Nejnovější poznatky v biologii chronické lymfocytární leukemie (CLL) mají významný dopad na léčbu tohoto onemocnění. Buňky CLL vykazují závislost na zvýšené expresi BCL-2, autonomní BCR signalizaci a vyznačují se nadměrnou expresí delta izoformy p110 PI3K kinázy a BTK kinázy, která podporuje přežívání nádorových buněk. Cílená léčba monoklonálními protilátkami rituximabem a obinutuzumabem spolu s malými molekulami, jako je ibrutinib, idelalisib a venetoklax, výrazně rozšířila terapeutické možnosti, což vedlo ke zlepšení celkového přežití pacientů. V této souvislosti je pozoruhodné, že pacienti, kteří zahájili léčbu ibrutinibem, vykazují míru přežití srovnatelnou s celkovou populací. Ne všechny problémy spojené s CLL však byly vyřešeny, neboť stále přetrvávají otázky týkající se dysfunkce imunitního systému a sekundárních malignit, jednotnosti léčebných přístupů pro pacienty s vysokým a nízkým rizikem, dlouhodobých strategií pro mladé pacienty a terapie pro pacienty s Richterovou transformací. Přestože inhibitory BTK a BCL-2 mohou pozitivně ovlivnit imunitní systém, problémy spojené s infekcemi a sekundárními nádory přetrvávají. Pokud jde o Richterovu transformaci, identifikace specifických genetických abnormalit může v budoucnu umožnit cílenější a účinnější léčbu, včetně terapie CAR-T a bispecifických protilátek.

New findings in the biology of chronic lymphocytic leukemia (CLL) have major implications for the treatment of this disease. CLL cells exhibit a dependence on increased expression of BCL-2, an autonomous BCR signaling pathway, and are charac­terized by overexpression of the p110 PI3K delta kinase isoform and BTK kinase, which promotes tumor cell survival. Targeted therapies such as the monoclonal antibodies rituximab and obinutuzumab, along with small molecules such as ibrutinib, idelalisib, and venetoclax, have dramatically expanded therapeutic options, resulting in improved overall patient survival. In this context, it is note­worthy that patients starting treatment with ibrutinib have survival rates comparable to the general population. However, not all issues have been resolved, as there are questions regarding the immune system, consistency in treatment approaches and long-term strategies for young patients, especially those with Richter transformation. Although BTK and BCL-2 inhibitors can positively influence the immune system, we still face challenges related to infections and secondary tumors. Regarding Richter transformation, identification of specific genetic abnormalities may allow more targeted and effective therapies in the future, including CAR-T therapy and bispecific antibodies.

• Keywords
• Richterova transformace,
• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   genetics   pathology   MeSH
• Immune System immunology   pathology   MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors   MeSH
• Antineoplastic Agents administration & dosage   therapeutic use   MeSH
• Antineoplastic Protocols MeSH
• Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH

PICC-port představuje nový druh dlouhodobého žilního přístupu, který je indikován čím dál častěji z důvodu snížení rizika komplikací při zavádění a výborného estetického efektu ve srovnání s porty hrudními. Jedná se o další generaci portů, která nahradila historicky zaváděné pažní nebo brachiální porty, kdy nevhodně prováděná implantace nevedla k rozšíření jejich používání pro vysoký výskyt komplikací. Při dodržení moderních doporučení se stává PICC-port ve specifických klinických situacích žilním vstupem první volby.

The PICC-port is a novel type of long-term venous access device that is increasingly indicated for use because of the reduced risk of complications during insertion and excellent aesthetic effect when compared with a chest port. It is the next generation of ports that has replaced the previously inserted arm or brachial ports in which inappropriate implantation hindered their widespread use due to high rates of complications. When modern recommendations are followed, the PICC-port can become the first-choice venous access in specific clinical situations.

• MeSH
• Vascular Access Devices MeSH
• Infusions, Intravenous methods   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Catheterization, Peripheral * methods   MeSH
• Antineoplastic Agents administration & dosage   MeSH
• Check Tag
• Humans MeSH

Autoři popisují klinický případ pacientky s metastazujícím melanomem, u níž se v samém počátku cílené léčby enkorafenibem a binimetinibem objevila oční toxicita ve formě bilaterálního odloučení zevních vrstev sítnice. Subjektivní obtíže se zrakem odezněly do 2 měsíců a kontrolní OCT potvrdilo reparaci odloučení. Cílená léčba dabrafenibem a trametinibem v další linii léčby nevykázala příznaky oční toxicity. Diskutována je oční toxicita cílené léčby u melanomu, její typy, závažnost a management. Při každé návštěvě pacienta léčeného cílenou léčbou BRAF a MEK inhibitorem byl měl být pacient tázán na subjektivní obtíže se zrakem. Pro včasnou a správnou diagnostiku oční toxicity je nutná úzká spolupráce se specialistou v oboru oftalmologie.

