Impending HCC diagnosis in patients with cirrhosis after HCV cure features a natural killer cell signature.

BACKGROUND AND AIMS: The risk of developing HCC in chronically infected patients with AQ2 HCV with liver cirrhosis is significantly elevated. This risk remains high even after a sustained virological response with direct-acting antivirals. To date, disease-associated signatures of NK cells indicating HCC development are unclear. APPROACH AND RESULTS: This study investigated NK cell signatures and functions in 8 cohorts covering the time span of HCC development, diagnosis, and onset. In-depth analysis of NK cell profiles from patients with cirrhosis who developed HCC (HCV-HCC) after sustained virological response compared with those who remained tumor-free (HCV-noHCC) revealed increasingly dissimilar NK cell signatures over time. We identified expression patterns with persistently high frequencies of TIM-3 and CD38 on NK cells that were largely absent in healthy controls and were associated with a high probability of HCC development. Functional assays revealed that the NK cells had potent cytotoxic features. In contrast to HCV-HCC, the signature of HCV-noHCC converged with the signature found in healthy controls over time. Regarding tissue distribution, single-cell sequencing showed high frequencies of these cells in liver tissue and the invasive margin but markedly lower frequencies in tumors. CONCLUSIONS: We show that HCV-related HCC development has profound effects on the imprint of NK cells. Persistent co-expression of TIM-3hi and CD38 + on NK cells is an early indicator for HCV-related HCC development. We propose that the profiling of NK cells may be a rapid and valuable tool to assess the risk of HCC development in a timely manner in patients with cirrhosis after HCV cure.

The impact of subthalamic deep-brain stimulation in restoring motor symmetry in Parkinson's disease patients: a prospective study.

BACKGROUND AND OBJECTIVES: The impact of subthalamic deep-brain stimulation (STN-DBS) on motor asymmetry and its influence on both motor and non-motor outcomes remain unclear. The present study aims at assessing the role of STN-DBS on motor asymmetry and how its modulation translates into benefits in motor function, activities of daily living (ADLs) and quality of life (QoL). METHODS: Postoperative motor asymmetry has been assessed on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. Asymmetry was evaluated at both baseline (pre-DBS) and 1 year after STN-DBS. A patient was considered asymmetric when the right-to-left MDS-UPDRS part III difference was ≥ 5. In parallel, analyses have been carried out using the absolute right-to-left difference. The proportion of asymmetric patients at baseline was compared to that in the post-surgery evaluation across different medication/stimulation conditions. RESULTS: 537 PD patients have been included. The proportion of asymmetric patients was significantly reduced after both STN-DBS and medication administration (asymmetric patients: 50% in pre-DBS MedOFF, 35% in MedOFF/StimON, 26% in MedON/StimOFF, and 12% in MedON/StimON state). Older patients at surgery and with higher baseline UPDRS II scores were significantly less likely to benefit from STN-DBS at the level of motor asymmetry. No significant correlation between motor asymmetry and ADLs (UPDRS II) or overall QoL (PDQ-39) score was observed. Asymmetric patients had significantly higher mobility, communication, and daily living PDQ-39 sub-scores. CONCLUSIONS: Both STN-DBS and levodopa lead to a reduction in motor asymmetry. Motor symmetry is associated with improvements in certain QoL sub-scores.

Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1-KMT2A Interaction.

