A Systematic Review and Meta-Analysis of Malignant Rhabdoid and Small Cell Undifferentiated Liver Tumors: A Rational for a Uniform Classification

Background: Rhabdoid liver tumors in children are rare and have a devastating prognosis. Reliable diagnosis and targeted treatment approaches are urgently needed. Immunohistochemical and genetic studies suggest that tumors formerly classified as small cell undifferentiated hepatoblastoma (SCUD) belong to the entity of malignant rhabdoid tumors of the liver (MRTL), in contrast to hepatoblastomas with focal small cell histology (F-SCHB). This may have relevant implications on therapeutic approaches. However, studies with larger cohorts investigating the clinical relevance of the histological and genetic similarities for patients are lacking. Purpose: To analyze possible similarities and differences in patient characteristics, tumor biology, response to treatment, and clinical course of patients with MRTL, SCUD and F-SCHB. Applied therapeutic regimens and prognostic factors are investigated. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed for this PRISMA-compliant systematic review. All studies of patients with MRTL, SCUD and F-SCHB that provided individual patient data were included. Demographic, histological, and clinical characteristics of the three subgroups were compared. Overall survival (OS) was estimated with the Kaplan–Meier method and prognostic factors investigated in a multivariable Cox regression model. Protocol registered: PROSPERO 2021 CRD42021258760. Results: Fifty-six studies with a total of 118 patients were included. The two subgroups MRTL and SCUD did not differ significantly in baseline patient characteristics. However, heterogenous diagnostic and therapeutic algorithms were applied. Large histological and clinical overlap between SCUD and MRTL could be shown. Two-year OS was 22% for MRTL and 13% for SCUD, while it was significantly better in F-SCHD (86%). Chemotherapeutic regimens for hepatoblastoma proved to be ineffective for both SCUD and MRTL, but successful in F-SCHB. Soft tissue sarcoma chemotherapy was associated with significantly better survival for MRTL and SCUD, but was rarely applied in SCUD. Patients who did not undergo surgical tumor resection had a significantly higher risk of death. Conclusions: While F-SCHB is a subtype of HB, SCUD should be classified and treated as a type of MRTL. Surgical tumor resection in combination with intensive, multi-agent chemotherapy is the only chance for cure of these tumors. Targeted therapies are highly needed to improve prognosis. Currently, aggressive regimens including soft tissue sarcoma chemotherapy, extensive resection, radiotherapy or even liver transplantation are the only option for affected children.

Immune Checkpoint Inhibitor-Induced Cerebral Pseudoprogression: Patterns and Categorization

BackgroundThe inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system.MethodsWe screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria.ResultsWe identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern.ConclusionCerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions.

Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib

The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.

Comparison of the effectiveness of various conservative treatment options for trophic ulcers and varicose eczema

Introduction. It has been for a long time considered that treatment of trophic venous ulcers and varicose eczema should be operative only. However, practice shows that such treatment doesn’t guarantee the complete healing of an ulcer or eczema and doesn’t always prevent the recurrence of pathological processes. It suggests the need for an integrated approach to the treatment of trophic venous ulcers and varicose eczema.Aim. Analyze the effectiveness of various methods of non-surgical treatment of venous trophic ulcers (TU) and varicose eczema (VE) to create an optimal algorithm for managing this category of patients in outpatient practice.Materials and methods. A prospective comparative cohort study of 252 patients with C4-C6 CVD classes (CEAP) was conducted. 178 people (71%) had venous TU , 74 (29%) – VE. 3 groups of patients were formed: 1 gr. – (n = 68) was treated with traditional medicines and standard topical therapy (control); 2 gr. – (n = 90) received MOFF, elastic compression (Pütterbinde bandage), systemic antibiotic therapy for TU and corticosteroids for VE, dressings using Hartmann wound coverings; 3 gr. – (n = 94) in addition to the treatment similar to group 2, sclerotherapy (ST) of pathological venous reflux was performed. The follow-up lasted 6 months (8 visits) with a comprehensive clinical, laboratory and instrumental assessment. Statistical processing of the results was carried out using the STATISTICA software package (StatSoft, Inc., 2001, version 6.0).Results. By the end of the study, the following positive trends were registered in group 2 compared to group 1: the total VCSS index was 1.5 times lower, and according to the 10 – point VAS – 3 times; TU healing/ VE remission occurred 2 months earlier, complete healing of TU was noted in 75% of patients vs 63%, remission of VE-in 81% vs 47%. The combination of elimination of pathological reflux by CT and MOFF therapy (group 3 patients) was particularly effective. When comparing group 1 with group 3, it turned out that in the latter, by the end of the study, the total VCSS index was 3 times lower; the total indicator for the 10 – point VAS was 5.5 times lower for TU, 10 times higher for VE; TU healing/VE remission occurred 4 months earlier, complete healing was noted in TU in 88% of patients vs 63%, remission of VE in 96% vs 47%. Based on the obtained data, therapeutic algorithms were proposed for the management of patients with venous TU and VE in outpatient settings.Conclusions. Conservative treatment of venous TU and VE can be an alternative to surgical treatment, or an addition to it. MOFF is the most effective venotonic of complex action prescribed for the treatment of TU/VE in the form of monotherapy. Sclerosing therapy is a full-fledged element of the complex treatment of venous TU. The use of the proposed treatment algorithms makes it possible to speed up the healing process of venous TU and achieve remission of VE by three times.