The authors describe a clinical case of a patient with metastatic melanoma treated with the targeted therapy by encorafenib and binimetinib. In the very beginning of the treatment, the ocular toxicity in the form of the bilateral detachment of the outer retinal layers was detected. Subjective symptoms disappeared in 2 months and follow-up OCT confirmed the restoration of the detachment. The targeted therapy with dabrafenib and trametinib in the subsequent line of the treatment was not complicated by the symptoms of the ocular toxicity. The article discusses the ocular toxicity of the targeted therapy in melanoma, its types, grading, and management. During each patient's visit in case the patient is treated with the targeted therapy by BRAF and MEK inhibitor, the patient should be asked about any subjective vision impairment. The close cooperation with the ophthalmology specialist is crucial for the early and correct diagnosis of the ocular toxicity.

• MeSH
• Molecular Targeted Therapy adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma * diagnosis   drug therapy   MeSH
• Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors   adverse effects   therapeutic use   MeSH
• Retinal Diseases diagnosis   therapy   MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Tomography, Optical Coherence MeSH
• Antineoplastic Agents administration & dosage   therapeutic use   toxicity   MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   adverse effects   therapeutic use   MeSH
• Proto-Oncogene Proteins B-raf antagonists & inhibitors   administration & dosage   therapeutic use   MeSH
• Toxic Optic Neuropathy diagnosis   veterinary   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Získaná hemofilie A (AHA) je vzácné krvácivé onemocnění vyskytující se především ve vyšším věku. Je způsobená přítomností autoprotilátek proti koagulačnímu faktoru VIII (FVIII). Může být asociována s autoimunitním onemocněním, malignitou či po porodu nebo vzniká idiopaticky. Důležitá je včasná diagnóza a léčba, která spočívá v léčbě krvácení a imunosupresivní léčbě k navození remise onemocnění čili k eradikaci inhibitoru. Zmiňujeme případ pacientky s revmatoidní artritidou s krvácivými projevy z gastrointestinálního traktu (GIT), kožními sufuzemi a protrahovaným krvácením po extrakci zubu. U pacientky byla diagnostikována AHA a bylo nutné zahájit léčbu rekombinantním aktivovaným faktorem VII (rFVIIa). Vstupně zjištěn vysoký inhibitor, který po léčbě kombinované imunosuprese (kortikoidy, cyklofosfamid, rituximab) klesal velice pomalu. Pro nově zjištěné krvácení do musculus psoas byla navýšena substituce rFVIIa a byl indikován emicizumab, k prevenci dalšího krvácení u pacientky s přetrvávajícím inhibitorem. Díky jeho s. c. aplikaci mohla být pacientka propuštěna do ambulantní péče.

Acquired haemophilia A (AHA) is a rare bleeding disorder occurring particularly in the elderly. It is caused by the presence of autoantibodies against coagulation factor VIII (FVIII). It may be associated with an autoimmune disease, malignancy, occur after birth, or arise idiopathi­cally. Early diagnosis and treatment are important, which involves treatment of bleeding and immunosuppressive therapy to induce disease remission or eradicate the inhibitor. We report a case of a female patient with rheumatoid arthritis with bleeding manifestations from the gastrointestinal tract (GIT), skin suffusions, and prolonged bleeding after tooth extraction. The patient was diagnosed with AHA and had to be started on treatment with recombinant activated factor VII (rFVIIa). Initially, a high inhibitor level was found that decreased very slowly after treatment with combined immunosuppression (corticoids, cyclophosphamide, rituximab). Due to newly detected bleeding into the psoas muscle, rFVIIa replacement therapy was increased and emicizumab was indicated to prevent further bleeding in the patient with persistent inhibitor. Thanks to the subcutaneous route of administration, the patient could be discharged to outpatient care.