Menin/MEN1 is a scaffold protein that participates in proliferation, regulation of gene transcription, DNA damage repair, and signal transduction. In hematological malignancies harboring the KMT2A/MLL1 (MLLr) chromosomal rearrangements, the interaction of the oncogenic fusion protein MLLr with MEN1 has been shown to be essential. MEN1 binders inhibiting the MEN1 and KMT2A interaction have been shown to be effective against MLLr AML and B-ALL in experimental models and clinical studies. We hypothesized that in addition to the MEN1-KMT2A interaction, alternative mechanisms might be instrumental in the MEN1 dependency of leukemia. We first mined and analyzed data from publicly available gene expression databases, finding that the dependency of B-ALL cell lines on MEN1 did not correlate with the presence of MLLr. Using shRNA-mediated knockdown, we found that all tested B-ALL cell lines were sensitive to MEN1 depletion, independent of the underlying driver mutations. Most multiple myeloma cell lines that did not harbor MLLr were also sensitive to the genetic depletion of MEN1. We conclude that the oncogenic role of MEN1 is not limited to the interaction with KMT2A. Our results suggest that targeted degradation of MEN1 or the development of binders that induce global changes in the MEN1 protein structure may be more efficient than the inhibition of individual MEN1 protein interactions.

Complex, atypical clubfoot: follow-up after up to 16 years reveals a high risk of relapse but good functional and radiological outcomes.

INTRODUCTION: The treatment of complex atypical clubfoot poses many challenges. In this paper, we report on the course of complex clubfoot, primary correction using the modified Ponseti method and midterm outcomes. Special consideration is given to clinical and radiological changes in cases of relapse. MATERIALS AND METHODS: Twenty-seven cases of complex, atypical, non-syndromic clubfoot were treated in 16 children between 2004 and 2012. Patient data, treatment data, functional outcomes and, in the relapse cohort, radiological findings were documented during the course of treatment. The radiological findings were correlated with the functional outcomes. RESULTS: All atypical complex clubfeet could be corrected using a modified form of the Ponseti method. Over an average study period of 11.6 years, 66.6% (n = 18) of clubfeet relapsed. Correction after relapse showed an average dorsiflexion of 11.3° during a 5-years' follow-up period. Radiological results showed residual clubfoot pathologies such as a medialized navicular bone in four clubfeet. There were no instances of subluxation or dislocation of the talonavicular joint. Extensive release surgery was not necessary. Nevertheless, after 2.5 preoperative casts (1-5 casts), bone correction was performed in n = 3 feet in addition to Achilles tendon lengthening and tibialis anterior tendon transfer. CONCLUSION: Good primary correction of complex clubfoot using the modified Ponseti technique results in a high recurrence rate in the medium term. Relapse treatment without peritalar arthrolysis procedures produces good functional results even though minor residual radiological pathologies did persist in a minor number of cases.

Monocyte chemoattractant protein 1 as a potential biomarker for immune checkpoint inhibitor-associated neurotoxicity.

BACKGROUND: Oncological patients can benefit substantially from treatment with immune checkpoint inhibitors (ICI). However, there is a growing awareness of immune-related adverse events (irAE). Especially ICI-mediated neurological adverse events (nAE(+)), are tough to diagnose and biomarkers to identify patients at risk are missing. METHODS: A prospective register with prespecified examinations was established for ICI treated patients in December 2019. At the time of data cut-off, 110 patients were enrolled and completed the clinical protocol. Herein, cytokines and serum neurofilament light chain (sNFL) from 21 patients were analyzed. RESULTS: nAE of any grade were observed in 31% of the patients (n = 34/110). In nAE(+) patients a significant increase in sNFL concentrations over time was observed. Patients with higher-grade nAE had significantly elevated serum-concentrations of monocyte chemoattractant protein 1 (MCP-1) and brain-derived neurotrophic factor (BDNF) at baseline compared to individuals without any nAE (p < 0.01 and p < 0.05). CONCLUSION: Here, we identified nAE to occur more frequently than previously reported. Increase of sNFL during nAE confirms the clinical diagnosis of neurotoxicity and might be a suitable marker for neuronal damage associated with ICI therapy. Furthermore, MCP-1 and BDNF are potentially the first clinical-class nAE predictors for patients under ICI therapy.

Supracondylar Dome Osteotomy With a Posterior Triceps-splitting Approach for Acute Correction of Posttraumatic Cubital Axis Deformities in Adolescent Patients.

