secure and standardized manner. The developed extension should be embedded in the patient view of cBioPortal to enable easy documentation during MTB sessions. The resulting architecture for storing therapy recommendations should be integrable into various hospital information systems. METHODS: On the basis of a requirements analysis and technology analysis for authentication techniques, a prototype was developed and iteratively refined through a user-centered development process. In conclusion, the tool was evaluated via a usability evaluation, including interviews, structured questionnaires, and the System Usability Scale. RESULTS: The patient view of cBioPortal was extended with a new tab that enables users to document MTB sessions and therapy recommendations. The role-based access control was expanded to allow for a finer distinction among the rights to view, edit, and delete data. The usability evaluation showed overall good usability and a System Usability Scale score of 83.57. CONCLUSIONS: This study demonstrates how cBioPortal can be extended to not only visualize MTB patient data but also be used as a documentation platform for therapy recommendations.

Management of traumatic superficial palmar arch pseudoaneurysm: a therapeutic challenge.

Pseudoaneurysm of the palmar arch is a rare entity. Diagnosis is dependent on high clinical suspicion. We present a case referred to the emergency department, with a history of glass penetrating trauma to the palmar surface with a pulsatile mass and jet bleeding. Doppler ultrasound evidenced a partially thrombosed pseudoaneurysm. A CT angiography examination showed a saccular formation arising from the superficial palmar arch. A conventional surgical approach was indicated. A clinical suspicion must be ventured to arrive at the correct diagnosis. Imaging modalities are needed to identify the pseudoaneurysm and plan the treatment course. Nonetheless, the sequence of diagnosis is individual, because further evaluation with different imaging methods may not change the rationale for the intervention. In our experience, conventional surgical removal is preferable, due to its safety and well-established outcomes.

O pseudoaneurisma do arco palmar é uma entidade rara, cujo diagnóstico depende de alta suspeição clínica. Apresentamos o caso de um paciente encaminhado ao pronto-socorro com história de traumatismo penetrante por vidro na face palmar, com massa pulsátil e sangramento em jato. A ultrassonografia com Doppler evidenciou pseudoaneurisma parcialmente trombosado, e a angiotomografia demonstrou formação sacular originada do arco palmar superficial. Uma abordagem cirúrgica convencional foi indicada. Para prosseguir com o diagnóstico correto, essa suspeita clínica deve ser aventada. Modalidades de imagem são necessárias para identificar o pseudoaneurisma e planejar o curso do tratamento. No entanto, a sequência diagnóstica é individual, pois uma avaliação mais aprofundada, com diferentes métodos de imagem, pode não alterar o racional da intervenção. Em nossa experiência, a remoção cirúrgica convencional é preferível, visto sua segurança e seus resultados bem estabelecidos.

Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients.

A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions. Tumor and matched normal DNA from 30 patients were analyzed using custom sequencing protocols and bioinformatic pipelines. Calling of somatic variants was highly concordant with a positive percentage agreement (PPA) between 91 and 95% and a positive predictive value (PPV) between 82 and 95% compared with a three-institution consensus and full agreement for 16 of 17 druggable targets. Explanations for deviations included low VAF or coverage, differing annotations, and different filter protocols. CNAs showed overall agreement in 76% for the genomic sequence with high wet-lab variability. Complex biomarkers correlated strongly between institutions (HRD: 0.79-1, TMB: 0.97-0.99) and all institutions agreed on microsatellite instability. This study will contribute to the development of quality control frameworks for comprehensive genomic profiling and sheds light onto parameters that require stringent standardization.

MIRACUM-Pipe: An Adaptable Pipeline for Next-Generation Sequencing Analysis, Reporting, and Visualization for Clinical Decision Making.

