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Lege Artis Medicinae

NOVEMBER 30, 2020

[Some newly discovered mechanisms of action of the immune response and the conceptual transformation of immunology]

FALUS András

[Immunology is a complex science studying healthy and abnormal immune responses. This discipline of physiology and pathophysiology primarily understands the individual mechanisms through a cellular and molecular biological, genetic, epigenetic and (neuro) endocrinological approach, as well as by exploring the details of pathological processes. Im­mu­nology is one of the very rapidly evolving sciences, and its results have repercussions on other disciplines at both theoretical (eg network sciences, systems biology) and methodological (monoclonal antibodies, biomarkers, immune assays) levels. In recent decades, a number of conceptual novelty have been uncovered and immunologists have recognized essential details in their assertion in immunity. ]

Clinical Neuroscience

SEPTEMBER 30, 2020

Late simultaneous carcinomatous meningitis, temporal bone infiltrating macro-metastasis and disseminated multi-organ micro-metastases presenting with mono-symptomatic vertigo – a clinico-pathological case reporT

JARABIN András János, KLIVÉNYI Péter, TISZLAVICZ László, MOLNÁR Anna Fiona, GION Katalin, FÖLDESI Imre, KISS Geza Jozsef, ROVÓ László, BELLA Zsolt

Although vertigo is one of the most common complaints, intracranial malignant tumors rarely cause sudden asymmetry between the tone of the vestibular peripheries masquerading as a peripheral-like disorder. Here we report a case of simultaneous temporal bone infiltrating macro-metastasis and disseminated multi-organ micro-metastases presenting as acute unilateral vestibular syndrome, due to the reawakening of a primary gastric signet ring cell carcinoma. Purpose – Our objective was to identify those pathophysiological steps that may explain the complex process of tumor reawakening, dissemination. The possible causes of vestibular asymmetry were also traced. A 56-year-old male patient’s interdisciplinary medical data had been retrospectively analyzed. Original clinical and pathological results have been collected and thoroughly reevaluated, then new histological staining and immunohistochemistry methods have been added to the diagnostic pool. During the autopsy the cerebrum and cerebellum was edematous. The apex of the left petrous bone was infiltrated and destructed by a tumor mass of 2x2 cm in size. Histological reexamination of the original gastric resection specimen slides revealed focal submucosal tumorous infiltration with a vascular invasion. By immunohistochemistry mainly single infiltrating tumor cells were observed with Cytokeratin 7 and Vimentin positivity and partial loss of E-cadherin staining. The subsequent histological examination of necropsy tissue specimens confirmed the disseminated, multi-organ microscopic tumorous invasion. Discussion – It has been recently reported that the expression of Vimentin and the loss of E-cadherin is significantly associated with advanced stage, lymph node metastasis, vascular and neural invasion and undifferentiated type with p<0.05 significance. As our patient was middle aged and had no immune-deficiency, the promoting factor of the reawakening of the primary GC malignant disease after a 9-year-long period of dormancy remained undiscovered. The organ-specific tropism explained by the “seed and soil” theory was unexpected, due to rare occurrence of gastric cancer to metastasize in the meninges given that only a minority of these cells would be capable of crossing the blood brain barrier. Patients with past malignancies and new onset of neurological symptoms should alert the physician to central nervous system involvement, and the appropriate, targeted diagnostic and therapeutic work-up should be established immediately. Targeted staining with specific antibodies is recommended. Recent studies on cell lines indicate that metformin strongly inhibits epithelial-mesenchymal transition of gastric cancer cells. Therefore, further studies need to be performed on cases positive for epithelial-mesenchymal transition.

Lege Artis Medicinae

JULY 01, 2020

[Persisting Hashimoto’s thyroiditis converting to Graves’ disease]

TÓTH Géza

[Graves’disease and Hashimoto’s thyroiditis are the two most important types of autoimmune thyroid dis­eases. Autoimmune hyperthyroidism commonly leads later on to hypothyroidism. The conversion from persisting Hashimoto-thyroiditis to hyperthyroidism is rare in the literature. The author presents the cases of two patients, whose Hashimoto’s thyroiditis treated with thyroxin for years, changed into Graves’ hyperthyroidism sponta­neously. CASE REPORT – The patients had been diagnosed with autoimmune hypothyroidism since several years. The clinical symp­­toms, the low peripheral hormone le­vels, the high level of antithyroid antibo­dies and the ultrasound imaging confirmed the hypertrophic form of Hashimoto’s thy­roiditis. After several years of high dose le­vothyroxin treatment, clinical symptoms of hyperthyroidism have appeared. After omit­ting the substitution, the thyroid hormone levelled off at high values and the level of anti-TSH receptor antibodies raised too. The diffuse, obviously increased blood flow of the thyroid glands, and in one of the patients the thyroid scan, confirmed the Graves’ disease. During the thyreostatic treatment, the symptoms of the patients disappeared, they became euthyreoid and the antibody levels decreased as well. The Graves’ disease and the Hashimoto’s thyroiditis have many common features. These immunological, ge­netic and other common features enable the mutual transition of these two diseases.]