BACKGROUND: Fractures around the elbow are common in children. Their management remains challenging. Inadequate treatment often leads to malunion, causing growth disturbance or avascular necrosis. This can develop into cubital axis deformities. This study evaluated our modified supracondylar dome osteotomy technique for acute correction of posttraumatic cubital axis deformities in adolescent patients. METHODS: Eighteen cases of posttraumatic cubital axis deformity that underwent acute correction through supracondylar dome osteotomy in our department between 2012 and 2019 were retrospectively evaluated. The radiologic results were measured through the carrying angle. The clinical functional outcomes were assessed using the Mayo Elbow Performance Index. RESULTS: No neurovascular injuries occurred and there was no notable loss of muscular strength or functional deficiencies in any of the patients. Symmetrical cubital axes were achieved in all cases. All cases were consolidated in a timely matter and no malunion was observed upon consolidation. Besides 1 case of hardware damage caused by a severe fall due to heavy alcohol intoxication, there was no correction loss, no secondary displacement, and no implant-related discomfort. None of the patients were left with a limited range of motion or reduced weight-bearing capacity. An excellent level of elbow functionality was achieved in all cases, with an average Mayo Elbow Performance Index of 97.8. CONCLUSIONS: The supracondylar dome osteotomy technique showed promising results in both radiologic outcomes and clinical performance, with a low complication rate. The dome-shaped osteotomy allows simultaneous multiplanar correction of not only varus or valgus deformities but also additional extension or flexion deformities. This technique also enables translation of the distal fragment in the frontal plane, which contributes to a more balanced anatomic geometry of the distal humerus. We consider the posterior triceps-splitting approach to be a safe technique that preserves muscle strength and improves the cosmetic appearance of the surgical scar. We recommend a cast-free plate fixation to allow early movement after surgery. We believe any residual deformities that present 18 months after the initial trauma should be addressed through surgical correction before clinical symptoms become apparent to avoid the chronic manifestation of functional deficiencies. LEVEL OF EVIDENCE: Level IV, therapeutic study, case series.

Ultra-Late Osteosarcoma Recurrences: An Analysis of 17 Cooperative Osteosarcoma Study Group Patients with a First Recurrence Detected More Than 10 Years After Primary Tumor Diagnosis.

Purpose: Osteosarcoma is a typical malignancy of childhood and adolescence. Recurrences usually occur early, but rarely may arise after decades of remission. Little is known about these very late events and we set out to fill this knowledge gap. Methods: The database of the Cooperative Osteosarcoma Study Group (COSS) was searched for patients with a first recurrence of a high-grade central osteosarcoma occurring >10 years after diagnosis of the primary disease. Identified patients were analyzed for demographic, tumor-, and treatment-related factors as well as outcomes. Results: Among a total of 1,178 10-year relapse-free survivors, 17 affected patients were identified. Only five of these had a documented good response to initial chemotherapy. No presenting factor was identified to predict these very late events. Prognosis was generally very poor despite intensive multimodal therapy. Inoperability of the recurrences seems to have constituted a major limiting factor. Conclusion: Osteosarcoma patients should be followed for potential recurrences for well >10 years from initial diagnosis. Only through such an extended truly long-term follow-up and a structured transition of young patients can these be detected while they are still operable and, hence, potentially curable.

The inherited cerebellar ataxias: an update.

This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.

Language and verbal fluency outcome after bilateral subthalamic Nucleus Deep Brain Stimulation in Parkinson's disease.

