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Lege Artis Medicinae

APRIL 18, 2020

[Interrelations between antidepressants and diabetes]

HARGITTAY Csenge, GONDA Xénia, MÁRKUS Bernadett, VÖRÖS Krisztián, TABÁK Gy. Ádám, KALABAY László, RIHMER Zoltán, TORZSA Péter

[Diabetes and depression are frequent comorbidities. They are a heavy burden by themselves, however, as comorbidities increase additionally the number of diabetes-related complications, morbidity, and mortality. In the background of interrelations, there are both well-known and hypothetical mechanisms. The aim of the present review is to outline these interrelations between antidepressants and diabetes and to discuss the effect of medications on carbohydrate metabolism respectively. Anti­depressant treatment on the one hand may improve mood, cognitive function and medication adherence leading to an improved glucose metabolism, on the other hand through their metabolic side effects, they may worsen carbohydrate metabolism. Concerning metabolic side effects, selec­tive serotonin reuptake inhibitors are the sa­fest, while tricyclic antidepressants and mo­noamine oxidase inhibitors should be administered under close monitoring. Se­rotonin and noradrenaline reuptake inhibitors may deteriorate gly­cae­mic control via increased noradre­nergic activation. Novel antidepressants, how­ever, have a neutral or positive impact on gly­caemic measures. Screening for and temporally adjusted treatment of depres­sion may decrease the risk of comorbidities ge­nerated complications. While caring for diabetic patients with depression, one should consider metabolic side effects of antidepressants and close monitoring of carbohydrate metabolism.]

Clinical Oncology

APRIL 10, 2019

[CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions]

SPRING M. Laura, WANDER A. Seth, ZANGARDI Mark, BARDIA Aditya

[Purpose of review: To describe the clinical role of CDK 4/6 inhibitors in hormone receptor-positive (HR+) metastatic breast cancer (HR+MBC) as well as current controversies and evolving areas of research. Recent fi ndings: Palbociclib, ribociclib, and abemaciclib are each approved in combination with an aromatase inhibitor or fulvestrant for HR+MBC. Abemaciclib is also approved as monotherapy for pre-treated patients. Key questions in the fi eld include whether all patients with HR+MBC should receive a CDK 4/6 inhibitor up front versus later line, impact on overall survival, role of continued CDK 4/6 blockade, mechanism of clinical resistance, and treatment sequencing. Summary: The development of CDK 4/6 inhibitors has changed the therapeutic management of HR+MBC. Additional research is needed to determine optimal treatment sequencing, understand mechanisms governing resistance, and develop novel therapeutic strategies to circumvent or overcome clinical resistance and further improve the outcomes of patients with MBC.]

Hypertension and nephrology

SEPTEMBER 12, 2018

[Treatment of hypertension in kidney transplant patients]

KOVÁCS Tibor, WAGNER László

[Most of the renal transplant recipients suffer from hypertension. Hypertension substantially contributes to the high cardiovascular mortality in this population. The recommendation of the Hungarian Society of Hypertension and the international guidelines suggest to achieve less than 130/80 mmHg as target blood pressure in these patients. Several factors may be in the background of hypertension after kidney transplantation, which can be summarized as factors from the recipient-side, the donorside and factors provoked by transplantation itself. In most of the cases early after transplantation high doses of immunosuppressive drugs (especially calcineurin inhibitors and steroids) are responsible for the increased blood pressure. There are some further special methods apart from the general recommendations which are needed during the examination of hypertension of kidney transplant patients: e.g. measurement of blood trough-level of immunosuppressive drugs, investigation of bone-mineral disorder, screening for the level and causes of anaemia, check-up of the renal graft circulation. Kidney transplant patients suffering from hypertension usually need more than two antihypertensive drugs beyond the use of non-pharmaceutical antihypertensive methods. In the early posttransplantation period calcium channel blockers are preferred antihypertensive medications, because they counterbalance the vasoconstrictive effect of calcineurin inhibitors. The administration of renin-angiotensin-aldosterone inhibitors are rather suggested after the stabilization of renal function (from the 1-3 months posttransplantation). When designing antihypertensive strategy, comorbidities and special factors should be regarded as well, especially volume overload, proteinuria, allograft function (GFR), diabetes, other cardiovascular risk factors, previous cardiovascular events. The setup of an individual therapeutical strategy is advised in view of all these factors, which is different according to the timing after transplantation: the perioperative, the early postoperative phases and from 1-3 months after transplantation have special focuses.]

