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Lege Artis Medicinae

SEPTEMBER 30, 2020

[The pain-trigger role of cytokines in the nervous system – the direct analgesic effect of anti-cytokine therapy ]


[Nociceptive, neuropathic and central me­chanisms are involved in the perception, transmission and processing of chronic pain and shaping of cerebral pain image. Alar­mins – molecules alarming defence and signing the presence of pathogens and tissue damage - trigger a series of pathogenic events resulting in inflammatory pain stimuli. Proinflammatory cytokines play a determining role in the pain perception at the level of the nervous system. Continuous inflammatory stimuli while sensitizing the periferic and central neurons activate the pain-related cerebral areas and develop the complex pain image, the pain matrix. Ce­reb­ral functional connections are operating in networks and can be visualized by functional MRI. Cytokines activate the neurons directly or indirectly by other neuromediators. Cytokine receptors are expressed on no­ciceptors and even on higher-level neurons and on various non-neural cells, such as microglia and astrocytes. The most ubiquitous cytokines are the Tumour Necrosis Factor and Interleukin 6 in the nervous sys­tem. The signaling pathways are the Nuclear Factor κB and the Janus-kinase enzyme system. The proinflammatory cytokines and the Janus-kinase are therefore primary therapeutic targets. Anti-cytokine biologicals and small molecular kinase inhibitors decrease the pain and improve functional activity in rheumatoid arthritis. Decrease of pain was more pronounced than expected only from the decrease of the clinical biomarkers of inflammation. The early and ra­pid painkiller effect of targeted biological and chemical-biological response modifiers is attributed to their direct analgesic effect on the brain.]

Clinical Neuroscience

JULY 30, 2020

[Recurrent inhibition during Jendrassik maneuver]


[Objective – Conflicting theoretical models exist regarding the mechanism related to the ability of the Jendrassik maneuver to reinforce reflex parameters. Our objective was to investigate if vigorous handgrip would induce changes in recurrent inhibition of soleus motoneurons. Method – Soleus H reflex was evoked by stimulating the tibial nerve at rest and during bilateral vigorous handgrip, alternating single (H1) and paired stimulation (H2). At paired stimulation we used interstimulus intervals of 10, 15, 20 and 25 ms and supramaximal test stimulus. H1- and H2-wave amplitudes were expressed as percentage of maximal M-wave amplitude. Conditioned H2 wave maximal (H2max) and minimal (H2) amplitudes evoked at rest and expressed as a percentage of the unconditioned H1max amplitude were compared with the corresponding values obtained during handgrip by means of paired Student test and Bonferroni correction. Subjects – At the study participated 28 healthy volunteers. Results – The H1max/Mmax × 100 values obtained during handgrip (37.5±10.1) were significantly higher than those obtained at rest (27.1±7.4). The H2max/H1max × 100-va­lues obtained at paired stimulation were significantly higher during handgrip than at rest, while no significant diffe­rence was found between the H2/H1max × 100-values obtained during handgrip and at rest respectively. Discussion – The H2max/H1max is determined by both the excitability of the motoneurons and the recurrent inhibition elicited by the conditioning stimulus, while H2/H1max indicates only the level of recurrent inhibition. According to our results the Renshaw cells retain their inhibitory effect on the soleus alpha motoneurons during remote muscle contraction. Conclusion – Soleus H reflex enhancement during Jendrassik maneuver is not due to decrease of recurrent inhibition. ]

Clinical Oncology

APRIL 10, 2019

[New perspectives in the treatment of lung cancer]

SZONDY Klára, BOGOS Krisztina

[In recent years, huge research is going on in the fi eld of oncology and as a result, we can see a signifi cantly longer survival in this area of medicine. Lung cancer, which has been taken places in the back for decades, it has not become a curable disease, but begins to belong to the chronic diseases. As a result of brilliant surgical technics and stereotactic radiotherapy, or as a result of changes in drug treatment, 5-year survival is not uncommon in metastatic lung cancer patients, next to relatively long progression free survive. After the third-generation cytotoxic combinations the added growth inhibition (VEGF inhibitor) maintenance therapy or continuous pemetrexed cytotoxic chemotherapy were resulted in high survival benefi ts. The fi rst real breakthrough, long progression-free survival was achieved by targeted treatment, which proved to be effective with known driver mutations. The other great result, especially in squamous cell carcinoma, was the immunotherapy, the inhibition of immune checkpoints, which effi cacy was confi rmed in adenocarcinoma also. Several studies are going on with adjuvant or neoadjuvant immunotherapy, and combined use of immunotherapy (either in combination with radiotherapy or cytotoxic chemotherapy).]

Clinical Oncology

FEBRUARY 20, 2019

[Molecular subtypes and the evolution of treatment decisions in metastatic colorectal cancer]

RODRIGO Dienstmann, RAMON Salazar, JOSEP Tabernero

[Colorectal cancer (CRC) has clinically-relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations defi ne a population refractory to EGFR monoclonal antibodies, BRAFV600E mutations associate with poor outcome under standard therapies and response to targeted inhibitors in combinations, while HER2 amplifi cations confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to EGFR monoclonal antibodies have been described with signifi cant overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers refl ect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable (MSI) or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, while tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratifi ed development of novel immunotherapy combinations. In this manuscript we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.]