BACKGROUND: Language disorders in Parkinson's Disease (PD) following bilateral subthalamic Nucleus Deep Brain Stimulation (STN-DBS) are common. OBJECTIVE: To assess STN-DBS impact on language and observe clinical and anatomical predictors of poor outcome. METHODS: We prospectively included PD patients undergoing STN-DBS. We performed a neuropsychological evaluation focusing on language before (V0), 3 days after (V1), and 3 months after (V2) surgery. Patients performed all assessments in ON drug condition, V1 with the stimulation turned OFF to evaluate the lesion effect, and V2 with the stimulation turned ON to evaluate the stimulation effect. Electrodes and active contact locations were determined with MRI-Atlas fusion. The stimulation parameters and the total electrical energy delivered (TEED) were recorded for each patient. RESULTS: 18 PD patients consecutively operated were included. We identified a decline in phonemic verbal fluency (VFP) at V1 and V2 (p = 0.023 and 0.032 respectively), as well as in semantic verbal fluency (VFS) (p = 0.025 and 0.019, respectively). There was a significant slowdown in the verbs naming test (p = 0.048). No other language alteration was recorded. There was no correlation between demographic or clinical factors and verbal fluency (VF) evolution. Active contact location within substantia nigra was associated with VFP worsening (p = 0.047), while elevated TEED on the left-sided electrode was associated with VFS decline (p = 0.021). CONCLUSION: VF was significantly altered following STN-DBS. Location outside the dorsolateral sensorimotor STN, and high stimulation power appeared to promote this decline. Other language domains remained stable.

Current trends in the treatment of supracondylar fractures of the humerus in children: Results of a survey of the members of European Paediatric Orthopaedic Society.

Purpose: The purpose of this study was to evaluate the current trends in the treatment of supracondylar humerus fractures as well as the preferred post-operative follow-up protocol among members of the European Paediatric Orthopaedic Society. Methods: The survey was composed by four main domains and 26 items: (1) surgeon information (3 items); (2) treatment (8 items); (3) post-operative treatment (3 items); and (4) factors influencing the outcome (12 items). All active members of European Paediatric Orthopaedic Society were invited by email to answer an electronic questionnaire. Results: The survey was submitted to 397 European Paediatric Orthopaedic Society active members; 184 members answered (46.3%) the questionnaire. Among respondents, 64.1% declared >10 years of experience and 55.4% declared to treat >20 supracondylar humerus fractures per year. Closed reduction, percutaneous pinning, and supine position were the preferred treatment option for Gartland type II and III supracondylar humerus fractures by 79.9%, 95.5%, and 84.8% of respondents, respectively. Supracondylar humerus fractures are treated within 24 h from trauma by 33.2% of respondents. Pins are removed 4 weeks from index procedure by 58.2% of respondents. Fracture type (72.3%), surgeon experience, and (71.2%) are of "crucial importance" for expected outcome of supracondylar humerus fractures treatment. Conclusion: Surgeon experience, type of fracture, treatment modality, and pins configuration were considered the main factors potentially influencing the outcome of supracondylar humerus fractures. European Paediatric Orthopaedic Society members agreed on the treatment modality of Gartland type II and III supracondylar humerus fractures, patient positioning, and timing of hardware removal. Other important issues such as timing of surgery, pins configuration, surgical approach, and post-operative protocol are still debated. Level of evidence: level II.

Four in one-Combination therapy using live Lactococcus lactis expressing three therapeutic proteins for the treatment of chronic non-healing wounds.