• Keywords
• emicizumab,
• MeSH
• Factor VIII administration & dosage   therapeutic use   MeSH
• Hemophilia A * etiology   drug therapy   complications   MeSH
• Antibodies, Monoclonal, Humanized administration & dosage   therapeutic use   MeSH
• Immunosuppression Therapy methods   MeSH
• Hemorrhage etiology   therapy   MeSH
• Humans MeSH
• Antibodies, Bispecific administration & dosage   therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Sekundární imunodeficience (SID) je velmi častou komplikací hematologických, onkologických či jiných chronických onemocnění a je velmi často podceňována a přehlížena. SID vzniká jak vlivem základního onemocnění, tak vlivem podávané léčby a zvyšuje morbiditu i mortalitu. Nejčastěji se jedná o deficit humorální imunity a klinicky se SID projevuje zvýšenou frekvencí, přítomností neobvyklých komplikací u běžných infekcí a také výskytem oportunních infekcí. Substituční léčba imunoglobuliny je u těchto pacientů indikovaná a významně snižuje nemocnost pacientů včetně spotřeby antibiotik, potřeby hospitalizací pro infekční komplikace a zároveň snižuje mortalitu způsobenou infekčními agens. Moderní terapie, jako je CAR T terapie či bispecifické protilátky, prokazatelně zhoršují imunitu, a proto potřeba substituční terapie imunoglobuliny, ať ve formě subkutánní či intravenózní, bývá nezbytná. V tomto textu není řešena problematika antiinfekční profylaxe ani vakcinace, je řešena až kauzální léčba SID.

Secondary immunodeficiency (SID) is a very common complication of hematologic, oncologic, or other chronic diseases and is often underestimated and overlooked. SID arises both as a result of the underlying disease and as a consequence of the administered treatment, leading to increased morbidity and mortality. It most commonly involves a deficiency in humoral immunity and clinically manifests as an increased frequency of infections, the presence of unusual complications from common infections, and the occurrence of opportunistic infections. Immunoglobulin replacement therapy is indicated for these patients as it significantly reduces patient morbidity, including the use of antibiotics, the need for hospitalization due to infectious complications, and also decreases mortality caused by infectious agents. Modern therapies, such as CAR-T therapy or bispecific antibodies, have been shown to impair the immune system, making immunoglobulin replacement therapy, whether in subcutaneous or intravenous form, often necessary. This text does not address the issue of anti-infective prophylaxis or vaccination; it only deals with the causal treatment of SID.

• MeSH
• Receptors, Chimeric Antigen administration & dosage   therapeutic use   MeSH
• Hematologic Neoplasms complications   MeSH
• Immunoglobulins administration & dosage   therapeutic use   MeSH
• Immunotherapy, Adoptive MeSH
• Middle Aged MeSH
• Humans MeSH
• Opportunistic Infections drug therapy   microbiology   MeSH
• Immunization, Passive MeSH
• Immunologic Deficiency Syndromes * diagnosis   etiology   therapy   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

• Keywords
• Mediately,
• MeSH
• Digital Health * MeSH
• Humans MeSH
• Mobile Applications MeSH
• Breast Neoplasms diagnosis   MeSH
• Neoplasms therapy   MeSH
• Antineoplastic Agents, Immunological administration & dosage   adverse effects   MeSH
• Telemedicine MeSH
• Check Tag
• Humans MeSH
• Publication type
• Interview MeSH

This study aims to determine the effect of chronic hyperglycemia, induced by a high-fat diet and STZ-induced diabetes, on the development of Parkinson's disease-like characteristics. Understanding this relationship is crucial in pharmacology, neurology, and diabetes, as it could potentially lead to developing new therapeutic strategies for Parkinson's disease. Our study employed a comprehensive approach to investigate the effect of hyperglycemia on Parkinson's disease-like characteristics. Hyperglycemia was induced by a high-fat diet for 6- and 9-week duration with a single intraperitoneal STZ (100 mg/kg) injection at week 5 in C57/BL6 mice. Rotenone (10 mg/kg p.o.) was administered to C57/BL6 mice for 6 and 9 weeks. Time-dependent behavioral studies (wire-hang tests, pole tests, Y-maze tests, and round beam walk tests) were carried out to monitor pathology progression and deficits. Molecular protein levels (GLP1, PI3K, AKT, GSK-3β, NF-κB, and α-syn), oxidative stress (GSH and MDA) parameters, and histopathological alterations (H&E and Nissl staining) were determined after 6 weeks as well as 9 weeks. After 9 weeks of study, molecular protein expression (p-AKT and p-α-syn) was determined. Hyperglycemia induced by HFD and STZ induced significant motor impairment in mice, correlated with the rotenone group. Insulin receptor signaling (GLP1/PI3K/AKT) was found to be disrupted in the HFD+STZ group and also in rotenone-treated mice, which further enhanced phosphorylation of α-syn, suggesting its role in α-syn accumulation. Histopathological alterations indicating neuroinflammation and neurodegeneration were quite evident in the HFD+STZ and rotenone groups. Exposure to hyperglycemia induced by HFD+STZ administration exhibits PD-like characteristics after 9 weeks of duration, which was correlative with rotenone-induced PD-like symptoms.

