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This was a prospective cohort study of eighteen patients with large and debilitating vascular malformations with one or more major systemic complications. In all patients, we discovered activating alterations in either TEK or PIK3CA. Based on these findings, targeted treatment using the PI3K inhibitor alpelisib was started with regular check-ups, therapy duration varied from 6 to 31 months. In all patients, marked improvement in quality of life was observed. We observed radiological improvement in fourteen patients (two of them being on combination with either propranolol or sirolimus), stable disease in 2 patients. For 2 patients, an MRI scan was not available as they were shortly on treatment, however, a clinically visible response in size reduction or structure regression, together with pain relief was observed. In patients with elevated D-dimer levels before alpelisib administration, a major improvement was noted, suggesting its biomarker role. We observed overall very good tolerance of the treatment, documenting a single patient with grade 3 hyperglycemia. Patients with size reduction were offered local therapies wherever possible. Our report presents a promising approach for the treatment of VMs harboring different targetable TEK and PIK3CA gene mutations with a low toxicity profile and high efficacy., (© 2023. The Author(s).)

In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry. These results explain different treatment responses of the three histologically identical but molecularly different tumors. Our findings support a personalized approach for patient with high risk, refractory, and rare diseases and may contribute to personalized and customized treatment efforts for patients with limited treatment options like relapsed/refractory Burkitt lymphoma., Summary: The main aim of this study is to analyze three relapsed Burkitt lymphoma patients using a comprehensive molecular profiling, in order to explain their different outcomes and to propose a biomarker-based targeted treatment. In cases 1 and 3, the tumor tissue and the host were analyzed prospectively and appropriate target for the treatment was successfully implemented; however, in case 2, analyses become available only retrospectively and his empirically based rescue treatment did not hit the right target of his disease., (Copyright © 2020 Polaskova, Merta, Martincekova, Zapletalova, Kyr, Mazanek, Krenova, Mudry, Jezova, Tuma, Skotakova, Cervinkova, Valik, Zdrazilova-Dubska, Noskova, Pal, Slaby, Fabian, Kozakova, Neradil, Veselska, Kanderova, Hrusak, Freiberger, Klement and Sterba.)

Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort ( n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma., (Copyright © 2020 Gojo, Pavelka, Zapletalova, Schmook, Mayr, Madlener, Kyr, Vejmelkova, Smrcka, Czech, Dorfer, Skotakova, Azizi, Chocholous, Reisinger, Lastovicka, Valik, Haberler, Peyrl, Noskova, Pál, Jezova, Veselska, Kozakova, Slaby, Slavc and Sterba.)

Wolfram-like syndrome (WFSL) is a rare autosomal dominant disease characterised by congenital progressive hearing loss, diabetes mellitus, and optic atrophy. The patient was a boy with the juvenile form of diabetes mellitus and findings which clinically matched the symptoms of Wolfram syndrome. At the age of 3 1/4 years, diabetes mellitus was diagnosed in this boy who also had severe psychomotor retardation, failure to thrive, a dysmorphic face with Peters anomaly type 3 (i.e. posterior central defect with stromal opacity of the cornea, adhering stripes of the iris, and cataract with corneolenticular adhesion), congenital glaucoma, megalocornea, severe hearing impairment, a one-sided deformity of the auricle with atresia of the bony and soft external auditory canal, non-differentiable eardrum, missing os incus, hypothyreosis, and nephrocalcinosis. Molecular-genetic examinations revealed a de novo mutation p.(Glu809Lys) in the WFS1 gene. No mutations were detected in the biological parents. The mutation p.(Glu809Lys) in the WFS1 gene is associated with WFSL., Competing Interests: Financial Disclosure: This work was funded by the project of the Internal Grant Agency of the Czech Ministry of Health (NT/14574-3) and the project of the Czech Ministry of Health for conceptual development of research organization 65269705 (University Hospital Brno, Brno, Czech Republic).

Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used., Competing Interests: There is no conflict of interest.

Prognosis for children with relapsed medulloblastoma remains poor. Metronomic chemotherapy may offer some benefit to patients treated initially with intensive regimens. However, dosing and duration of such palliative treatment have not been systematically studied. Here we describe a child with medulloblastoma relapsing after initial high-dose chemotherapy and standard radiotherapy. The patient was then treated with metronomic chemotherapy and achieved second complete remission after 21 months of treatment. Three months off therapy he relapsed again and died from progressive disease. This case illustrates the potential benefit of metronomic chemotherapy but also shows the uncertainty of when to stop metronomic chemotherapy while balancing toxicity.