Diabetes mellitus is one of the major concerns for health care systems, affecting 382 million people worldwide. Among the different complications of diabetes, lower limbs chronic ulceration is a common, severe and costly cause of morbidity. Diabetic foot ulcers are a leading cause of hospitalization in diabetic patients and its rate exceed the ones of congestive heart failure, depression or renal disease. Diabetic non-healing ulcers account for more than 60% of all non-traumatic lower limb amputations and the five-year mortality after amputation is higher than 50%, being equal to several types of advanced cancer. The primary management goals for an existing diabetic foot ulcer are to achieve primary healing as expeditiously as possible and to achieve a reduction of the amputation rate in the patients. Unfortunately, approximately a quarter of patients do not partially or fully respond to the standard of care. Advanced therapies for chronic wounds are existing, however, recent guidelines including the latest reviews and meta-analyses of the scientific and clinical evidence available from current treatment strategies and new therapeutic agents revealed that there is a lack of clinical data and persistent gap of evidence for many of the advanced therapeutic approaches. In addition, no pharmacological wound healing product has gained authority approval for more than 10 years in both US and EU, constituting a highly unmet medical need. In this publication we present data from a live biopharmaceutical product AUP1602-C designed as a single pharmaceutical entity based on the non-pathogenic, food-grade lactic acid bacterium Lactococcus lactis subsp. cremoris that has been genetically engineered to produce human fibroblast growth factor 2,interleukin4 and colony stimulating factor 1. Designed to address different aspects of wound healing (i.e. fibroblast proliferation, angiogenesis and immune cell activation) and currently in phase I clinical study, we show how the combination of the individual components on the wound micro-environment initiates and improves the wound healing in chronic wounds.

CCND3 is indispensable for the maintenance of B-cell acute lymphoblastic leukemia.

The D-type cyclins (CCND1, CCND2, and CCND3) in association with CDK4/6 are known drivers of cell cycle progression. We reported previously that inactivation of FOXO1 confers growth arrest and apoptosis in B-ALL, partially mediated by subsequent depletion of CCND3. Given that previously the canonical MYC target CCND2 has been considered to play the major role in B-ALL proliferation, further investigation of the role of FOXO1 in CCND3 transcription and the role of CCND3 in B-ALL is warranted. In this study, we demonstrated that CCND3 is essential for the proliferation and survival of B-ALL, independent of the mutational background. Respectively, its expression at mRNA level exceeds that of CCND1 and CCND2. Furthermore, we identified FOXO1 as a CCND3-activating transcription factor in B-ALL. By comparing the effects of CCND3 depletion and CDK4/6 inhibition by palbociclib on B-ALL cells harboring different driver mutations, we found that the anti-apoptotic effect of CCND3 is independent of the kinase activity of the CCND3-CDK4/6 complex. Moreover, we found that CCND3 contributes to CDK8 transcription, which in part might explain the anti-apoptotic effect of CCND3. Finally, we found that increased CCND3 expression is associated with the development of resistance to palbociclib. We conclude that CCND3 plays an essential role in the maintenance of B-ALL, regardless of the underlying driver mutation. Moreover, downregulation of CCND3 expression might be superior to inhibition of CDK4/6 kinase activity in terms of B-ALL treatment.

Molecular diagnostics and therapies for gastrointestinal tumors: a real-world experience.

PURPOSE: Several targeted agents demonstrated efficacy in early clinical trials for gastrointestinal (GI) cancers, but in many cases, phase-III trials and/or approval by the European Medicines Agency (EMA) are lacking. The primary focus of this study was to assess the regulatory processes associated with use and reimbursement of off-label treatment in precision oncology and to evaluate the benefit of targeted therapy in a real-world population in Germany. METHODS: Our cohort comprises 137 patients with GI cancers and is biased towards cancer entities with a high frequency of known targetable alterations, such as cholangiocarcinoma. Genetic testing was used to identify molecular targets, and therapy response was evaluated based on CT scans. RESULTS: A molecular target for precision oncology was identified in 53 patients and 43 requests for cost coverage were submitted to health insurance companies. 60% of the requests received approval after initial application and another 7% after appeal. Half of the rejected requests were denied despite ESCAT IA level evidence. The median time between initiation of molecular testing and start of therapy was 75 days. 35 patients received matched targeted therapies (n = 28) or, in the case of MSI, immunotherapy (IO) (n = 7). We observed a trend in favor of molecular therapy when compared to the immediate prior treatment. CONCLUSION: Relevant treatment options were identified by molecular testing in a significant subset of patients. When targeted therapies that lack EMA approval are considered, treatment initiation may be delayed by the duration of the molecular analysis and the regulatory processes.