(1) Background: Next-generation sequencing (NGS) of patients with advanced tumors is becoming an established method in Molecular Tumor Boards. However, somatic variant detection, interpretation, and report generation, require in-depth knowledge of both bioinformatics and oncology. (2) Methods: MIRACUM-Pipe combines many individual tools into a seamless workflow for comprehensive analyses and annotation of NGS data including quality control, alignment, variant calling, copy number variation estimation, evaluation of complex biomarkers, and RNA fusion detection. (3) Results: MIRACUM-Pipe offers an easy-to-use, one-prompt standardized solution to analyze NGS data, including quality control, variant calling, copy number estimation, annotation, visualization, and report generation. (4) Conclusions: MIRACUM-Pipe, a versatile pipeline for NGS, can be customized according to bioinformatics and clinical needs and to support clinical decision-making with visual processing and interactive reporting.

Association between the degree of iliac venous outflow obstruction by intravascular ultrasound and lower limb venous reflux.

OBJECTIVE: The present study aims to evaluate the association between the degree of iliac venous outflow obstruction (IVOO) identified by intravascular ultrasound (IVUS) and venous reflux presentation in the lower limbs on duplex ultrasound (DU). METHODS: Patients with bilateral chronic venous insufficiency, CEAP (clinical-etiology-anatomy-pathophysiology) C3 to C6, and a visual analog scale score for pain >5 underwent DU for reflux evaluation of the deep venous system (reflux ≥1 second); superficial system, great saphenous vein, and small saphenous vein (reflux ≥0.5 second); and perforator system (reflux ≥0.35 second). All patients underwent IVUS in the iliac venous territory. The area of the impaired venous segments was categorized as obstruction <50% (category 1), 50% to 79% (category 2), and ≥80% (category 3). The venous clinical severity score and reflux multisegment score (RMS) were assessed. RESULTS: A total of 51 patients (n = 102 limbs; age, 50.53 ± 14.5 years; 6 men) were included. The predominant clinical severity CEAP class was C3 in 54 of 102 limbs (52.9%). The mean VCSS was 14.3 ± 6.7. A severe RMS (≥3) was registered in 63.4% of the limbs. Of the 102 limbs, 51 (50%) presented with category 1, 27 (26.5%) with category 2, and 24 (23.5%) with category 3. Previous deep vein thrombosis (DVT) was associated with critical obstruction (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.29-10.38; P = .015). The superficial and perforator venous systems had no association with the degree of IVOO. Deep venous reflux (DVR) had a significant association with significant IVOO (obstruction ≥50%; OR, 6.44; 95% CI, 2.19-18.93; P = .001) and critical IVOO (obstruction ≥80%; OR, 4.57; 95% CI, 1.70-12.27; P = .003) and a significant linear association with the IVOO degree and reflux in the femoral veins (P < .001) and popliteal vein (P = .008). Significant lesions were significantly more likely to develop in the left limb (OR, 5.76; 95% CI, 2.46-13.50; P < .001). After multivariate analysis, DVR remained a predictor for significant and critical obstruction (P < .003 and P < .012, respectively). Left limb and previous DVT remained as predictors for IVOO of ≥50% and ≥80% (P < .001 and P = .043, respectively). CONCLUSIONS: We found a significant linear association between the degree of IVOO and reflux in the deep venous system on DU. Limbs with DVR, a severe RMS, loss of respiratory variation on DU, and previous DVT were more likely to be affected by IVOO of ≥50%, especially with left leg involvement.

Profile of the multicenter cohort of the German Cancer Consortium's Clinical Communication Platform.