• Publication type
• Journal Article MeSH

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection. Analysis of BRCA1/2 status showed that in our cohort of 31 ovarian cancer PDX models 22.6% harbored a BRCA1/2 alteration (7/31), and 48.3% (15/31) were genomically unstable as measured by copy number alteration analysis. In vivo, PARPi olaparib response was measured in 15 selected PDX models. Functional assessment of HR using ex vivo irradiation-induced RAD51 foci formation identified all olaparib-sensitive PDX models, including four models without BRCA1/2 alterations. In contrast, replication fork protection or replication speed in ex vivo tumor tissue did not correlate with olaparib response. Targeted panel sequencing in olaparib-sensitive models lacking BRCA1/2 alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that ex vivo RAD51 analysis effectively predicts in vivo olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.

• Publication type
• Journal Article MeSH

OBJECTIVE: To evaluate the benefits of surgical repair acute type A aortic dissection (ATAAD) on survival of octogenarians. METHODS: Patients who underwent surgery for acute ATAAD from the multicenter European Registry of Type A Aortic Dissection (ERTAAD) were the subjects of the present analysis. RESULTS: 326 (8.4%) patients were aged ≥ 80 years. Among 280 propensity score matched pairs, in-hospital mortality was 30.0% in patients aged ≥ 80 years and 20.0% in younger patients (P = 0.006), while 10-year mortality were 93.2% and 48.0%, respectively (P < 0.001). The hazard of mortality was higher among octogenarians up to two years after surgery, but it became comparable to that of younger patients up to 5 years. Among patients who survived 3 months after surgery, 10-year relative survival was 0.77 in patients aged < 80 years, and 0.46 in patients aged ≥ 80 years. Relative survival of octogenarians decreased markedly 5 years after surgery. Age ≥ 85 years, glomerular filtration rate, preoperative invasive ventilation, preoperative mesenteric mal-perfusion and aortic root replacement were independent predictors of in-hospital mortality among octogenarians (AUC = 0.792; E:O ratio = 0.991; CITL = 0.016; slope = 1.096). An additive score was developed. A risk score ≤ 1 was observed in 68.4% of patients, and their in-hospital mortality was 20.9%. CONCLUSIONS: Provided a thoughtful patient selection, surgery may provide a survival benefit in patients aged ≥ 80 years with ATAAD that, when compared to younger patients and the general population, may last up to 5 years after the procedure. These findings have significant epidemiologic and clinical relevance because of the increasing longevity of the population of the Western countries.

• Publication type
• Journal Article MeSH

PURPOSE: This study aimed to evaluate one-year clinical outcomes in cataract patients with pre-existing corneal astigmatism implanted with a biconvex aspheric toric monofocal intraocular lens (IOL) with a double C-loop haptic-design. METHODS: One hundred and eighteen patients (236 eyes) with corneal astigmatism (≥0.75D) were implanted bilaterally with the PODEYE toric IOL and assessed up to 1-year after surgery. Postoperative evaluation included monocular and binocular uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA), under both photopic and mesopic lighting conditions, refraction, photopic and mesopic contrast sensitivity (with and without glare), and rotational stability. RESULTS: At the last postoperative visit, 74.6% and 95.8% of eyes were within ±0.50D and ±1.00D of the target refraction, respectively. About 78.0% and 97.5% of eyes showed a postoperative refractive cylinder of ≤0.50D and ≤1.00D, respectively. The mean manifest spherical equivalent value was 0.16±0.40D, and the mean refractive cylinder value was -0.42±0.33D. 97.5% and 100% of patients had a binocular UDVA and CDVA of ≥20/32, respectively. The mean binocular UDVA and CDVA were 0.01±0.09 and -0.03±0.07 logMAR, respectively. Under mesopic conditions, 79.5% and 89.8% of patients showed a binocular UDVA and CDVA of ≥20/32, respectively. The mean binocular UDVA and CDVA were 0.15±0.11 and 0.10±0.10 logMAR, respectively. Binocular contrast sensitivity function both under photopic and mesopic conditions was good. The mean absolute IOL rotation was 2.52±2.59 degrees with 98.56% of eyes having a rotation of less than 10 degrees. CONCLUSION: Bilateral implantation of an aspheric toric monofocal IOL with a double C-loop haptic design in cataract patients with corneal astigmatism provides good visual and refractive outcomes up to 1-year post-surgery.

• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Clinical Trial MeSH