Invasive fungal infections are serious complications of cancer therapy. We present a case report of a 12-year-old boy diagnosed with abdominal non-Hodgkin lymphoma and fecal and Candida peritonitis during induction chemotherapy. The invasive mycosis was managed using a combined approach of systemic antifungal agents including efungumab and surgical interventions. Efungumab, a recombinant antibody that inhibits extracellular heat shock protein 90, was used in combination with amphotericin B colloid dispersion after the failure of standard approaches.

Secondary hypertension (SH) is much more common in children than in adults. We report a 17-year-old girl with severe hypertension, hypokalemia and metabolic alkalosis. Because of these findings, primary or secondary hyperaldosteronism was suspected. Her initial treatment with spironolactone and ACE inhibitor was unsuccessful. With consideration of high plasma renin activity, the renal computed tomography angiography was performed and showed tumor mass in the left kidney. An uncomplicated partial left nephrectomy was performed. Histopathological examination and electron microscopy showed typical features of juxtaglomerular cell tumor (JCT). Imunohistochemistry of tumor was positive for CD34 and CD117 and this finding is effective in the diagnosis of JCT if immunostain for renin is unavailable. After the resection of JCT, the patient's blood pressure and hypokalemia returned to normal range. JCT is a rare renal neoplasm and an unusual cause of SH in children or adolescents (Fig. 2, Ref. 12).

Few complete reports exist regarding treatment of venous thromboembolism in children undergoing chemotherapy. We designed this study to unify the treatment of venous thromboembolism in oncology pediatric patients at our department. At the same time, we wanted to evaluate the safety and efficacy of our newly designed treatment schedule. Data from pediatric oncology patients with deep venous thrombosis (DVT) treated at the Department of Pediatric Oncology, Brno, was collected prospectively over a 2-year period (1 January 2006 to 31 December 2007). All patients received low molecular weight heparin (LMWH) at an initial dose of 1.2-1.5 mg/kg body weight subcutaneously (s.c.) twice daily for the first 7-10 days. Afterwards, the dose was lowered to 1.5 mg/kg s.c. once daily. We kept this dose unchanged for a minimum of 3 months. For the first 6 weeks of treatment, the platelet count was maintained 20 x 10/l or more with no concomitant LMWH withdrawal. For the rest of the treatment, LMWH was interrupted once platelets dropped below 20 x 10/l. A total of 33 patients were followed for a median of 6 months. DVT was symptomatic in 15 of 33 patients (46%) and asymptomatic in 18 of 33 (54%) patients. Complete thrombus resolution occurred in 22 of 33 (67%) patients, partial or no recanalization was achieved in 11 of 33 (33%) patients. Eight patients (eight of 33, 24%) were diagnosed with postthrombotic syndrome (PTS). The risk of PTS was significantly higher for patients with symptomatic DVT than in those with asymptomatic DVT. Neither patency rates nor the risk of PTS showed a positive correlation with the achievement of therapeutic anti-Xa activity. Thrombocytopenia less than 20 x 10/l occurred at least once during LMWH treatment in 30/33 (91%) patients. None of the patients experienced severe bleeding, whereas mild bleeding episodes were observed in five of 33 (15%) patients. Our treatment schedule has proved to be both well tolerated and reasonably efficient in treating DVT in children undergoing chemotherapy. Further studies on larger patient groups are warranted.

Invasive fungal infection continues to pose a significant threat to immunocompromised patients, with cerebral aspergillosis being among the most feared ones. The authors describe an adolescent girl with acute lymphoblastic leukemia (ALL) with subsequent acute liver failure, who developed an aspergillus brain abscess. The patient was treated with combined antifungal therapy using amphotericin B local instillation, prolonged systemic amphotericin B colloidal dispersion along with vinca alkaloids-containing chemotherapy, followed by neurosurgical débridement and oral voriconazole in the setting of ongoing antileukemic maintenance chemotherapy. Her ALL remains now in complete remission 30 months from diagnosis, with no evidence of fungal infection.