Treatment concepts in oncology are becoming increasingly personalized and diverse. Successively, changes in standards of care mandate continuous monitoring of patient pathways and clinical outcomes based on large, representative real-world data. The German Cancer Consortium's (DKTK) Clinical Communication Platform (CCP) provides such opportunity. Connecting fourteen university hospital-based cancer centers, the CCP relies on a federated IT-infrastructure sourcing data from facility-based cancer registry units and biobanks. Federated analyses resulted in a cohort of 600,915 patients, out of which 232,991 were incident since 2013 and for which a comprehensive documentation is available. Next to demographic data (i.e., age at diagnosis: 2.0% 0-20 years, 8.3% 21-40 years, 30.9% 41-60 years, 50.1% 61-80 years, 8.8% 81+ years; and gender: 45.2% female, 54.7% male, 0.1% other) and diagnoses (five most frequent tumor origins: 22,523 prostate, 18,409 breast, 15,575 lung, 13,964 skin/malignant melanoma, 9005 brain), the cohort dataset contains information about therapeutic interventions and response assessments and is connected to 287,883 liquid and tissue biosamples. Focusing on diagnoses and therapy-sequences, showcase analyses of diagnosis-specific sub-cohorts (pancreas, larynx, kidney, thyroid gland) demonstrate the analytical opportunities offered by the cohort's data. Due to its data granularity and size, the cohort is a potential catalyst for translational cancer research. It provides rapid access to comprehensive patient groups and may improve the understanding of the clinical course of various (even rare) malignancies. Therefore, the cohort may serve as a decisions-making tool for clinical trial design and contributes to the evaluation of scientific findings under real-world conditions.

Management of traumatic superficial palmar arch pseudoaneurysm: a therapeutic challenge / Manejo de pseudoaneurisma do arco palmar superficial traumático: desafio terapêutico

Abstract Pseudoaneurysm of the palmar arch is a rare entity. Diagnosis is dependent on high clinical suspicion. We present a case referred to the emergency department, with a history of glass penetrating trauma to the palmar surface with a pulsatile mass and jet bleeding. Doppler ultrasound evidenced a partially thrombosed pseudoaneurysm. A CT angiography examination showed a saccular formation arising from the superficial palmar arch. A conventional surgical approach was indicated. A clinical suspicion must be ventured to arrive at the correct diagnosis. Imaging modalities are needed to identify the pseudoaneurysm and plan the treatment course. Nonetheless, the sequence of diagnosis is individual, because further evaluation with different imaging methods may not change the rationale for the intervention. In our experience, conventional surgical removal is preferable, due to its safety and well-established outcomes.

Resumo O pseudoaneurisma do arco palmar é uma entidade rara, cujo diagnóstico depende de alta suspeição clínica. Apresentamos o caso de um paciente encaminhado ao pronto-socorro com história de traumatismo penetrante por vidro na face palmar, com massa pulsátil e sangramento em jato. A ultrassonografia com Doppler evidenciou pseudoaneurisma parcialmente trombosado, e a angiotomografia demonstrou formação sacular originada do arco palmar superficial. Uma abordagem cirúrgica convencional foi indicada. Para prosseguir com o diagnóstico correto, essa suspeita clínica deve ser aventada. Modalidades de imagem são necessárias para identificar o pseudoaneurisma e planejar o curso do tratamento. No entanto, a sequência diagnóstica é individual, pois uma avaliação mais aprofundada, com diferentes métodos de imagem, pode não alterar o racional da intervenção. Em nossa experiência, a remoção cirúrgica convencional é preferível, visto sua segurança e seus resultados bem estabelecidos.

PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma.

BACKGROUND: Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying key players in the oncogenic progression to tailor more effective therapies. METHODS: We performed a comprehensive molecular and phenotypic characterization of a panel of patient-derived BRAFV600E-positive melanoma cell lines. Transcriptional profiling was used to identify groups of coregulated genes whose expression relates to an increased migratory potential and a higher resistance. RESULTS: A decrease in sensitivity to MAPK/ERK pathway inhibition with vemurafenib or trametinib corresponded with an increasing quiescence and migratory properties of the cells. This was accompanied by the loss of transcriptional signatures of melanocytic differentiation, and the gain of stem cell features that conferred highly-resistant/mesenchymal-like cells with increased xenobiotic efflux capacity. Nevertheless, targeting of the implicated ABC transporters did not improve the response to vemurafenib, indicating that incomplete BRAF inhibition due to reduced drug uptake is not a main driver of resistance. Rather, indifference to MAPK/ERK pathway inhibition arose from the activation of compensatory signaling cascades. The PI3K/AKT pathway in particular showed a higher activity in mesenchymal-like cells, conferring a lower dependency on MAPK/ERK signaling and supporting stem-like properties that could be reverted by dual PI3K/mTOR inhibition with dactolisib. CONCLUSIONS: In case of MAPK/ERK independency, therapeutic focus may be shifted to the PI3K/AKT pathway to overcome late-stage resistance in melanoma tumors that have acquired a mesenchymal phenotype. Video Abstract.

ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma.

Metastatic clear cell renal cell carcinomas (ccRCCs) are resistant to DNA-damaging chemotherapies, limiting therapeutic options for patients whose tumors are resistant to tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCCs were frequently characterized by high levels of endogenous DNA damage and that cultured ccRCC cells exhibited intact cellular responses to chemotherapy-induced DNA damage. We identify that pharmacological inhibition of the DNA damage-sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) with the orally administered, potent, and selective drug M4344 (gartisertib) induced antiproliferative effects in ccRCC cells. This effect was due to replication stress and accumulation of DNA damage in S phase. In some cells, DNA damage persisted into subsequent G2/M and G1 phases, leading to the frequent accumulation of micronuclei. Daily single-agent treatment with M4344 inhibited the growth of ccRCC xenograft tumors. M4344 synergized with chemotherapeutic drugs including cisplatin and carboplatin and the poly(ADP-ribose) polymerase inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC.

Krüppel-like factor 7 influences translation and pathways involved in ribosomal biogenesis in breast cancer.

BACKGROUND: Ribosomal biogenesis and ribosomal proteins have attracted attention in the context of tumor biology in recent years. Instead of being mere translational machineries, ribosomes might play an active role in tumor initiation and progression. Despite its importance, regulation of ribosomal biogenesis is still not completely understood. METHODS: Using Gene Set Enrichment Analysis of RNA sequencing and proteomical mass spectrometry data in breast cancer cells expressing Krüppel-like factor 7 (KLF7), we identified processes altered by this transcription factor. In silico analyses of a cohort of breast cancer patients in The Cancer Genome Atlas confirmed our finding. We further verified the role of KLF7 the identified ribosomal processes in in vitro assays of mammary carcinoma cell lines and analyses of breast cancer patients' tissue slices. RESULTS: We identified the transcription factor Krüppel-like factor 7 (KLF7) as a regulator of ribosomal biogenesis and translation in breast cancer cells and tissue. Highly significant overlapping processes related to ribosomal biogenesis were identified in proteomics and transcriptomics data and confirmed in patients' breast cancer RNA Seq data. Further, nucleoli, the sites of ribosomal biogenesis, were morphologically altered and quantitatively increased in KLF7-expressing cells. Pre-rRNA processing was identified as one potential process affected by KLF7. In addition, an increase in global translation independent from proliferation and transcription was observed upon exogenous KLF7 expression in vitro. Importantly, in a cohort of breast cancer patients, KLF7-expression levels correlated with aggressiveness of the intrinsic breast cancer subtype and tumor grading. Moreover, KLF7 correlated with nucleolar characteristics in human breast tumor tissue, indicating a role for KLF7 in ribosomal biogenesis. CONCLUSION: In mammary carcinoma, KLF7 is involved in ribosomal biogenesis. Alterations of ribosomal biogenesis has far reaching quantitative and qualitative implications for the proteome of the cancer cells. This might influence the aggressiveness of cancer cells.

Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations.

Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. We performed massively parallel sequencing by using cohorts of genetically unsolved individuals with unexplained liver and kidney failure and correlated this with clinical, imaging, and histopathological analyses. Mechanistic studies were conducted with a vertebrate model and primary cells. We detected bi-allelic deleterious variants in TULP3, encoding a critical adaptor protein for ciliary trafficking, in a total of 15 mostly adult individuals, originating from eight unrelated families, with progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. We recapitulated the human phenotype in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. Further, we show interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis, and report increased DNA damage ex vivo. Transcriptomic studies demonstrated upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy and WNT and TGF-ß signaling. These findings identify variants in TULP3 as a monogenic cause for progressive degenerative disease of major organs in which affected individuals benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for DNA damage repair and tissue maintenance will guide novel therapeutic avenues for this and similar genetic and non-genomic diseases.