A CT-free protocol to treat osteoid osteoma of the hip region in childhood and adolescence by percutaneous drilling and by hip arthroscopy.

INTRODUCTION: It is often difficult to clinically and radiologically diagnose intra-articular osteoid osteomas and osteoid osteomas of the hip joint. Treatment can also be difficult due to complex locational relationships. CT-guided radiofrequency ablation is currently the standard form of treatment.In this paper we report on a minimally-invasive concept for treating osteoid osteomas near the hip joint in children and adolescents which does not involve using computed tomography. MATERIAL AND METHOD: 10 patients with an average age of 12.1 years underwent treatment for osteoid osteomas in the hip joint region. The diagnosis was made using a contrast-enhanced MRI. The osteoid osteomas were marked percutaneously using x-ray and MRI guidance. MRI-guided drilling/curettage was performed in 4 cases and arthroscopic resection in 6 cases. RESULTS: All lesions were successfully treated using the MRI-guided method. All patients were free of pain after the treatment. There was no instance of recurrence during the follow-up period, which averaged 10 months. The effective dose for marking the lesion was between 0.0186 mSv and 0.342 mSV (mean 0.084 mSV). CONCLUSIONS: Our MRI diagnostics protocol, the MRI-guided drilling and the minimally invasive hip arthroscopy represent an alternative to CT-guided radiofrequency ablation in the treatment of osteoid osteomas. Radiation exposure can thereby be significantly reduced. Hip arthroscopy can also be used to treat secondary pathologies such as femoroacetabular impingement.

Deletion of NEMO Inhibits EMT and Reduces Metastasis in KPC Mice.

Pancreatic ductal adenocarcinoma (PDAC) remains a largely incurable cancer type. Its high mortality is attributed to the lack of efficient biomarkers for early detection combined with its high metastatic properties. The aim of our study was to investigate the role of NF-κB signaling in the development and metastasis of PDAC. We used the well-established KPC mouse model, and, through genetic manipulation, we deleted NF-κB essential modulator (NEMO) in the pancreata of KPC mice. Interestingly, NEMO deletion altered the differentiation status of the primary tumor but did not significantly affect its development. However, in the absence of NEMO, the median survival of the mice was prolonged by 13.5 days (16%). In addition, examination of the liver demonstrated that, whereas KPC mice occasionally developed liver macro-metastasis, NEMO deletion completely abrogated this outcome. Further analysis of the tumor revealed that the expression of epithelial-mesenchymal transition (EMT) transcription factors was diminished in the absence of NEMO. Conclusively, our study provides evidence that NF-κB is dispensable for the progression of high-grade PanINs towards PDAC. In contrast, NF-κB signaling is essential for the development of metastasis by regulating the gene expression program of EMT.

Lower limb reconstruction for malignant bone tumours in children.

Malignant bone tumours of the lower limb represent the majority of cases in both osteosarcoma and Ewing sarcoma in the growth period. Surgical treatment represents a key element of treatment. Different localizations and age groups require a differentiated surgical approach. Life and limb salvage are first on the list of treatment goals, followed by functional and cosmetic considerations. This review article delivers and discusses current surgical treatment strategies and outcomes for lower limb malignant bone tumours in children.

Prospects and Challenges for T Cell-Based Therapies of HCC.

The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.

Chemotherapy and Hepatic Steatosis: Impact on Postoperative Morbidity and Survival after Liver Resection for Colorectal Liver Metastases.