Clinical Neuroscience

JANUARY 30, 2021

Electrophysiological investigation for autonomic dysfunction in patients with myasthenia gravis: A prospective study

NALBANTOGLU Mecbure, AKALIN Ali Mehmet, GUNDUZ Aysegul, KIZILTAN Meral

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission. Autonomic dysfunction is not a commonly known association with MG. We conducted this study to evaluate autonomic functions in MG & subgroups and to investigate the effects of acetylcholinesterase inhibitors. This study comprised 30 autoimmune MG patients and 30 healthy volunteers. Autonomic tests including sympathetic skin response (SSR) and R-R interval variation analysis (RRIV) was carried out. The tests were performed two times for patients who were under acetylcholinesterase inhibitors during the current assessment. The RRIV rise during hyperventilation was better (p=0.006) and Valsalva ratio (p=0.039) was lower in control group. The SSR amplitudes were lower thereafter drug intake (p=0.030). As much as time went by after drug administration prolonged SSR latencies were obtained (p=0.043).Valsalva ratio was lower in the AchR antibody negative group (p=0.033). The findings showed that both ocular/generalized MG patients have a subclinical parasympathetic abnormality prominent in the AchR antibody negative group and pyridostigmine has a peripheral sympathetic cholinergic noncumulative effect.

Clinical Neuroscience

JANUARY 30, 2021

Matrix metalloproteinases and their tissue inhibitors in relapsing remitting multiple sclerosis: Possible markers and treatment agents

SANLI Arzu, OZTURK Musa, SOYSAL Aysun, DOVENTAS Yasemin, BASOGLU Fulya, GOZUBATIK-CELIK R. Gokcen, BAYBAS Sevim

Matrix metalloproteinases (MMPs), which are synthesized by many cell groups and responsible for the destruction of matrix proteins, and endogen tissue inhibitors of MMPs (TIMPs) have a role in the pathogenesis of Multiple Sclerosis (MS) by affecting the blood-brain barrier. We aimed to investigate the role of MMPs and TIMPs in the immunopathogenesis and in the course of multiple sclerosis (MS). We enrolled 25 relapsing remitting MS patients, who had a definite MS diagnosis according to McDonald criteria and 25 healthy subjects similar for age and gender as control group. MMP-9- and TIMP-1 levels were measured twice in patient group (one time during an attack and one in remission) and once in healthy subjects. MMP-9- and TIMP-levels of patients during attack and remission period and MMP-9/TIMP-1 ratio were found significantly higher than in the control subjects. In patient group MMP-9 and TIMP-1 levels and MMP-9/TIMP-1 ratio during attacks were not significantly different than during remission period. However, when subdivided according to their number of attacks, patients with 2 attacks had significantly higher levels during attack period comparing to remission period (p<0.05); in case of patients with more than 2 attacks did not have a statistically significant difference in attack and remission periods. Matrix metalloproteinases are important actors in MS immunopathogenesis, particularly in the early period and inhibitor agents for these enzymes can be used as a treatment option.

Clinical Oncology

FEBRUARY 28, 2020

[Non-surgical treatment of ovarian cancer]