Dynamic transcriptome analysis reveals signatures of paradoxical effect of vemurafenib on human dermal fibroblasts.

BACKGROUND: Vemurafenib (PLX4032) is one of the most frequently used treatments for late-stage melanoma patients with the BRAFV600E mutation; however, acquired resistance to the drug poses as a major challenge. It remains to be determined whether off-target effects of vemurafenib on normal stroma components could reshape the tumor microenvironment in a way that contributes to cancer progression and drug resistance. METHODS: By using temporally-resolved RNA- and ATAC-seq, we studied the early molecular changes induced by vemurafenib in human dermal fibroblast (HDF), a main stromal component in melanoma and other tumors with high prevalence of BRAFV600 mutations. RESULTS: Transcriptomics analyses revealed a stepwise up-regulation of proliferation signatures, together with a down-regulation of autophagy and proteolytic processes. The gene expression changes in HDF strongly correlated in an inverse way with those in BRAFV600E mutant malignant melanoma (MaMel) cell lines, consistent with the observation of a paradoxical effect of vemurafenib, leading to hyperphosphorylation of MEK1/2 and ERK1/2. The transcriptional changes in HDF were not strongly determined by alterations in chromatin accessibility; rather, an already permissive chromatin landscape seemed to facilitate the early accessibility to MAPK/ERK-regulated transcription factor binding sites. Combinatorial treatment with the MEK inhibitor trametinib did not preclude the paradoxical activation of MAPK/ERK signaling in HDF. When administered together, vemurafenib partially compensated for the reduction of cell viability and proliferation induced by trametinib. These paradoxical changes were restrained by using the third generation BRAF inhibitor PLX8394, a so-called paradox breaker compound. However, the advantageous effects on HDF during combination therapies were also lost. CONCLUSIONS: Vemurafenib induces paradoxical changes in HDF, enabled by a permissive chromatin landscape. These changes might provide an advantage during combination therapies, by compensating for the toxicity induced in stromal cells by less specific MAPK/ERK inhibitors. Our results highlight the relevance of evaluating the effects of the drugs on non-transformed stromal components, carefully considering the implications of their administration either as mono- or combination therapies. Video Abstract.

Challenges and Experiences Extending the cBioPortal for Cancer Genomics to a Molecular Tumor Board Platform.

In Molecular Tumor Boards (MTBs), therapy recommendations for cancer patients are discussed. To aid decision-making based on the patient's molecular profile, the research platform cBioPortal was extended based on users' requirements. Additionally, a comprehensive dockerized workflow was developed to support the deployment of cBioPortal and connected services. In this work, we present the challenges and experiences of nearly two years of implementing and deploying an MTB platform based on cBioPortal and compare those to findings of a previous study.

Budd-Chiari syndrome due to hepatic venous web outflow obstruction: percutaneous treatment with balloon angioplasty.

The Budd-Chiari syndrome is a rare hepatic venous disease. It is more prevalent in young adults and may present in acute, subacute, or chronic forms, causing portal hypertension. Traditional treatment consists of thrombolysis techniques and transjugular intrahepatic portosystemic shunt, as a bridge to liver transplantation. Recently, use of balloon or stent angioplasty techniques has been reported for treatment of this condition. In this article, we report and discuss a case of BCS by membranous obstruction in the hepatic vein outflow tract, with middle hepatic vein thrombosis, in a 24-year-old patient. The treatment chosen and employed was transjugular balloon angioplasty, which achieved satisfactory results and good clinical evolution.

Remodeling technique using T-stenting and coils to treat complex renal aneurysm.

Renal artery aneurysm is a rare condition that is being diagnosed with increasing frequency because of wider use of angiotomography. We describe a case of complex type II renal artery aneurysm in a patient with systemic arterial hypertension and non-dialysis chronic kidney disease. The treatment performed was endovascular repair using the remodeling technique with T-stenting and coils to preserve the renal arterial branches, obtaining satisfactory arteriographic results and good clinical outcomes.