Lege Artis Medicinae

JULY 20, 2019

[Severe polymyositis associated with multiplex pulmonary abscesses]

SZABÓ Katalin, VINCZE Anett, NAGY-VINCZE Melinda, DANKÓ Katalin, GRIGER Zoltán

[INTRODUCTION – Idiopathic inflammatory myopathies are heterogeneous autoimmune diseases characterized by immune mediated inflammation of the skeletal muscles. CASE REPORT – A case of a 62-year-old male patient with severe proximal muscle weakness, elevated creatine kinase and swallowing difficulity is presented. Electromyography showed myogenic pattern, thus probable polymyositis was diagnosed. Radiological examination has confirmed bilateral multiplex lung lesions, which were caused by the possibility of tumor, tuberculosis, vasculitis and abscess as well. The condition of the patient deteriorated, nasogastric feeding, high dose steroid treatment was initiated, which reduced the patient's creatinine kinase values, but muscle strength was not changed. Based on the results of various investigations, the condition of the patient was finally confirmed by the development of myositis, resulting dysphagia, chronic aspiration, and multiplex lung abscess. Antibiotic therapy, steroid treatment was continued and finally intravenous immunoglobulin treatment was administered. The condition of the patient gradually improved, the swallowing dysfunction disappeared, and the lung abscesses were resolved. As a result of physiotherapy and rehabilitation treatment, the patient could walk again. CONCLUSIONS – Nasogastric feeding is recommended to prevent aspiration in the case of myositis-associated dysphagia. In case of steroid refractory therapy, the use of intravenous immunoglobulin may be effective. ]

Lege Artis Medicinae

MAY 20, 2019

[Immuno-oncology therapy in patients with non-small cell lung cancer]


[Despite decades of smoking cessation programs, and lung cancer screening programs, mortality due to bronchial cancer leads the mortality statistics among cancer deaths worldwide. Platinum-based chemotherapy has not fundamentally altered the effectiveness of treating non-small cell lung cancer (NSCLC). One of the newest approaches to the use of immunotherapeutic treatments in recent years is the so-called. use of immune checkpoint blocking agents. PD-1 and PD-L1 blockers of this type have been subjected to a large number of clinical trials in lung cancer and were reported by the tumor III.b / IV. stage. Last year, in 2018, we again came up with a milestone in the treatment of lung cancer immuno-oncology, as compared to the previous stage, III.a / III.b Durvalumab con­solidation therapy for non-small cell lung cancer after inoperative, non-chemo-radiotherapy phase I, is based on the results of the PACIFIC clinical trial. PACIFIC was a triple-phase, randomized, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of durvalumab consolidation therapy, irresistible, III. patients with non-small cell lung carcinoma who have not progressed after platinum-based chemo-radiotherapy. The PD-L1 expression level of the tumor was not an admission criterion. In the study, 713 patients were randomized to durvalumab and placebo for 2:1, progression-free survival (PFS) and over­all survival (OS) as their primary endpoint. Summarizing the results of the study, durvalumab provided significant benefit to patients at both endpoints. PFS and OS values were also significantly longer for durvalumab than placebo, and the safety profile of durvalumab was consistent with previous PD-1, PD-L1 inhibition tests.]

Lege Artis Medicinae

JUNE 20, 2018

[Treatment of EGFR mutant lung adenocarcinoma after progression]

BOGOS Krisztina

[Precision medicine proposes the personalization of health services in order to make the best individual decisions about the interventions and treatments for the patient. Molecular genetic diagnostic tests help to select the appropriate therapy, so-called targeted therapy. In the case of extensive lung cancer with EGFR mutation, EGFR tyrosine kinase inhibitors are immediately applicable; they are very effective and can reach long-term remission of the disease. However, resistance mutation can develop during the treatment, which causes the progression of the disease; therefore change of therapy is needed. In our case, we show the possibility of targeted treatment beyond the progression, emphasizing the importance of detecting resistance mutation. ]

Clinical Oncology

DECEMBER 05, 2017

[Complex therapy of bladder cancer]


[Bladder cancer is the most common malignancy involving the urinary system. Urothelial (formerly called transitional cell) carcinoma is the predominant histologic type in the developed countries, where it accounts for approximately 90 percent of all bladder cancers. The optimal management of nonmuscle invasive urothelial cancer is highly important. For patients with muscle invasive cancer the gold standard treatment is the cystectomy. If the patient unable or unwilling to undergo radical cystectomy with urinary diversion, complete TURBT combined with radiation therapy plus chemotherapy may offer an alternative bladder-sparing approach. Patients with muscle invasive disease and regional lymph node metastasis limited to the pelvis (N1-N3), but without more distant lymph node or visceral metastasis may be treated with six cycles of cisplatin-based chemotherapy followed by cystectomy or a combined-modality approach. In metastatic cases the combination chemotherapy may prolong survival and often provides palliation of symptomatic disease. Checkpoint inhibition immunotherapy has substantial clinical activity in post-chemotherapy patients and is the preferred therapy for patients who have progressed after platinumbased therapy or is not suitable for them.]

Clinical Oncology

DECEMBER 05, 2017

[Inhibition of proteasome in cancer therapy]


[The ubiquitin-proteasome pathway is the most important element in the regulation of intracellular protein metabolism. Its main function is the degradation of the unnecessary proteins either as part of normal metabolic balance or in case of misfolding or part of the deregulation as in cancer cells using proteolytic enzymes. The importance of this pathway has been acknowledge by Nobel prize. In certain diseases as in several malignancies, where the ubiquitin-proteasome pathway is not able to remove the proteins due to dysfunction or accumulation in a high quantity. The unregulated accumulation of proteins could lead to cell death. This phenomenon was proven by the appearance of proteasome-inhibitors targeting mainly myeloma. It should be mentioned that clinical aspects myeloma has been discussed in an excellent review by Mikala and his colleagues in Klinikai Onkológia.]