Clinical Neuroscience

MARCH 30, 2020

CANOMAD syndrome with respiratory failure

SALAMON András, DÉZSI Lívia, RADICS Bence, VARGA Tímea Edina, HORTOBÁGYI Tibor, TÖMÖSVÁRI Adrienn, VÉCSEI László, KLIVÉNYI Péter, RAJDA Cecília

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, M-protein agglutination, disialosyl antibodies) syndrome is a rare polyneuropathy. IgM paraproteins react with ganglioside-containing disialylated epitopes resulting in dorsal root ganglionopathy and B-lymphocyte infiltration of cranial and peripheral nerves. Clinical features include ataxia, slight muscle weakness, areflexia, sensory- and cranial nerve symptoms. Case studies have reported the efficacy of rituximab and intravenous immunoglobulin (IVIg) treatments. We present the case of a 57-year-old man, who had difficulty walking, with numbness and clumsiness in all limbs. He had areflexia, vibratory sensation loss and ataxia. Laboratory tests showed IgM monoclonal components and disialosyl antibodies in the serum. Nerve conduction studies indicated severe sensorimotor demyelinating polyneuroradiculopathy. Despite IVIg and rituximab treatments, the patient’s disease course gradually worsened and he died of respiratory failure. Neuropathological examination revealed dorsal column- and dorsal root atrophy with mixed mononuclear cell infiltration. This article aims to draw attention to this syndrome, and the use of early potent immunosuppressive treatment to improve patients’ quality of life.

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

SEPTEMBER 10, 2019

[Anti-allergic agents and ICAM-1-antibodies for the control of upper respiratory infections]

SZABADKA Hajnalka

[Rhinoviruses are responsible for more than 50 percent of upper respiratory infections. It is well-established that the „Intercellular Adhesion Molecule 1” (ICAM-1) plays a crucial role in the adhesion of rhinoviruses and the relevant secondary bacterial pathogen Haemophilus influenzae to the epithelial cells of the respiratory tract. Both rhinoviruses and H. influenzae enhance the expression of ICAM-1 promoting their own attachment and mutually promoting that of the associated pathogen. It was experimentally shown that anti-ICAM-1 antibodies will inhibit infection by both rhinoviruses and H. influenzae. Since some anti-allergic agents - desloratadine and levocetirizine - also inhibit the expression of ICAM-1, their use may be beneficial in controlling some respiratory infections ]

Clinical Neuroscience

JULY 30, 2019

A case report of Morvan syndrome

AYTAC Emrah, ACAR Türkan

Morvan syndrome is a rare disease characterized by peripheral nerve hyperexcitability, encephalopathy, dys­autonomia and significant insomnia. The patient, who was included in the present study, was followed-up at our clinics for confusion, myokymia, hyperhidrosis, epileptic seizures, tachycardia, agitation, hypokalemia, and hyponatremia. The cranial MRI of the patient demonstrated hyperintensities at the T2 and FLAIR sections of the medial temporal lobe and insular lobes. Electromyography and neurotransmission examination results were concordant with peripheral nerve hyperreactivity. Contactin-associated protein-like 2 antibodies and leucine-rich glioma inactivated protein 1 antibodies were detected as positive. The patient was diagnosed with Morvan syndrome; intravenous immunoglobulin and corticosteroid treatment was started. Almost full remission was achieved. This very rare syndrome implies challenges in diagnosis and treatment; however, remission can be achieved during the follow-up. In addition, caution is needed in the long-term follow-up of these patients regarding the development of malignancies.

Clinical Oncology

SEPTEMBER 10, 2017

[Challenges in Molecular Targeted Therapy for Gastric Cancer: Considerations for Effi cacy and Safety]

KEI Muro

[The Cancer Genome Atlas Research Network recently proposed a molecular classifi cation for gastric cancer (GC) into four subtypes based on comprehensive evaluation. While the mechanisms of molecular targeted therapies in GC were confi rmed by multiple clinical studies, only a limited number of therapeutics for GC have been approved to date. In this systematic review of the available literature, we discuss the completed and ongoing clinical trials of molecular targeted therapies in patients with GC, with a focus on their effi cacy and safety. Results of recent studies clearly demonstrated that trastuzumab and ramucirumab, monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF), respectively, improved overall survival (OS) in GC with manageable safety profi les. Careful surveillance of ongoing clinical trials and timely profi ling and monitoring of genetic signatures are imperative to establish a strong foundation for precision medicine in GC.]

Hypertension and nephrology

OCTOBER 20, 2017

[New results on the pathomechanism of antibody-mediated renal allograft rejection]

MEZÔ Blanka, ANDREAS Heilos, RUSAI Krisztina, PROHÁSZKA Zoltán

[Antibody mediated rejection (ABMR) is a severe clinical problem which is the major immunological cause of kidney transplant failure and may develop slowly months or years after transplantation. According to current knowledge, late ABMR is classically caused by the development of donor specific antibodies (DSA) and the complement system is believed to contribute to tissue damage. The detection of ABMR has been facilitated by improved techniques and new test, resulting in changes of the diagnostic criteria from time to time. The clinical interpretation of DSAs is still not clear however the complement binding ability could help to judge their relevance. In this review we discuss the new results on the pathomechanism and current diagnostic guideline of ABMR. Identification and treatment of ABMR before onset of clinical symptoms is still a big challenge but may lead to a significantly better outcome. In our study we are investigating the role of the complement system including quantitative and genetic testing of several complement proteins that can serve as a diagnostic/prognostic marker of the disease.]