Master Protocols for Precision Medicine in Oncology: Overcoming Methodology of Randomized Clinical Trials

Randomized clinical trials are considered the milestones of clinical research in oncology, and guided the development and approval of new compounds so far. In the last few years, however, molecular and genomic profiling led to a change of paradigm in therapeutic algorithms of many cancer types, with the spread of different biomarker-driven therapies (or targeted therapies). This scenario of “personalized medicine” revolutionized therapeutic strategies and the methodology of the supporting clinical research. New clinical trial designs are emerging to answer to the unmet clinical needs related to the development of these targeted therapies, overcoming the “classical” structure of randomized studies. Innovative trial designs able to evaluate more than one treatment in the same group of patients or many groups of patients with the same treatment (or both) are emerging as a possible future standard in clinical trial methodology. These are identified as “master protocols”, and include umbrella, basket and platform trials. In this review, we described the main characteristics of these new trial designs, focusing on the opportunities and limitations of their use in the era of personalized medicine.

Establishing and Boosting Communication in The European Reference Network For Rare Neurological Diseases (ERN-RND): The Impact of Offering Free Educational Webinars

Background: Since it first started operating in 2017, the European Reference Network for Rare Neurological Diseases (ERN-RND) implemented a multi-channel communication strategy to effectively reach its target audience: healthcare professionals, patients, researchers, industry representatives and the general public. It first created a website containing useful and up to date information followed by social media accounts. We compared the analytical data collected about the ERN-RND website and social media channels (Twitter, Facebook, YouTube) during two periods: October 2018 to September 2019 and the year after the ERN-RND free educational webinars were launched, from October 2019 to September 2020. This allowed us to quantify the impact of offering a tangible product (webinars) on the communication strategy. Results: The analytical data obtained from October 2018 to September 2019 and from October 2019 to September 2020 clearly shows a significant increase in traffic and followers since the launch of the ERN-RND webinars in November 2019. We also created a communication survey which was disseminated between February and June 2021. We collected responses from 61 people: 38 healthcare professionals, 11 scientists, 10 patients (advocates), 2 industry representatives, 1 patient association, 1 charity representative, 1 resident and 1 master student. Most respondents answered ”webinars” as the number one reason when asked about which content they look for on the ERN-RND website. Conclusions: Offering a tangible product - such as the webinars presented in this report - to a specific target group (healthcare professionals) supported our communication strategy by driving traffic to ERN-RND communication channels. It has also successfully tackled ERN-RND’s general aim: by enabling the flow of knowledge on rare neurological and movement disorders reach the medical community in hospitals treating patients with these rare and complex conditions, patients ultimately benefit from improved and faster diagnosis, care, and treatment. We aim to set up similar strategies to effectively reach other or the same target groups. For healthcare professionals, organising eConsultations via the Clinical Patient Management System (CPMS) or disseminating standards of care such as diagnostic and therapeutic algorithms as well as clinical practice guidelines might offer potential. For the patient community, organising customised and multilingual webinars could also work.

Methodological aspects of creation of patient-derived tumor xenografts

High rates of cancer incidence and mortality from malignant neoplasms remains an urgent health problem. The development of the most effective therapeutic algorithms is required to improve the survival of cancer patients. An important condition for the discovery of new anticancer drugs and their translation into clinical practice involves the ability to model tumor growth, reproduce the characteristics of human disease, and evaluate measurable effects of pharmacological substances in laboratory facilities. Xenograft models established by direct implantation of fresh tumor tissue samples from individual patients into immunodeficient mice are considered suitable for both preclinical trials and for solving fundamental problems in oncology. The review highlights the significance of patient-derived xenograft models as a platform with high predictive value and the prerequisites that make them the preferred tool for research in cancer biology. The most important methodological aspects in the creation of these models are considered. Methods for obtaining and preparing biological tumor samples for xenotransplantation are discussed. The significance of the immune status, as well as the phenotypic and genetic characteristics of recipient animals, is described. The article presents the limitations of animal models associated with their immunodeficiency status and ways to overcome them. The principles for choosing xenotransplantation sites (heterotopic and orthotopic) and their advantages and disadvantages are discussed. In conclusion, we emphasize the need to continue the work on optimizing PDX (Patient-Derived Xenograft) models to overcome their limitations and to obtain the most reliable and valuable research results in oncology.