PIKÓ Béla, LACZÓ Ibolya,, MARIK László

[The primary surgery with an optimal cytoreduction is an essential step during the treatment of the epithelial ovarian cancer because it determines the effectiveness of other therapeutic options as well. Immediately after the surgery a cytostatic infusion typically 40-42.5 degrees Celsius is pumped directly to the abdomen. During the systemic therapy the main point is the 6 months progression free survival because beyond this time the disease could be considered as platinum sensitive, inside this time as platinum refracter or resistant disease. The cytostatic treatment improved during the years from the alkylating agents through the platinum derivates to the administration of paclitaxel with several combinations of them and with more and more signifi cant results and less side effects. The most signifi cant targeted agents are the angiogenesis inhibitors (mainly the bevacizumab) and the PARP-inhibitors which prevents DNA repairs. In order to a PARP-inhibitor could be administered a platinum sensitivity is required while BRCA mutation not. Recently there are promising clinical researches with immunotherapy as well. The main benefi t of the hormonal therapy is the tolerability. Besides the signifi cant improvement in the systemic agents the role of radiotherapy is more and more decreasing, however the treatment of the whole peritoneal surface – mainly with the modern radiation techniques – could be an alternative solution for the chemotherapy. The palliative irradiation which relieve the symptoms could extend the drug-free period and the combination of radiation and chemotherapy could provide further possibilities.]

Clinical Oncology

FEBRUARY 28, 2020

[Treatment sequencing in metastatic colorectal cancer]

MODEST D. P., PANT S., SARTORE-BIANCHI A.

[Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival has improved with advances in cytotoxic chemotherapy and targeted agents. However, the optimal use and sequencing of these agents across multiple lines of treatment is unclear. Here, we review current treatment approaches and optimal treatment sequencing across the fi rst-, second- and third-line settings in mCRC, including biological aspects affecting sequencing and rechallenge. Effective fi rst-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in fi rst-line. Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and afl ibercept) are indicated for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not improve survival in the second-line setting. Molecular profi ling is important in thirdline treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib and trifl uridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab may be considered for patients with high microsatellite instability disease. Targeting HER2/neu amplifi cation shows promise for the subset of CRC tumours displaying this abnormality. Sequencing decisions are complicated by the potential for any treatment break or de-escalation to evoke a distinct clinical progression type. Ongoing trials are investigating the optimal sequencing and timing of therapies for mCRC. Molecular profi ling has established new targets, and increasing knowledge of tumour evolution under drug pressure will possibly impact on sequencing.]

Clinical Oncology

DECEMBER 30, 2019

[Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond]

MASATOSHI Kudo

[Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since the survival benefi t of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacifi c trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However, development of a more potent fi rst-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1st line and 2nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed. On the other hand, clinical trials of 4 agents (regorafenib, lenvatinib, cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible (regorafenib and lenvatinib) or underway (cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization (TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib (TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early, intermediate and advanced stage, is expected to be changed drastically in the very near future.]

Clinical Neuroscience

MARCH 30, 2016

[The importance of anticoagulant therapy in patients with artial fibrillation in stroke prevention – summary of international data and novel therapeutic modalities]

MIROLOVICS Ágnes, PAPP Csaba, ZSUGA Judit, BERECZKI Dániel

[The most common cardiogenic cause of ischaemic stroke is atrial fibrillation which increases the probability of stroke five-fold and doubles case fatality. Based on international data the incidence of atrial fibrillation is approx. 2% however this rapidly increases with age. The necessity of using oral anticoagulants in the prevention of non-valvular atrial fibrillation related stroke is decided based on estimated stroke risk. The CHADS2 and the more predictive CHA2DS2-VASc scales are used for this purpose while the bleeding risk of patients treated with anticoagulant may be estimated by the HAS-BLED scoring scale. For decades oral anticoagulation meant using vitamin-K antagonists. Based on international data we can see that rate of anticoagulation is unacceptably low, furthermore most of the anticoagulated patients aren’t within the therapeutic range of INR (INR: 2-3). A lot of disadvantages of vitamin-K antagonists are known (e.g. food-drug interaction, need for regular coagulation monitoring, increased risk of bleeding), therefore compounds with new therapeutic target have been developed. The novel oral anticoagulants (NOAC) can be divided in two major subgroups: direct thrombin inhibitors (dabigatran etexilate) and Xa-factor inhibitors (rivaroxaban, apixaban, edoxaban). These products are administered in fix doses, they less frequently interact with other medications or food, and regular coagulation monitoring is not needed when using these drugs. Moreover several studies have shown that they are at least as effective in the prevention of ischaemic stroke than the vitamin-K antagonists, with no more haemorrhagic complications.]

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.]