BACKGROUND: Hepatic steatosis and chemotherapy in the treatment of colorectal liver metastases (CLM) are often linked to increased mortality and morbidity after liver resection. This study evaluates the influence of macrovesicular hepatic steatosis and chemotherapeutic regimes on graded morbidity and mortality after liver resection for CLM. METHODS: A total of 323 cases of liver resection for CLM were retrospectively analysed using univariable and multivariable linear, ordinal and Cox regression analyses. The resected liver tissue was re-evaluated by a single observer to determine the grade and type of hepatic steatosis. RESULTS: Macrovesicular steatosis did not influence postoperative morbidity and survival, as evidenced by risk-adjusted multivariable Cox regression analysis (p = 0.521). Conversion chemotherapy containing oxaliplatin was an independent and significant risk factor for mortality in risk-adjusted multivariable Cox regression analysis (p = 0.005). Identified independently, significant risk factors for postoperative morbidity were neoadjuvant treatment of metastases of the primary tumour with irinotecan (p = 0.003), the duration of surgery in minutes (p = 0.001) and the number of intraoperatively transfused packed red blood cells (p ≤ 0.001). Surprisingly, macrovesicular hepatic steatosis was not a risk factor for postoperative morbidity and was even associated with lower rates of complications (p = 0.006). CONCLUSION: The results emphasize the multifactorial influence of preoperative liver damage and chemotherapy on the severity of postoperative morbidity, as well as the significant impact of conversion chemotherapy containing oxaliplatin on survival.

A roadmap to surgery in osteogenesis imperfecta: results of an international collaboration of patient organizations and interdisciplinary care teams.

Background and purpose - Involvement of patient organizations is steadily increasing in guidelines for treatment of various diseases and conditions for better care from the patient's viewpoint and better comparability of outcomes. For this reason, the Osteogenesis Imperfecta Federation Europe and the Care4BrittleBones Foundation convened an interdisciplinary task force of 3 members from patient organizations and 12 healthcare professionals from recognized centers for interdisciplinary care for children and adults with osteogenesis imperfecta (OI) to develop guidelines for a basic roadmap to surgery in OI.Methods - All information from 9 telephone conferences, expert consultations, and face-to-face meetings during the International Conference for Quality of Life for Osteogenesis Imperfecta 2019 was used by the task force to define themes and associated recommendations.Results - Consensus on recommendations was reached within 4 themes: the interdisciplinary approach, the surgical decision-making conversation, surgical technique guidelines for OI, and the feedback loop after surgery.Interpretation - The basic guidelines of this roadmap for the interdisciplinary approach to surgical care in children and adults with OI is expected to improve standardization of clinical practice and comparability of outcomes across treatment centers.

ω-Imidazolyl-alkyl derivatives as new preclinical drug candidates for treating non-alcoholic steatohepatitis.

Cytochrome P450 2E1 (CYP2E1)-associated reactive oxygen species production plays an important role in the development and progression of inflammatory liver diseases such as alcoholic steatohepatitis. We developed two new inhibitors for this isoenzyme, namely 12-imidazolyl-1-dodecanol (I-ol) and 1-imidazolyldodecane (I-an), and aimed to test their effects on non-alcoholic steatohepatitis (NASH). The fat-rich and CYP2E1 inducing Lieber-DeCarli diet was administered over 16 weeks of the experimental period to induce the disease in a rat model, and the experimental substances were administered simultaneously over the last four weeks. The high-fat diet (HFD) pathologically altered the balance of reactive oxygen species and raised the activities of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP) and γ-glutamyl-transferase (γ-GT); lowered the level of adiponectine and raised the one of tumor necrosis factor (TNF)-α; increased the hepatic triglyceride and phospholipid content and diminished the serum HDL cholesterol concentration. Together with the histological findings, we concluded that the diet led to the development of NASH. I-ol and, to a lesser extent, I-an shifted the pathological values toward the normal range, despite the continued administration of the noxious agent (HFD). The hepatoprotective drug ursodeoxycholic acid (UDCA), which is used off-label in clinical practice, showed a lower effectiveness overall. I-ol, in particular, showed extremely good tolerability during the acute toxicity study in rats. Therefore, cytochrome P450 2E1 may be considered a suitable drug target, with I-ol and I-an being promising drug candidates for the treatment of NASH.