Remnant cholesterol is an independent determinant of the presence and extent of subclinical carotid atherosclerosis in statin-naive individuals

Background Despite continuous improvements of diagnostic and therapeutic algorithms for cardiovascular disease (CVD), mortality from CVD remains high suggesting unaddressed residual risk. Remnant cholesterol (RC) consists the cholesterol content of triglyceride-rich lipoproteins, which along with LDL cholesterol infiltrate the arterial wall, accumulate and cause atherosclerosis. Increased remnant cholesterol (RC) levels have been previously associated with future adverse cardiac events despite hypolipidemic therapy. However, a mechanistic association of RC levels with human atherosclerosis in vivo has not been proven in a clinical setting. Purpose To evaluate the association of RC levels with the presence and extend of subclinical carotid atherosclerosis. Methods In this retrospective cohort study, 438 subjects from the Athens Vascular Registry without clinically overt CVD or treatment with statin were recruited. Atherosclerotic burden was assessed by B-mode carotid ultrasonography using: 1. Maximal carotid wall thickness [maxWT, the highest intima-media thickness (IMT) or highest atherosclerotic plaque thickness (PLQ) if present derived from all carotid sites], 2. Total thickness (sumWT, sum of maximal wall thickness), 3) high plaque burden (PLQ ≥2) and 4) average carotid IMT (avgIMT). RC was calculated using the formula RC=total cholesterol-LDL-C-HDL-C. Results Mean (SD) age was 54.8±12.4 years old with 41% being males. Subjects with RC>median (=18mg/dl) had higher sumWT (6.12±0.7 vs 5.57±1.7, p=0.002), maxWT (1.61±0.7 vs 1.43±0.7, p=0.008) and avgIMT (0.88±0.16 vs 0.83±0.16, p=0.003) vs RC<median.>median was associated with higher odds for increased sumWT (highest tertile, OR: 2.15 95% CI 1.26–3.66, p=0.006) and maxWT (OR: 2.15 95% CI: 1.38–3.33, p=0.001), and a higher plaque burden (≥2 plaques, OR: 2.1 95% CI 1.93–3.1, p<0.001) after adjustment for age, gender and systolic blood pressure, glomerular filtration rate, smoking, diabetes mellitus, body mass index and LDL-C Conclusion In a statin-naive population without clinically overt CVD, increased RC levels were associated with the presence and extend of subclinical carotid atherosclerosis. These findings provide novel mechanistic insight into mechanisms associated with increased CVD risk in individuals with high RC levels. FUNDunding Acknowledgement Type of funding sources: None.

The role of glucocorticoids in the treatment of acute anaphylactic reaction

Food allergy is a growing health problem, which is particularly common among the youngest children. Anaphylaxis, which is defined as a sudden-onset and potentially fatal response to an allergen, is an indication for urgent treatment. Although intramuscular epinephrine is the treatment of choice, all therapeutic algorithms also recommend glucocorticoids. They play an important role in reducing the risk of late allergic reaction, and, due to their non-genomic effects, are also increasingly often mentioned in the context of early response to shock. This effect is directly proportional to the dose of the drug, and a reduced duration of the symptoms of anaphylactic shock is achieved with the use of high doses of glucocorticoids. The paper presents a case of a 3-month-old girl with an anaphylactic reaction after consuming a modified milk preparation. After systemic administration of glucocorticoids, a satisfactory therapeutic effect was observed in the child.

Thyroid Cancer Risk Factors in Children with Thyroid Nodules: A One-Center Study

Thyroid nodules are common in the adult population (13%), but in childhood, they are relatively rarely diagnosed (0.2–5%). The risk factors and diagnostic and therapeutic algorithms are well-known and effectively used in adults, but no clear procedures supported by scientific research are available in the pediatric population. Our aim in this study was to identify predictive factors for thyroid cancer in a pediatric population. We retrospectively analyzed 112 children (80 girls and 32 boys, aged 0.6–18 years, with an average group age of 13.4 ± 4.5 years) with thyroid nodules who presented or were referred between 2010 and 2021. A total of 37 children qualified for partial or total thyroidectomy. After histopathological nodule examination, the most common cases were benign lesions in 23 patients (57.5%) and malignant lesions in 14 children (32.5%). Solitary benign thyroid nodules were found in 16 children (40%). Malignancy risk was higher in children with increased nodule diameter (greater than 7 mm; p = 0.018) or hypoechogenic lesions in ultrasound (p = 0.010), with no correlation between increased blood flow in the vessels and tumor diagnosis. The relative risk of developing thyroid cancer for class III was found to be higher in comparison to adults and 11.1 times higher than for classes I and II combined.